Papers by Antonella Verrienti
Endocrine Abstracts, May 7, 2022
Clinical Immunology, Dec 1, 2003
The contribution of age and/or sex to the transglutaminase (tTG) autoantibody response in celiac ... more The contribution of age and/or sex to the transglutaminase (tTG) autoantibody response in celiac disease (CD) is not known. To gain insights into transglutaminase humoral autoimmunity at CD diagnosis, our aim was to characterize the autoimmune response against three tTG constructs [(full-length tTG(a.a.1-687), tTG(a.a.227-687), and tTG(a.a.473-687)] and to investigate into its relationship with CD patients' age and sex. One hundred seventy-five newly diagnosed CD patients (115 females and 60 males), subdivided into different groups according to age and sex, were studied using a serum 35 S-radioimmunoassay. We found that among full-length tTG autoantibody-positive CD subjects (175/175), 50.9% (89/175) and 83.4% (146/175) had autoantibodies against tTG(227-687) and tTG(473-687) domains, respectively. Female patients of less than 4 years expressed tTG(227-687)Abs in significantly higher percentage and mean autoantibody titers vs. all other groups investigated, and tTG(473-687)Abs in significantly higher titers with respect to adult female patients. Our data identify a subset of CD patients showing a strong humoral tTG immunoreactivity at diagnosis, thus suggesting that age and sex influence the anti-tTG autoantibody response.
High blood pressure & cardiovascular prevention, Jul 1, 2008
Introduction. 'Left ventricular ballooning' or 'tako-tsubo' cardiomiopathy or 'tako-tsubo syndrom... more Introduction. 'Left ventricular ballooning' or 'tako-tsubo' cardiomiopathy or 'tako-tsubo syndrome' is a particular condition characterized by a typical morphological aspect during coronary artery angiography, this is a transitory alteration of contractile pattern of the apex of left ventricle and it is induced by stress. In medical literature, some cases of association of tako-tsubo syndrome with pheochromocytoma are reported. Discussion. We report a case of a 72-year-old woman referred to our department of emergency for chest pain associated with paroxysmal elevation of blood pressure, EKG revealed an ST alteration in specific ECG leads (DIII, AVF, V1) with elevation of troponin. An echocardiogram showed a reduction of contractile action of left ventricle (ejection fraction 40%) with an acinesia of apex and antero-lateral wall of left ventricle. A coronary artery angiography didn't show luminal stenosis of the arteries while left ventricular angiography showed medio-apical acinesia involving antero-lateral wall with an exalted contractility of the basal portion of left ventricle. In the following days the patient presented paroxysmal attacks associated with dizziness and a 24 h urine collection of metanephrine and VMA revealed high levels of both. A MRI of abdomen showed the presence of a mass of left adrenal gland of 32 mm. The patient underwent the surgical resection via laparotomic approach of the gland with a previous preparation with alpha-blockers. Genetic analysis didn't show any mutations of susceptibility gene for pheochromocytoma (RE T, VHL, NF1, SHDB/D). During the follow up the patient was asymptomatic for chest pain and blood pressure came back to normal range. Conclusions. In the described case of pheochromocytoma, tako-tsubo syndrome could be caused by a direct damage of catecholamine on the myocytes.
Biomedicine & Pharmacotherapy, Aug 1, 2023
Introduction: The molecular mechanism underlying the induction of resistance to tyrosine kinase i... more Introduction: The molecular mechanism underlying the induction of resistance to tyrosine kinase inhibitors (TKIs) via the membranous/cytoplasmic/nuclear translocation of EGFR has not yet been reported. Methods: We performed immunohistochemistry to detect the distribution of EGFR in lung adenocarcinoma specimens after TKI treatment and analyzed the relationship between different EGFR locations and patient survival duration. Mass spectrometry analysis and immunoprecipitation were performed to show the interaction of cytosolic EGFR with YY1 associated protein 1 (YAP) and salt inducible kinase 2 (SIK2). Dual-luciferase assays, immunoblotting, real-time polymerase chain reaction, and functional experiments were used to elucidate the role of EGFR cytoplasmic/nuclear translocation in Hippo pathway dysregulation. Results: Patients with advanced lung adenocarcinoma with membranous mutant EGFR (19del or 21 L858R) showed significantly longer progression-free survival than those with cytoplasmic mutant EGFR after gefitinib treatment. The concentration that inhibits 50% in PC-9 with cytoplasmic EGFR was higher than that in hunman non-small cell lung cancer 827 with membranous EGFR. During firstgeneration TKI resistance induction, membrane EGFR translocated to the cytoplasm/nucleus, accompanied by the Hippo pathway inhibition. Cytoplasmic EGFR and SIK2 interaction inhibited large tumor suppressor kinase 1 (LATS1) and macrophage stimulating 1 (MST1) interaction, promoting YAP nuclear translocation. However, cells with osimertinib-induced resistance also showed EGFR translocation and lower phospho-EGF receptor but did not show Hippo pathway inhibition. Moreover, osimertinib and erlotinib could restore sensitivity to each other in resistant cells. Conclusions: Plasma/nuclear translocation of EGFR and inhibition of the Hippo pathway are some of the important mechanisms underlying the resistance induced by firstgeneration TKIs. Membrane/plasma translocation of EGFR induced by osimertinib may be another resistance phenomenon besides MNNG HOS transforming gene (c-MET) amplification, C797S mutation, and ERK pathway inhibition.
Endocrine Abstracts, Sep 2, 2022
Pediatric Research, Aug 1, 2005
Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischem... more Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury (HII) occurring in human neonates but not in older children or adults. Histologically, PSN is characterised by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. The expression of Rbm3, a glycine-rich RNA-binding protein, is enhanced under hypoxic conditions and independent of HIF (hypoxia inducible factor). It is well known, that proteins which are dependant on HIF, e.g. Erythropoetin play an important role in HII. This study aims to determine whether the HIF-independent activation of Rbm3 is also a significant factor in the pathogenesis of PSN. Methods: We have investigated the expression of Rbm3 in human autopsy material consisting of 12 PSN cases and 10 age-matched controls without PSN. Immunohistochemistry and double labeling for Rbm3 and the astrocyte marker glial fibrillary acid protein (GFAP), the microglia/macrophage specific marker KiM1P and the neuronal marker NeuN was performed on formalin-fixed, paraffin-embedded brain specimens. Results: In PSN cases and controls, mainly neuronal cells expressed Rbm3. The number of immunopositive cells was significantly increased (pϭ0.001) in PSN cases. Predominantly degenerating cells with signs of later apoptotic stages showed Rbm3 expression. In earlier stages of apoptosis immunopositivity for Rbm3 was increased compared to contols, but less prominent. Conclusion: In addition to HIF-dependant proteins, the induction of the HIF-independent protein RMB3 is observed in response to human hypoxic-ischemic injury.
Endocrine Abstracts, May 7, 2022
Journal of Endocrinological Investigation, Jun 7, 2023
Purpose/methods The determination of tumour biomarkers is paramount to advancing personalized med... more Purpose/methods The determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated. Results The samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients. Conclusion This study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine. Keywords Medullary thyroid carcinoma • Diagnostic biomarkers • miR-26b-5p • miR-451a • Liquid biopsy • Plasma extracellular miRNAs/circulating miRNAs Abbreviations MTC Medullary thyroid carcinoma (MTC) Ctn Calcitonin MEN Multiple endocrine neoplasia RET Rearranged during transfection FNA Fine needle aspiration CEA Carcinoembryonic antigen EVs Extracellular vesicles * C. Durante
Journal of Endocrinological Investigation
Nutrition, Metabolism and Cardiovascular Diseases, 2013
Several studies have reported that the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1)... more Several studies have reported that the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism (rs1044498) interacts with increased adiposity in affecting glucose homeostasis and insulin sensitivity. Conversely, one would expect that the amelioration of glucose homeostasis observed after weight loss is modulated by the ENPP1 K121Q polymorphism. The aim of our study was to test such hypothesis, in non-diabetic overweight-obese individuals. Two hundred eleven non-diabetic overweight-obese individuals were studied. Body mass index (BMI), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR index) and lipid levels were obtained before and after 6-week lifestyle intervention (LI; diet and exercise) and their changes calculated as baseline minus 6-week values. LI decreased BMI, glucose, HOMA-IR and triglyceride levels (p < 0.001 for all). No difference across genotype groups (160 KK and 51 KQ or QQ - named as XQ - individuals) was observed in these changes. In a multivariate model, BMI changes predicted fasting glucose changes (β = 0.139 mmol/L (2.50 mg/dl) for 1 unit BMI change, p = 0.005). This correlation was not significant among KK individuals (β = 0.082; p = 0.15), while much steeper and highly significant among XQ individuals (β = 0.336; p = 0.00008) (p-value for Q121-by-weight loss interaction = 0.047). Individuals carrying the ENPP1 Q121 variant are highly responsive to the effect of weight loss on fasting glucose. This reinforces the previously suggested hypothesis that the Q121 variant interacts with adiposity in modulating glucose homeostasis.
Human Mutation, Dec 20, 2017
Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET geno... more Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.
Journal of Endocrinological Investigation
Purpose Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC).... more Purpose Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC). Between 5% and 15% of DTC patients become RAI refractory, due to the loss of expression/function of iodide metabolism components, especially the Na/I symporter (NIS). We searched for a miRNA profile associated with RAI-refractory DTC to identify novel biomarkers that could be potential targets for redifferentiation therapy. Methods We analyzed the expression of 754 miRNAs in 26 DTC tissues: 12 responsive (R) and 14 non-responsive (NR) to RAI therapy. We identified 15 dysregulated miRNAs: 14 were upregulated, while only one (miR-139-5p) was downregulated in NR vs. R tumors. We investigated the role of miR-139-5p in iodine uptake metabolism. We overexpressed miR-139-5p in two primary and five immortalized thyroid cancer cell lines, and we analyzed the transcript and protein levels of NIS and its activation through iodine uptake assay and subcellular protein localization. Results The findi...
Atlas of Thyroid and Neuroendocrine Tumor Markers, 2018
Thyroid cancers exhibit intra- and inter-tumor heterogeneity in terms of molecular profiles, morp... more Thyroid cancers exhibit intra- and inter-tumor heterogeneity in terms of molecular profiles, morphology, and clinical behavior. There is thus a clear need to develop sensitive and specific biomarkers that can efficiently classify and stratify these tumors. The efficient management of thyroid cancer is based on early diagnosis and/or follow-up, which is often difficult to achieve with currently available serum biomarkers (i.e., thyroglobulin, calcitonin) and cytological examination. In this setting, liquid biopsy represents a new and powerful approach for early diagnosis and prompt detection of disease persistence or relapse. Although the development of circulating biomarkers for thyroid cancer is in its infancy, it offers several advantages, such as the rapid, low-cost, noninvasive nature of sample collection and depiction of “whole-tumor” heterogeneity. This chapter looks at the feasibility of using circulating mRNA and miRNA levels to guide thyroid cancer management and the principal methods used to isolate and analyze these species.
Endocrine, 2012
Carotid intima-media thickness (CIMT) is an intermediate phenotype for early atherosclerosis and ... more Carotid intima-media thickness (CIMT) is an intermediate phenotype for early atherosclerosis and a strong predictor of myocardial infarction and ischemic stroke [1]. Several studies have described the effects of candidate genes on CIMT, being unclear, however, the relative contribution of genetic variation to the development of the early stages of atherosclerosis [2]. The ectoenzyme pyrophosphatase phosphodiesterase 1 (ENPP-1) inhibits insulin receptor signaling [3]. A non synonymous polymorphism (K121Q, rs1044498) of the ENPP-1 gene is responsible for a gain of function of the protein [3], resulting in an increased ability to inhibit insulin receptor signaling. This variant has been associated with insulin resistance and type 2 diabetes in most studies [4, 5]. In agreement with the link between insulin resistance and cardiovascular disease (CVD), the Q121 variant has been shown to modulate susceptibility to premature myocardial infarction [6] and ischemic stroke [7] and to increase pulse pressure, a marker of arterial stiffness [8]. Some of these associations have been shown to be stronger in obese subjects, suggesting a gene-byobesity interaction in facilitating insulin resistance and atherogenic process [4, 9]. Up to date no results on ENPP-1 function on CIMT are available. Thus, we tested whether the ENPP-1 Q121 variant exerts an effect on CIMT measured at the common carotid artery (CCA) and at bulb and interacts with overweight–obesity in modulating CIMT.
Uploads
Papers by Antonella Verrienti