Patients with Carotid Intraplaque Hemorrhage Have Higher Incidence of Cerebral Microbleeds

Aims: Carotid intraplaque hemorrhage (IPH) is considered a marker of plaque vulnerability. Cerebral microbleeds (CMBs) are recognized on magnetic resonance imaging (MRI) in patients with cerebrovascular disease. Any connection between carotid IPH and CMBs remains scantly investigated. This study aimed to determine whether the histologic evidence of carotid IPH is related to CMBs. Methods: We retrospectively enrolled 101 consecutive patients undergoing carotid endarterectomy with symptomatic (ischemic stroke, TIA, and amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. The presence and the extent (%) of IPH were identified on carotid plaques stained with Movat Pentachrome. CMBs were localized on T2*-weighted gradient-recalled echo or susceptibility-weighted imaging sequence on brain MRI before surgery. The degree of carotid stenosis was measured by neck CTA. Results: IPH was identified in 57 (56.4%) patients, and CMBs were found in 24 (23.7%) patients. CMBs were more commonly observed in patients with carotid IPH compared to those without [19 (33.3%) vs 5 (11.4%); P=0.010]. The carotid IPH extent was significantly higher in patients with CMBs than in those without [9.0 % (2.8-27.1%) vs 0.9% (0.0-13.9%); P=0.004] and was associated with the number of CMBs (P=0.004). Logistic regression analysis demonstrated an independent association between carotid IPH extent and the presence of CMBs [OR 1.051 (95% CI 1.012-1.090); P=0.009]. Additionally, patients with CMBs had a lower degree of ipsilateral carotid stenosis compared to those without [40% (35-65%) vs 70% (50-80%); P=0.049]. Conclusions: CMBs may be potential markers of the ongoing process of carotid IPH, especially in those with nonobstructive plaques

FOXO1a acts as a selective tumor suppressor in alveolar rhabdomyosarcoma

Rhabdomyosarcoma (RMS), the most common pediatric soft-tissue sarcoma, has two major histological subtypes: embryonal RMS (ERMS), which has a favorable prognosis, and alveolar RMS (ARMS), which has a poor outcome. Although both forms of RMS express muscle cell–specific markers, only ARMS cells express PAX3-FOXO1a or PAX7-FOXO1a chimeric proteins. In mice, Pax3 and Pax7 play key roles in muscle cell development and differentiation, and FoxO1a regulates myoblast differentiation and fusion; thus, the aberrant regulation of these proteins may contribute to the development of ARMS. In this paper, we report that FOXO1a is not expressed in primary ARMS tumors or ARMS-derived tumor cell lines and that restoration of FOXO1a expression in ARMS cells is sufficient to induce cell cycle arrest and apoptosis. Strikingly, the effects of FOXO1a are selective, as enforced expression of FOXO1a in ERMS-derived tumor cell lines had no effect. Furthermore, FOXO1a induced apoptosis in ARMS by directly activating the transcription of caspase-3. We conclude that FOXO1a is a potent and specific tumor suppressor in ARMS, suggesting that agents that restore or augment FOXO1a activity may be effective as ARMS therapeutics

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients

Crystal Structures of Tcl1 Family Oncoproteins and Their Conserved Surface Features

Members of the TCL1 family of oncogenes are abnormally expressed in mature T-cell leukemias and B-cell lymphomas. The proteins are involved in the coactivation of protein kinase B (Akt/PKB), a key intracellular kinase. The sequences and crystal structures of three Tcl1 proteins were analyzed in order to understand their interactions with Akt/PKB and the implications for lymphocyte malignancies. Tcl1 proteins are ~15 kD and share 25—80% amino acid sequence identity. The tertiary structures of mouse Tcl1, human Tcl1, and Mtcp1 are very similar. Analysis of the structures revealed conserved semi-planar surfaces that have characteristics of surfaces involved in protein-protein interactions. The Tcl1 proteins show differences in surface charge distribution and oligomeric state suggesting that they do not interact in the same way with Akt/PKB and other cellular protein(s)

Delamination properties of laminated glass windows subject to blast loading

Delamination processes absorb significant amounts of energy in laminated glass windows when they are subjected to blast loads. Blast tests were performed previously and their results had been used to calculate the loads imposed on the support systems. In this research, the delamination process at realistic deformation rates was studied to understand the reaction force response obtained. Laboratory tensile tests were performed on pre-cracked laminated glass specimens to investigate their delamination behaviour. The experiments confirmed the presence of a plateau in the force-deflection graphs, suggesting that the delamination process absorbed significant energy. The experimental results were then employed to calibrate FEA models of the delamination process with the aim of estimating the delamination energy of the polyvinyl butyral (PVB) membrane and glass layers and its relationship with deformation speed. The delamination energies obtained through this research, if used with the appropriate PVB material model, are a valuable new tool new tool in the modelling and design of laminated glass façade structures

Detection of Stance-Related Characteristics in Social Media Text

In this paper, we present a study for the identification of stance-related features in text data from social media. Based on our previous work on stance and our findings on stance patterns, we detected stance-related characteristics in a data set from Twitter and Facebook. We extracted various corpus-, quantitative- and computational-based features that proved to be significant for six stance categories (contrariety, hypotheticality, necessity, prediction, source of knowledge, and uncertainty), and we tested them in our data set. The results of a preliminary clustering method are presented and discussed as a starting point for future contributions in the field. The results of our experiments showed a strong correlation between different characteristics and stance constructions, which can lead us to a methodology for automatic stance annotation of these data