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SommarioL’iperparatiroidismo primitivo (IPP), condizione caratterizzata da aumentata secrezione di paratormone e conseguente aumento dei valori di calcemia, può presentarsi sia in forma sporadica che familiare. Tra le forme familiari, l’IPP rappresenta una manifestazione caratteristica delle sindromi da neoplasie endocrine multiple (MEN) tipo 1, 2A e 4. Le caratteristiche cliniche dell’IPP differiscono tra diverse forme di MEN e rispetto alla forma sporadica. L’incidenza di IPP nel contesto della MEN2A varia in base al codone di RET coinvolto dalla mutazione. Nella maggioranza dei casi l’IPP è diagnosticato nel corso del follow-up dei pazienti con MEN 2A, di solito successivamente alla comparsa del carcinoma midollare della tiroide (CMT), presentandosi clinicamente in forma lieve o del tutto asintomatica. Il trattamento di scelta è l’asportazione chirurgica delle paratiroidi iperfunzionanti, accompagnata dall’esplorazione cervicale bilaterale in considerazione del potenziale coinvolgimento multighiandolare.

Treatment Resistant Schizophrenia (TRS) is the persistence of significant symptoms despite adequate antipsychotic treatment. Although consensus guidelines are available, this condition remains often unrecognized and an average delay of 4-9 years in the initiation of clozapine, the gold standard for the pharmacological treatment of TRS, has been reported. We aimed to determine through a machine learning approach which domain of the Positive and Negative Syndrome Scale (PANSS) 5-factor model was most associated with TRS.In a cross-sectional design, 128 schizophrenia patients were classified as TRS (n = 58) or non-TRS (n = 60) after a structured retrospective-prospective analysis of treatment response. The random forest algorithm (RF) was trained to analyze the relationship between the presence/absence of TRS and PANSS-based psychopathological factor scores (positive, negative, disorganization, excitement, and emotional distress). As a complementary strategy to identify the variables most associated with the diagnosis of TRS, we included the variables selected by the RF algorithm in a multivariate logistic regression model.according to the RF model, patients with higher disorganization, positive, and excitement symptom scores were more likely to be classified as TRS. The model showed an accuracy of 67.19%, a sensitivity of 62.07%, and a specificity of 71.43%, with an area under the curve (AUC) of 76.56%. The multivariate model including disorganization, positive, and excitement factors showed that disorganization was the only factor significantly associated with TRS. Therefore, the disorganization factor was the variable most consistently associated with the diagnosis of TRS in our sample.

Currently, the differentiated thyroid cancer (DTC) management is shifted toward a tailored approach based on the estimated risks of recurrence and disease-specific mortality. While the current recommendations on the management of metastatic and progressive DTC are clear and unambiguous, the management of slowly progressive or indeterminate disease varies according to different centers and different physicians. In this context, active surveillance (AS) becomes the main tool for clinicians, allowing them to plan a personalized therapeutic strategy, based on the risk of an unfavorable prognosis, and to avoid unnecessary treatment. This review analyzes the main possible scenarios in treated DTC patients who could take advantage of AS.

Supplementary Table 3: EPHA2 expression in tumor samples with HSCORE

Supplementary Figure 1. A: Phosphoarray analysis of SW48 and SW48-CR cell lines. B: Silencing of EPHA2 decreases the sensitivity to ALW-II-41-27 in HCT15 and SW48-CR cell lines.

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

Supplementary Figure 2. A-B: Synergistic anti-proliferative effects of the combination of ALW-II-41-27 and cetuximab.C: Effect of Epha2 gene knockdown on cetuximab sensitivity in HCT116 and LOVO cell lines. D: Effects of combination treatment with ALW-II-41-27 and cetuximab on induction of apoptosis. E: Cell cycle distribution for HCT15 and SW48-CR following treatment with ALW-II-41-27 and/or cetuximab for 24, 48 and 72 hrs at indicated doses. F: Effects of EPHA2 blockade alone and in combination with cetuximab on intracellular signalling pathways of cell proliferation and survival.

Supplementary materials and methods

Supplementary Table 2: EPHA2 expression in tumor samples of 82 RAS WT colorectal cancer patients from the GOIM-CAPRI trial

Supplementary Table 1: Treatment with ALW-II-41-27 or cetuximab as single agents

In the geomatics domain the use of deep learning, a subset of machine learning, is becoming more and more widespread. In this context, the 3D semantic segmentation of heritage point clouds presents an interesting and promising approach for modelling automation, in light of the heterogeneous nature of historical building styles and features. However, this heterogeneity also presents an obstacle in terms of generating the training data for use in deep learning, hitherto performed largely manually. The current generally low availability of labelled data also presents a motivation to aid the process of training data generation. In this paper, we propose the use of approaches based on geometric rules to automate to a certain degree this task. One object class will be discussed in this paper, namely the pillars class. Results show that the approach managed to extract pillars with satisfactory quality (98.5% of correctly detected pillars with the proposed algorithm). Tests were also performed to use the outputs in a deep learning segmentation setting, with a favourable outcome in terms of reducing the overall labelling time (−66.5%). Certain particularities were nevertheless observed, which also influence the result of the deep learning segmentation., ISPRS Annals of the Photogrammetry, Remote Sensing and Spatial Information Sciences, V-2-2022, ISSN:2194-9042, ISSN:2194-9050

Numerical simulations of volcanic processes play a fundamental role in understanding the dynamics of magma storage, ascent and eruption. The recent extraordinary progress in computer performance and improvements in numerical modeling techniques allow simulating multiphase systems in mechanical and thermodynamical disequilibrium. Nonetheless, the growing complexity of these simulations requires the development of flexible computational tools that can easily switch between sub-models and solution techniques. In this work we present MagmaFOAM, a library based on the open source computational fluid dynamics software OpenFOAM, that incorporates models for solving the dynamics of multiphase, multicomponent magmatic systems. Retaining the modular structure of OpenFOAM, MagmaFOAM allows run-time selection of the solution technique depending on the physics of the specific process, and sets a solid framework for in-house and community model development, testing and comparison. MagmaFOAM models thermo-mechanical non-equilibrium phase coupling and phase change, and implements state-of-the-art multiple volatile saturation models and constitutive equations with composition-dependent and space-time local computation of thermodynamic and transport properties. Code testing is performed using different multiphase modeling approches for processes relevant to magmatic systems: Rayleigh-Taylor instability, for buyoancy-driven magmatic processes; multiphase shock tube simulations, propedeutical to conduit dynamics studies; bubble growth and breakage in basaltic melts. Benchmark simulations illustrate the capabilities and potential of MagmaFOAM to account for the variety of non-linear physical and thermodynamical processes characterizing the dynamics of volcanic systems.

Context Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. Objective The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). Methods We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features. Results Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092). Conclusions Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results.

Supplementary Methods from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Video 1 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Figure 1 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Video 2 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Video 1B from Microtentacles Tip the Balance of Cytoskeletal Forces in Circulating Tumor Cells

Supplementary Figure Legends 1-5 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Figure 1 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Video 5 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Video 3 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Figure 5 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Figure 3 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Video Legends from Microtentacles Tip the Balance of Cytoskeletal Forces in Circulating Tumor Cells

Solid tumor metastasis often involves detachment of epithelial carcinoma cells into the vasculature or lymphatics. However, most studies of cytoskeletal rearrangement in solid tumors focus on attached cells. In this study, we report for the first time that human breast tumor cells produce unique tubulin-based protrusions when detached from extracellular matrix. Tumor cell lines of high metastatic potential show significantly increased extension and frequency of microtubule protrusions, which we have termed tubulin microtentacles. Our previous studies in nontumorigenic mammary epithelial cells showed that such detachment-induced microtentacles are enriched in detyrosinated α-tubulin. However, amounts of detyrosinated tubulin were similar in breast tumor cell lines despite varying microtentacle levels. Because detyrosinated α-tubulin associates strongly with intermediate filament proteins, we examined the contribution of cytokeratin and vimentin filaments to tumor cell microtentacles. Increased microtentacle frequency and extension correlated strongly with loss of cytokeratin expression and up-regulation of vimentin, as is often observed during tumor progression. Moreover, vimentin filaments coaligned with microtentacles, whereas cytokeratin did not. Disruption of vimentin with PP1/PP2A-specific inhibitors significantly reduced microtentacles and inhibited cell reattachment to extracellular matrix. Furthermore, expression of a dominant-negative vimentin mutant disrupted endogenous vimentin filaments and significantly reduced microtentacles, providing specific genetic evidence that vimentin supports microtentacles. Our results define a novel model in which coordination of vimentin and detyrosinated microtubules provides structural support for the extensive microtentacles observed in detached tumor cells and a possible mechanism to promote successful metastatic spread. [Cancer Res 2008;68(14):5678–88]

Supplementary Video 4 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Detection of circulating tumor cells (CTC) is advancing as an effective predictor of patient outcome and therapeutic response. Unfortunately, our knowledge of CTC biology remains limited, and the impact of drug treatments on CTC metastatic potential is currently unclear. Improved CTC imaging in vivo and analysis of free-floating tumor cells now show that cytoskeletal regulation in CTCs contrasts starkly with tumor cells attached to extracellular matrix. In this review, we examine how persistent microtubule stabilization promotes the formation of microtentacles on the surface of detached breast tumor cells and enhances metastatic potential. Cancer Res; 70(20); 7737–41. ©2010 AACR.

Supplementary Figure 3 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Supplementary Figure 2 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Figure 4 from Epithelial-to-Mesenchymal Transition Promotes Tubulin Detyrosination and Microtentacles that Enhance Endothelial Engagement

Supplementary Figure 2 from Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells

Purpose Advanced thyroid cancer patients treated with tyrosine kinase inhibitors (TKI) can develop several adverse events (AEs), including adrenal insufficiency (AI). Methods We studied 55 patients treated with TKI for radioiodine-refractory or medullary thyroid cancer. The adrenal function was evaluated during follow-up by performing serum basal ACTH, and basal and ACTH-stimulated cortisol. Results Twenty-nine/55 (52.7%) patients developed subclinical AI during TKI treatment as demonstrated by a blunted cortisol response to ACTH stimulation. All cases showed normal values of serum sodium, potassium and blood pressure. All patients were immediately treated, and none showed an overt AI. Cases with AI were all negative for adrenal antibodies and did not show any adrenal gland alteration. Other causes of AI were excluded. The onset time of the AI, as measured in the subgroup with a first negative ACTH test, was 36 months in 2/9 (22.2%) cases. In our series, the only prognostic factor of AI was the elevated, although moderate, basal level of ACTH when the basal and stimulated cortisol were still normal. The glucocorticoid therapy improved fatigue in most patients. Conclusions Subclinical AI can be developed in > 50% of advanced thyroid cancer patients treated with TKI. This AE can develop in a wide period ranging from 36 months. For this reason, AI must be looked for throughout the follow-up to be early recognized and treated. A periodic ACTH stimulation test, every 6–8 months, can be helpful.

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.

Context The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. Objective This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features. Methods We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa. Results After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. Conclusion In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years.

Aim Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear. Methods We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset. Results The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects. Conclusions These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.

Background: Major Depressive Episodes (MDEs) may characterise many psychiatric disorders. Its pharmacotherapy is laid with unmet needs, rendering the testing of new drugs necessary. Objective: To compare the effects of vortioxetine with those of other antidepressants (OADs) in a 1-year naturalistic setting. Methods: We included 126 adult patients with anMDE in the course of major depressive (MDD), bipolar (BD), or schizophrenia spectrum disorders (SSOPDs), with or without substance use disorder (SUD), who received 5-20 mg/day oral vortioxetine, and compared them with 100 patients receiving OADs at baseline and after 1, 3, 8, and 12 months on their scores on the MADRS, the CGIS, the 24-item BPRS, the YMRS, the Hamilton Anxiety Rating Scale, a Visual Analogue Scale for craving, the Columbia-Suicide Severity Rating Scale, and the WHOQOL-BREF. Results: Patients on vortioxetine improved similarly to those on OADs on all measures, independently from having or not a comorbid SUD. However, they improved with time better than their OADcounterparts if affected by BD or SSOPDs, but not MDD, on the CGI-S, BPRS depression, anxiety, and manic symptoms. SUD hampered the response of anxiety to treatment. Men improved on depression with time better than women. Conclusion: MDEs responded to vortioxetine similarly to OADs by improving in depression, general psychopathology, anxiety, suicidal thinking, and quality-of-life, independently from SUD comorbidity. MDEs of patients with BD or SSOPDs on vortioxetine responded better than that of patients on OADs. Clinical Trial Registration No. 17354N.

The fundamental mechanisms of signal communication within the human body rely on the spiking frequency of action potentials.1,2 Through biological receptors and afferent neuronal cells, stimuli from the external world are encoded into a spiking pattern and transmitted to the central nervous systems where they are processed via interneurons. Replicating the interdependent functions of receptors, afferent neurons and interneurons with spiking circuits 1, sensors3 and biohybrid synapses4 is an essential first step towards merging neuromorphic circuits and biological systems, crucial for computing at the biological interface. We present a novel adaptive spiking circuit that replicates afferent neurons sensory coding from external physical stimuli. We emulate the neuromodulatory activity of interneurons by associating the spiking circuit with biohybrid synapses demonstrating an interdependent chemical synaptic connection. To establish a full neuronal pathway, we combine these key biological functions, showing the signal transduction from light stimulus to spiking frequency and to dopamine-mediated plasticity: a retinal pathway primitive.