Manifestation of vortex depinning transition in nonlinear current-voltage characteristics of polycrystalline superconductor Y_{1-x}Pr_{x}Ba_2Cu_3O_7

We present our recent results on the temperature dependence of current-voltage characteristics for polycrystalline Y_{1-x}Pr_{x}Ba_2Cu_3O_7 superconductors with x = 0.0, 0.1 and 0.3. The experimental results are found to be reasonably well fitted for all samples by a power like law. According to the theoretical interpretation of the obtained results, nonlinear deviation of our current-voltage characteristics curves from Ohmic behavior below Tc is attributed to the manifestation of dissipation processes related to the current induced depinning of Abrikosov vortices.Comment: Accepted for publication in PL

Exposure to reversine affects the chondrocyte morphology and phenotype in vitro

Articular chondrocytes derived from osteoarthritic tissues (OA HAC) show a severely reduced chondrogenic commitment. This impairment undermines their use for tissue-engineered cartilage repair, which relies on cell proliferation and growth to meet therapeutic needs, but also on efficient cell plasticity to recover the chondrogenic phenotype. Reversine (Rev), a 2,6-disubstituted purine inhibitor of spindle-assembly checkpoints, was described to convert differentiated mesenchymal cells to their undifferentiated precursors. We hypothesized that Rev exposure could divert OA HAC to more plastic cells, re-boosting their subsequent commitment. HAC were enzymatically released from OA cartilage specimens, expanded for 2 weeks and treated with 5 \u3bcm Rev in dimethylsulphoxide (DMSO) or with DMSO alone for 6 days. Cell growth was assessed using the AlamarBlueTM assay. Cytoskeletal structure, endoproliferation and caspase-3-immunopositivity were assayed by epifluorescence microscopy. The OA HAC chondrogenic performance was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) for glyceraldehyde-3-phosphate dehydrogenase, Sox9, Aggrecan (Agg), type II collagen (Col2), Ki67, cyclinD1, transforming growth factor-\u3b21 (TGF-\u3b21), -2 and -3, interleukin-1\u3b2 (IL-1\u3b2) and -6 , SMAD3 and -7, and vascular endothelial growth factor. Rev-treated OA HAC recovered polygonal morphology and reduced Ki67 expression and proliferation. Cell-cycle impairment accounted for altered cytoskeletal organization, endoproliferation and apoptosis, whereas a compensatory mechanism sustained the increased cyclinD1 transcript levels. Sox9, Agg and TGFs were overexpressed, but not Col2. IL transcripts were massively downregulated. These events were dose-related and transient. Overall, in spite of a higher Rev-induced transcriptional activity for extracellular matrix components and in spite of a Rev-treated cell phenotype closer to that of the three-dimensional native articular chondrocyte, Rev effects seem unleashed from a full regained chondrogenic potential

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Context: Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. Objective: This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). Methods: A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. Results: We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors-ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. Conclusion: We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers

Impact of 18F-FDG PET/CT on Clinical Management of Suspected Radio-Iodine Refractory Differentiated Thyroid Cancer (RAI-R-DTC).

Background: As reported in the literature, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) provides useful qualitative and semi-quantitative data for the prognosis of advanced differentiated thyroid cancer. Instead, there is a lack of data about the real clinical impact of 18F-FDG PET/CT on the choice of the more effective therapeutic approach for advanced differentiated thyroid cancer (DTC) that starts to lose iodine avidity. The primary aim of this retrospective study was to assess how 18F-FDG PET/CT can guide the choice of the best therapeutic approach to RAI-refractory DTC (RAI-R-DTC) in patients with a doubtful iodine uptake/negative 18F-FDG PET/CT I whole-body scan after several radioactive iodine therapies (RAIT). The secondary aim was to assess the prognostic role of clinical and semi-quantitative metabolic 18F-FDG PET/CT parameters in comparison to published data. Materials and methods: A monocentric retrospective observational study was performed, reviewing the medical records of 53 patients recruited from a database of 208 patients treated at our Institution between 2011 and 2019, with advanced DTC that underwent FDG PET/CT scan for a suspected RAI-R-DTC. Selected patients had to perform a 18F-FDG PET/CT scan after the second RAIT based on a doubtful iodine uptake/negative 131 I whole-body scan and/or persistent elevated thyroglobulin levels. Metabolic response was defined according to positron emission tomography response criteria in solid tumors (PERCIST) guidelines. Standardized uptake value (SUV)max, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The association between metabolic features, clinical parameters and progression free survival (PFS) was assessed applying Kruskal-Wallis, chi-square-Pearson correlation tests, and Cox regression analyses when appropriate. Results: Among our sample of 53 patients (mean age 52.0 ± 19.9 years; 31 women and 22 men), 27 (51.0%) presented a positive 18F-FDG PET/CT scan: 16 (59.0%) underwent watchful waiting, 4 (15.0%) received external-beam radiation therapy (EBRT), 4 (15.0%) underwent surgery, 2 (7.4%) received another course of RAI therapy, and 1 underwent surgery + EBRT. PERCIST response was evaluated in 14/27 patients. Median follow-up was 5.8 ± 3.9 years and median PFS was 38.0 ± 21.8 months. At the last follow-up assessment, 14/53 (26.4%) demonstrated disease progression, 13/53 (24.5) persistence of structural disease, 25/53 (47%) persistence of biochemical disease, and 15/53 (28%) had an excellent response. A significant association was found between therapeutic approach, metabolic response, and final disease response evaluation, as well as a linear correlation between MTV and TLG with thyroglobulin level. Conclusions: Our Institutional experience confirmed the role of 18F-FDG PET/CT as a useful guide in the clinical management of RAI-R-DTC and obviated further unnecessary RAIT

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004–March 2022) were identified through the high-level term “adrenal cortical hypofunctions”. Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14–201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42–3.04; IC = 0.25, 95%CI = 0.07–0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy

The Current-Temperature Phase Diagram of Layered Superconductors

The behavior of clean layered superconductors in the presence of a finite electric current and in zero-magnetic field behavior is addressed. The structure of the current temperature phase diagram and the properties of each of the four regions will be explained. We will discuss the expected current voltage and resistance characteristics of each region as well as the effects of finite size and weak disorder on the phase diagram. In addition, the reason for which a weakly non-ohmic region exists above the transition temperature will be explained.Comment: 8 pages (RevTeX), 4 encapsulated postscript figure

Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer

Background: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. Materials and methods: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. Results: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006). Conclusions: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC

Does the site of origin of the microcarcinoma with respect to the thyroid surface matter? A multicenter pathologic and clinical study for risk stratification

It is unclear whether the site of origin of papillary thyroid microcarcinoma (mPTC) with respect to the thyroid surface has an influence on clinicopathologic parameters. The objectives of the study were to: (i) Accurately measure the mPTC distance from the thyroid surface; (ii) analyze whether this distance correlates with relevant clinicopathologic parameters; and (iii) investigate the impact of the site of origin of the mPTC on risk stratification. Clinicopathologic features and BRAF mutational status were analyzed and correlated with the site of origin of the mPTC in a multicenter cohort of 298 mPTCs from six Italian medical institutions. Tumors arise at a median distance of 3.5 mm below the surface of the thyroid gland. Statistical analysis identified four distinct clusters. Group A, mPTC: size 65 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; group B, mPTC: size 65 5 mm and distance of the edge of the tumor from the thyroid capsule > 0 mm; group C, mPTC: size < 5 mm and distance of the edge of the tumor from the thyroid capsule = 0 mm; and group D, mPTC: size < 5 mm and distance of the edge of the tumor from the thyroid capsule > 0 mm. Univariate analysis demonstrates significant differences between the groups: Group A shows the most aggressive features, and group D the most indolent ones. By multivariate analysis, group A tumors are characterized by tall cell histotype, BRAF V600E mutation, tumor fibrosis, aggressive growth with invasive features, vascular invasion, lymph node metastases, and intermediate ATA risk. The mPTC clinicopathologic features vary according to the tumor size and distance from the thyroid surface. A four-group model may be useful for risk stratification and to refine the selection of nodules to be targeted for fine needle aspiration

Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders

Objective: The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. Design: We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. Methods: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. Results: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitro transcriptional activity, including increased stimulation of the PTH promoter. Conclusions: We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease