BackgroundAn international group of experts recommended reclassifying non-invasive follicular variant of papillary thyroid cancers (FVPTC) as ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP) in April 2016. The purpose of this study was to establish preoperative clinical, laboratory, ultrasonographic, and cytological variables, which can differentiate NIFTP from FVPTC.MethodsWe conducted a retrospective chart review of consecutive patients from a single institution evaluated between January 2012 and December 2017. 203 adult patients underwent lobectomy or total thyroidectomy for a FVPTC during that period. Each patient’s medical chart was reviewed and information on pre-operative variables was recorded. An expert pathologist reviewed all surgical specimens and reclassified a subset of FVPTC as NIFTP according to the specific criteria.ResultsOverall, 44 patients were included in the NIFTP group and 159 in the non-NIFTP group. Mean age was 50.1 years in the NIFTP group and 50.7 in the non-NIFTP group. Most patients were female (86.4% (38/44) in the NIFTP group vs 79.8% (127/159) in the non-NIFTP group). More patients underwent lobectomy in the NIFTP group (50% (22/44) vs 16.4% (26/159) in the non-NIFTP group, p = < 0.0001). Less patients received radioactive iodine in the NIFTP group (31.8% (14/44) vs 52.2% (83/159) in the non-NIFTP group, p = 0.0177). Preoperative thyroglobulin levels were lower in NIFTP patients (Median 25.55 mcg/L +/− 67.8 vs 76.06 mcg/L +/− 119.8 in Non-NIFTP, p = 0.0104). NIFTP nodules were smaller (Mean size 22.97 mm +/− 12.3 vs 25.88 mm +/− 11.2 for non-NIFTP, p = 0.0448) and more often solid than non-NIFTP (93.2% (41/44) vs 74.8% (119/159) for non-NIFTP, p = 0.0067). 2017 ACR TIRADS nodule category of 1–4 on ultrasound had a negative predictive value and a sensitivity of 100% for NIFTP. ROC Curve Analysis demonstrated that a preoperative thyroglobulin level of 31.3 mcg/L had a sensitivity of 75% and a specificity of 62.5% to differentiate NIFTP from non-NIFTP cancers.ConclusionLower preoperative thyroglobulin levels, smaller nodule size, solid texture and 2017 ACR TIRADS Category of 1–4 are more strongly associated with NIFTP than FVPTC and can favour less invasive surgical options such as lobectomy.

BackgroundValosin containing protein (VCP) is a critical mediator of protein homeostasis and may represent a valuable therapeutic target for several forms of cancer. Overexpression of VCP occurs in many cancers, and often in a manner correlating with malignancy and poor outcome. Here, we analyzed VCP expression in canine lymphoma and assessed its potential as a therapeutic target for this disease.MethodsVCP expression in canine lymphomas was evaluated by immunoblotting and immunohistochemistry. The canine lymphoma cell lines CLBL-1, 17–71 and CL-1 were treated with the VCP inhibitor Eeyarestatin 1 (EER-1) at varying concentrations and times and were assessed for viability by trypan blue exclusion, apoptosis by TUNEL and caspase activity assays, and proliferation by propidium iodide incorporation and FACS. The mechanism of EER-1 action was determined by immunoblotting and immunofluorescence analyses of Lys48 ubiquitin and markers of ER stress (DDIT3), autophagy (SQSTM1, MAP1LC3A) and DNA damage (γH2AFX). TRP53/ATM-dependent signaling pathway activity was assessed by immunoblotting for TRP53 and phospho-TRP53 and real-time RT-PCR measurement of Cdkn1a mRNA.ResultsVCP expression levels in canine B cell lymphomas were found to increase with grade. EER-1 treatment killed canine lymphoma cells preferentially over control peripheral blood mononuclear cells. EER-1 treatment of CLBL-1 cells was found to both induce apoptosis and cell cycle arrest in G1. Unexpectedly, EER-1 did not appear to act either by inducing ER stress or inhibiting the aggresome-autophagy pathway. Rather, a rapid and dramatic increase in γH2AFX expression was noted, indicating that EER-1 may act by promoting DNA damage accumulation. Increased TRP53 phosphorylation and Cdkn1a mRNA levels indicated an activation of the TRP53/ATM DNA damage response pathway in response to EER-1, likely contributing to the induction of apoptosis and cell cycle arrest.ConclusionsThese results correlate VCP expression with malignancy in canine B cell lymphoma. The selective activity of EER-1 against lymphoma cells suggests that VCP will represent a clinically useful therapeutic target for the treatment of lymphoma. We further suggest a mechanism of EER-1 action centered on the DNA repair response that may be of central importance for the design and characterization of VCP inhibitory compounds for therapeutic use.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1489-1) contains supplementary material, which is available to authorized users.

Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β-catenin pathway mediators, SFRP2, DVL2, GSK3β and β-catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real-Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK-3β, DVL2, and β-catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK-3β, DVL2, β-catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b, and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.

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