Indeterminate Thyroid Nodules: From Cytology to Molecular Testing

Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients’ management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAFV600E-like (including BRAFV600E mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients’ management

Plio-quaternary geology of L’Aquila-Scoppito basin (Central Italy)

We present a geological map at 1: 25,000 scale of the Plio-Quaternary L'Aquila-Scoppito intermontane basin (central Italy), which corresponds to the epicentral area of the 6th April 2009 L'Aquila earthquake (Mw: 6.29). The map is derived from geological field surveys at 1: 5000 scale and takes into account previously published maps. It is supported by a fine-scale LiDAR digital elevation model, paleontological analyses, C-14 dating, well log analyses of deep boreholes, and geophysical data interpretation. By taking into account that the remarkable historical and present-day seismicity of the area is the result of its PlioQuaternary geological evolution, the aim of this study is to produce a fine-scale geological map of the study area through a comprehensive analysis of the occurring Plio-Quaternary synthems and the tectonic processes that are taking place within it

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

Purpose: RAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes. Methods: Total RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform). Results: Comparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change. Conclusions: The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers

Site response analyses for complex geological and morphological conditions: relevant case-histories from 3rd level seismic microzonation in Central Italy

The paper presents the results of 5 case studies on complex site e ects selected within the project for the level 3 seismic microzonation of several municipalities of Central Italy dam- aged by the 2016 seismic sequence. The case studies are characterized by di erent geo- logical and morphological con gurations: Monte San Martino is located along a hill slope, Montedinove and Arquata del Tronto villages are located at ridge top whereas Capitignano and Norcia lie in correspondence of sediment- lled valleys. Peculiarities of the sites are constituted by the presence of weathered/jointed rock mass, fault zone, shear wave veloc- ity inversion, complex surface and buried morphologies. These factors make the de ni- tion of the subsoil model and the evaluation of the local response particularly complex and di cult to ascertain. For each site, after the discussion of the subsoil model, the results of site response numerical analyses are presented in terms of ampli cation factors and acceleration response spectra in selected points. The physical phenomena governing the site response have also been investigated at each site by comparing 1D and 2D numerical analyses. Implications are deduced for seismic microzonation studies in similar geological and morphological conditions.Published5741–57775T. Sismologia, geofisica e geologia per l'ingegneria sismicaJCR Journa

Understanding TERT promoter mutations: a common path to immortality

Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.Support was provided from a generous gift from the Dabbiere family(RJB,AM,JFC), the Hana Jabsheh Research Initiative (RJB,AM,JFC), and NIH grants NCI P50CA097257 (RJB,AM,JFC), P01CA118816-06 (RJB,AM,JFC), R01HG003008 (HTR), and R01CA163336 (JSS). Additional support was provided from the Sontag Foundation Distinguished Scientist Award (JSS), Fundação para a Ciência e Tecnologia SFRH/BD/88220/2012 (AXM), IF/00601/2012 (BMC), Programa Operacional Regional do Norte (ON.2—O Novo Norte) (BMC), Quadro de Referência Estratégico Nacional (BMC), and Fundo Europeu de Desenvolvimento Regional (BMC).info:eu-repo/semantics/publishedVersio

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Duns Scoto Magister e Teologo. Indagine sul pluralismo metodologico e conoscitivo nel pensiero di Giovanni Duns Scoto

L'articolo prende in considerazione il possibile dialogo tra i nostri modelli di razionalit\ue0 e quelli di autori medievali del tardo XIII secolo circa il concetto di laicit\ue0. Non si pu\uf2 certo parlare di laicit\ue0 nel senso contemporaneo del termine, ma un tema interessante - senza alcuna pretesa di riferirsi a impossibili precorrimenti - pu\uf2 essere il concetto, individuabile in alcuni autori del tardo XIII e degli inizi del XIV secolo, della possibile coesistenza di differenti tradizioni filosofiche e teologiche, con l'implicita conseguenza di una sorta di pluralismo metodologico. Tali concezioni possono essere accostate alla moderna idea di libera coesistenza di posizioni diverse, e quindi all'idea di tolleranza pi\uf9 che a quella di laicit\ue0, e vengono contrapposte a ogni pretesa di fondare e imporre una esclusiva e univoca lettura della realt\ue0. Da questo punto di vista viene analizzato il pensiero di un giovane magister artium della fine del XIII secolo e, nel contempo, di un giovane magister theologiae, che si identificano nella medesima persona, Giovanni Duns Scoto. This paper concerns the possible dialogue between our models of rationality and those of medieval authors of the late 13th century about the concept of secularism (it's difficult to find the right translation of the Italian term laicit\ue0). It's not possible of course to speak of secularism in the contemporary sense of the term, but an interesting theme - without any claim to speak of precursory theses - can be the concept, already recognizable in some authors of the late 13th century and the beginning of the 14th century, of the possible coexistence of different philosophical and theological traditions, with the implicit consequence of a sort of methodological pluralism. These ideas may be compared to modern idea of free coexistence of different theories, and therefore to idea of tolerance more than to that of secularism, and are opposed to any claim to ground and to impose an exclusive and authoritative interpretation of reality. From this point of view is here analysed the thought of a young magister artium of the last years of the 13th century and, at the same time, of a young magister theologiae, who must be overlapped in the same man, John Duns Scotus

NanoString in the screening of genetic abnormalities associated with thyroid cancer

In the setting of cancer pathology, molecular characterization of tumors providing diagnostic and predictive information is acquiring more and more relevance. Moreover, the advent of innovative technologies continuously improves the knowledge of the molecular landscape of tumors and strengthens the links between clinics, tumor pathology and molecular features. In the clinical management of patients with thyroid nodules and thyroid tumors, the aid of molecular testing is encouraged but still not strongly recommended by current guidelines. Also for this reason this field of study is attracting much interest. The nCounter system is a relatively new technology based on a direct hybridization of fluorescent probes to specific nucleic acid targets, followed by digital measurement of signals; the reaction is highly multiplexable and results are robust and reproducible. This review reports and discusses the available data related to the application of this specific technique to thyroid nodules and thyroid tumors samples. The available data indicate that nCounter system represents a solid approach for the research of relevant diagnostic and prognostic biomarkers in thyroid pathology

The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology

Purpose: Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25–30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. Methods: Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. Results: The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. Conclusions: Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology

A multidisciplinary approach to the seismic characterization of a mountain top (Monteluco, central Italy)

This study provides a seismic characterization of the flat top area of Monteluco carbonate mountain using a multidisciplinary approach. Recordings of ambient vibrations and local earthquakes, geophysical and borehole data, detailed geological surveys and rock mass characterizations were used to investigate the ground-motion amplification observed on the flat top of Monteluco. Weak motion measurements carried out on the top area gave resonance frequency (f0) in the range of 2–4 Hz, likely due to the occurrence of fractured rocks, tens of meters thick. In this frequency range and in the same target area, it was also possible to observe a nearly NW-SE polarization of the seismic signal, which we have tentatively correlated with the main mapped fault systems. Nevertheless, a topographic effect on noise polarization cannot be excluded.Published119-1354T. Sismologia, geofisica e geologia per l'ingegneria sismicaJCR Journa