Functions of cofilin in cell locomotion and invasion.

Recently, a consensus has emerged that cofilin severing activity can generate free actin filament ends that are accessible for F-actin polymerization and depolymerization without changing the rate of G-actin association and dissociation at either filament end. The structural basis of actin filament severing by cofilin is now better understood. These results have been integrated with recently discovered mechanisms for cofilin activation in migrating cells, which led to new models for cofilin function that provide insights into how cofilin regulation determines the temporal and spatial control of cell behaviour.

Vimentin-mediated myosin 10 aggregation at tips of cell extensions drives MT1-MMP-dependent collagen degradation in colorectal cancer.

Colorectal cancer (CRC) is a high prevalence adenocarcinoma with progressive increases in metastasis-related mortality, but the mechanisms governing the extracellular matrix (ECM) degradation important for metastasis in CRC are not well-defined. We investigated a functional relationship between vimentin (Vim) and myosin 10 (Myo10), and whether this relationship is associated with cancer progression. We tested the hypothesis that Vim regulates the aggregation of Myo10 at the tips of cell extensions, which increases membrane-type 1 matrix metalloproteinase (MT1-MMP)-associated local collagen proteolysis and ECM degradation. Analysis of CRC samples revealed colocalization of Vim with Myo10 and MT1-MMP in cell extensions adjacent to sites of collagen degradation, suggesting an association with local cell invasion. We analyzed cultured CRC cells and fibroblasts and found that Vim accelerates aggregation of Myo10 at cell tips, which increases the cell extension rate. Vim stabilizes the interaction of Myo10 with MT1-MMP, which in turn increases collagenolysis. Vim depletion reduced the aggregation of Myo10 at the cell extension tips and MT1-MMP-dependent collagenolysis. We propose that Vim interacts with Myo10, which in turn associates with MT1-MMP to facilitate the transport of these molecules to the termini of cell extensions and there enhance cancer invasion of soft connective tissues.

CD301 mediates fusion in IL-4-driven multinucleated giant cell formation.

Multinucleated giant cells (MGCs) are prominent in foreign body granulomas, infectious and inflammatory processes, and auto-immune, neoplastic and genetic disorders, but the molecular determinants that specify the formation and function of these cells are not defined. Here, using tandem mass tag-mass spectrometry, we identified a differentially upregulated protein, C-type lectin domain family 10 member (herein denoted CD301, also known as CLEC10A), that was strongly upregulated in mouse RAW264.7 macrophages and primary murine macrophages undergoing interleukin (IL-4)-induced MGC formation. CD301+ MGCs were identified in biopsy specimens of human inflammatory lesions. Function-inhibiting CD301 antibodies or CRISPR/Cas9 deletion of the two mouse CD301 genes (Mgl1 and Mgl2) inhibited IL-4-induced binding of N-acetylgalactosamine-coated beads by 4-fold and reduced MGC formation by 2.3-fold (P<0.05). IL-4-driven fusion and MGC formation were restored by re-expression of CD301 in the knockout cells. We conclude that in monocytes, IL-4 increases CD301 expression, which mediates intercellular adhesion and fusion processes that are required for the formation of MGCs.This article has an associated First Person interview with the first author of the paper.

Correction to: Three-Dimensional Quantification of Spheroid Degradation-Dependent Invasion and Invadopodia Formation.

[This corrects the article DOI: 10.1186/s12575-018-0085-6.].

Three-Dimensional Quantification of Spheroid Degradation-Dependent Invasion and Invadopodia Formation.

Invadopodia are actin-rich, proteolytic structures that enable cancer cell to invade into the surrounding tissues. Several in vitro invasion assays have been used in the literature ranging from directional quantitative assays to complex three-dimensional (3D) analyses. One of the main limitations of these assays is the lack of quantifiable degradation-dependent invasion in a three-dimensional (3D) environment that mimics the tumor microenvironment. In this article, we describe a new invasion and degradation assay based on the currently available tumor spheroid model that allows long-term high-resolution imaging of the tumor, precise quantification, and visualization of matrix degradation and multichannel immunocytochemistry. By incorporating a degradation marker (DQ-Green BSA) into a basement-membrane matrix, we demonstrate the ability to quantitate cancer cell-induced matrix degradation in 3D. Also, we describe a technique to generate histological sections of the tumor spheroid allowing the detection of invadopodia formation in the 3D tumor spheroid. This new technique provides a clear advantage for studying cancer in vitro and will help address critical questions regarding the dynamics of cancer cell invasion.

Does direct stenting with drug-eluting stents improve outcome? A meta-analysis of 10,900 patients.

OBJECTIVES: The aim of this study is to summarize the outcomes of patients undergoing direct stenting (DS) with drug-eluting stents (DES) compared to those who underwent balloon predilatation. BACKGROUND: DS has been associated with improved outcomes in the bare-metal stent era. Although DS with DES implantation has been increasingly adopted in clinical practice, its safety and effectiveness remain controversial. METHODS: The search criteria identified 546 studies in the Medline/PubMed, Cochrane, and EMBASE databases from 2001 to July 2014. From these, seven studies totaling 10,900 patients were selected. Summarized estimates [odds ratio (OR) and 95% confidence intervals] were obtained using a random-effects model. The primary outcomes were a composite of major adverse cardiac events (MACE), including all-cause death, myocardial infarction (MI), and repeat revascularization. The secondary outcomes included a composite of death and MI and the rates of target lesion revascularization (TLR). RESULTS: Overall, 4101 (38%) and 6799 (62%) patients underwent DS with DES and balloon pre-dilatation, respectively. DS with DES reduced the likelihood of MACE (OR: 0.81 [0.71-0.93]). Additionally, DS with DES was associated with reduced rates of death/MI (OR: 0.76 [0.62-0.92]), and TLR (OR: 0.66 [0.44-0.98]). CONCLUSIONS: DS with DES is safe and may be associated with better outcomes in selected patients. © 2016 Wiley Periodicals, Inc.

Clinical profiles and correlates of mortality in nonagenarians with severe aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is the current standard for nonoperable and high-risk surgical patients with aortic stenosis, including those of advanced age. However, the clinical profiles, procedural characteristics, and outcomes of nonagenarians undergoing TAVR have not been thoroughly reported. METHODS: A total of 654 patients (n = 107 >90 years old and n = 547 <90 years) with severe aortic stenosis undergoing TAVR were included in this analysis. Baseline characteristics, procedural variables, and in-hospital outcomes and complications at 30 days and 12 months were analyzed. RESULTS: Overall, of the patients included, 46% were high risk and 53% inoperable. Although nonagenarians had a higher Society of Thoracic Surgeons score of 9.2 ± 4 (12.1 ± 4 vs 8.6 ± 4, P < .001), other factors were considerably lower in this group: diabetes (22% vs 36%, P = .008), hyperlipidemia (65% vs 83%, P < .001), prior coronary artery bypass (13% vs 39%, P < .001), and mean body mass index (24.5 ± 5 vs 28.1 ± 7 kg/m(2), P < .001). The correlates for 1-year mortality in nonagenarians were as follows: ≥moderate aortic insufficiency post-TAVR (hazard ratio [HR] 5.07, 95% CI 1.17-22, P = .03), pacemaker implantation after TAVR (HR 6.87, 95% CI 2.32-20.3, P = .001), and peripheral vascular disease (HR 2.35, 95% CI 1.03-5.38, P = .042). Mortality at 30 days (12.1% vs 7.1%, P = .07) and at 1 year (25% vs 21%, P = .35) was similar between groups. CONCLUSION: Nonagenarians undergoing TAVR had a healthier clinical profile compared with younger patients. Age alone should not be a discriminatory factor when screening elderly patients with aortic stenosis because even the nonagenarians are doing well when compared with the younger elderly population. Transcatheter aortic valve replacement remains a viable option for the treatment of severe symptomatic aortic stenosis for the elderly regardless of their age.

Impact of baseline mitral regurgitation on short- and long-term outcomes following transcatheter aortic valve replacement.

BACKGROUND: The prevalence of concomitant significant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) ranges from 2% to 33%. The impact of significant MR on post-TAVR outcomes remains controversial. METHODS: The data from a cohort of patients with symptomatic severe AS undergoing TAVR at out institution were retrospectively analyzed. The last transthoracic echocardiogram (TTE) before the index TAVR procedure was selected as the baseline assessment of the degree of MR. The total study cohort (N = 589) was divided into 2 groups: significant ≥moderate MR (n = 68) versus nonsignificant

Does the disparity in baseline characteristics of patients undergoing transcatheter aortic valve replacement with 23 mm vs. 26 mm valves impact clinical outcome?

OBJECTIVES: We sought to identify if baseline characteristic differences in patients who receive a 23 mm vs. 26 mm valve impact clinical outcomes. BACKGROUND: Transcatheter aortic valve replacement (TAVR) is currently an approved therapy for patients with severe aortic stenosis who are considered inoperable or are at high risk. METHODS: We retrospectively examined baseline characteristics and outcomes of patients receiving a 23 mm (n = 132) vs. 26 mm valve (n = 81) via the transfemoral approach. RESULTS: Gender (P < 0.01), previous coronary artery bypass surgery (P < 0.01), history of atrial fibrillation (P = 0.04), and mean Society of Thoracic Surgeons (STS) score (P < 0.01) were significantly different between groups. There were no significant differences in the rates of minor/major vascular complications (2.2 vs. 3.7%, P = 0.68 and 13.0 vs. 12.3%, P = 0.89, respectively). Bleeding complications were also comparable (major bleed 2.3 vs. 1%, P >0.99, minor bleed 19.0 vs. 22.0%, P = 0.67 and life threatening bleed 7.0 vs. 5.0%, P = 0.77). In-hospital death (6.0 vs. 5.0%, P >0.99), 30-day all-cause death (7.6 vs. 6.2%, P = 0.69), and all-cause death at 1 year (17.4 vs. 25.9%, P = 0.13) were also similar between groups. Gender, valve size, previous coronary bypass surgery and atrial fibrillation were not independently associated with mortality; however, on multivariate analysis STS score was (HR 1.11; 95% CI 1.02-1.19; P = 0.01). CONCLUSION: Patients undergoing TAVR with 23 and 26 mm valves have similar clinical outcomes despite significant differences in baseline characteristics. © 2015 Wiley Periodicals, Inc.

Active Versus Passive Anchoring Vascular Closure Devices Following Percutaneous Coronary Intervention: A Safety and Efficacy Comparative Analysis.

OBJECTIVE: We evaluate the prevalence of complications and failure rates between the most commonly used "active" anchoring vascular closure device (VCD), AngioSeal™ and the "passive" anchoring VCD, Mynx™, in all-comers undergoing percutaneous coronary intervention (PCI). METHODS: A total of 4,074 patients between 2008 and 2014, representing an era when both devices were available, were included. Thirty-two percent were acute coronary syndromes (37% STEMI). VCD choice was at the operator's discretion and included AngioSeal (n = 2,910) or Mynx (1,164). Cardiogenic shock or patients receiving intra-aortic balloon pumps were excluded. Safety was assessed by vascular complications defined as either vascular injury (perforation, dissection, acute limb ischemia, arteriovenous fistula, pseudoaneurysm with thrombin injection, or surgical repair) or access-site bleed (hemoglobin droP >3 g/dL requiring transfusion, retroperitoneal bleed, or hematoma >5 cm, or the composite of both. Efficacy was evaluated by device failure and defined as inability to achieve immediate hemostasis or use of additional hemostatic mechanisms. Outcomes at 30-days were evaluated. RESULTS: Groups (AngioSeal vs Mynx) were fairly balanced with regards to bleeding risk factors of gender (male, 65% vs 66%), body mass index (30 ± 6 vs 30 ± 7), heart failure class III/IV (5% vs 6%), chronic kidney disease (15% vs 17%), use of glycoprotein IIb/IIIa inhibitor (5% vs 4%), or bivalirudin (86% vs 88%), all P >0.5. The AngioSeal group was slightly younger (64 ± 12 vs 65 ± 12, P < 0.001) with less peripheral arterial disease (11.3% vs 13.9%, P = 0.03), and increased 7F sheath use compared with Mynx (59% vs 22%, P < 0.001). Safety and efficacy outcomes were similar between groups. CONCLUSIONS: AngioSeal and Mynx appear to be equally safe and efficacious VCDs following PCI. The passive anchoring system may prove desirable as no intra-arterial anchor remains upon device removal.

The choice of arterial access for percutaneous coronary intervention and its impact on outcome: An expert opinion perspective.

The prevention of major bleeding during percutaneous coronary intervention is one of the most widely discussed and often controversial topics within interventional cardiology. The choice of arterial access should be considered a mechanism for bleeding avoidance, and various strategies have been proposed to prevent or lower major bleeding and vascular complications with varying levels of strength. Herein, we review the current literature on arterial access as a bleeding avoidance strategy during percutaneous coronary intervention and its impact on outcome and provide a consensus opinion based on the strength of the evidence supporting various techniques.

Outcome comparison of African-American and Caucasian patients with severe aortic stenosis subjected to transcatheter aortic valve replacement: a single-center experience.

OBJECTIVE: This study aimed to report the outcomes of African Americans (AAs) in the US undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). BACKGROUND: Compared to Caucasians, AAs are reported to have poorer outcomes from most cardiovascular diseases, including high complication rates after surgical aortic valve replacement. The outcomes of AAs undergoing TAVR are not well established. METHODS: Consecutive patients who underwent TAVR were included in this analysis. Patients' baseline characteristics, procedural data, in-hospital- and long-term outcomes were recorded and a comparison was performed between the AA and Caucasian cohorts. RESULTS: In a cohort of 469 consecutive patients, 51 (10.8%) were AA and 345 (74.5%) were Caucasian. The remaining patients (n = 73; 15.3%) self-reported their race as "unknown" or were from other races. Most baseline characteristics were similar between the two groups except for less men (33.3 vs. 50.1%; P = 0.016), a lower mean left ventricular ejection fraction (48.85 ± 16.35 vs. 53.24 ± 13.41%; P = 0.04) and lower rates of atrial fibrillation in AAs (15.7 vs.45.4%; P < 0.001). TAVR procedures in AAs were less frequently performed as part of a clinical trial (60.8 vs. 76.8%; P = 0.014). Most procedural and periprocedural outcome parameters were similar save for a higher rate of hemodynamic instability and postoperative need for intubation in AAs (10.4 vs. 2.5%; P = 0.018 and 29.4 vs. 16.9%; P = 0.03, respectively). This did not translate into a difference in mortality between AAs and Caucasians (30-day mortality 9.8 vs. 9.9%; P = 0.99; 1-year mortality 19.6 vs. 24.3%; P = 0.458, respectively). CONCLUSION: Unlike with other cardiovascular interventions, this study demonstrates that AA patients referred for TAVR shared similar risks and outcomes when compared to a Caucasian population.

Does baseline hematocrit influence the assays of on-treatment platelet reactivity to clopidogrel?

BACKGROUND: High on-treatment platelet reactivity (HTPR) has been shown to be associated with adverse cardiac events in patients undergoing percutaneous coronary intervention, but the effect of baseline hematologic parameters upon platelet reactivity remains controversial. OBJECTIVE: The present study aims to evaluate the impact of hematocrit on 2 different assay methods used to assess on-treatment platelet reactivity to clopidogrel. METHODS: We tested clopidogrel on-treatment platelet reactivity in 466 consecutive patients using VerifyNow P2Y12 (VN) and light transmission aggregometry (LTA) with adenosine diphosphate (ADP) 5 and 20 µM assays 6 to 24 hours after percutaneous coronary intervention. Patients were categorized into 4 groups according to baseline hematocrit. One-year major adverse cardiac events, including death, nonfatal myocardial infarction, and definite stent thrombosis, were collected. RESULTS: Lower hematocrit was associated with higher P2Y12 reaction unit (PRU) and a higher rate of HTPR (P < .001) as measured by VN assay. No differences were seen among the 4 groups in platelet reactivity measured by LTA using ADP 5 µM (P = .23) and ADP 20 µM (P = .21). In a multivariable logistic regression model, baseline hematocrit was independently associated with PRU ≥208 (odds ratio [OR] 0.92, 95% CI 0.86-0.97, P = .005) but had no correlation with LTA ADP 5 µM ≥46% (OR 1.0, 95% CI 0.95-1.06, P = .88) or LTA ADP 20 µM ≥59% (OR 1.03, 95% CI 0.97-1.09, P = .39). In a logistic regression model, the addition of VN assay results, hematocrit, and interaction between the hematocrit and assay results had shown a significant influence on the area under curve for prediction of 1-year major adverse cardiac events compared with baseline clinical variables only for PRU (0.63 vs 0.76, P = .006) but not with LTA (0.64 vs 0.74, P = .13). CONCLUSION: Baseline hematocrit has a differential influence on results of the ex vivo platelet functional assays. Lower baseline hematocrit was independently associated with HTPR by VN but not LTA. This may affect the interpretation of platelet function testing in patients with significant anemia.

Long-term safety and efficacy of second-generation everolimus-eluting stents compared to other limus-eluting stents and bare metal stents in patients with acute coronary syndrome.

OBJECTIVES: This study aimed to investigate the long-term safety and efficacy of everolimus-eluting stents (EES) compared with other limus-eluting stents and bare metal stents (BMS) in ACS patients. BACKGROUND: There have been concerns about the long-term safety of drug-eluting stents in the setting of acute coronary syndrome. METHODS: The study cohort included 1,612 patients presenting with acute coronary syndrome who underwent BMS, SES, E-ZES, or EES implantation. End points included probable or definite stent thrombosis and major adverse cardiovascular events (MACE), defined as a composite of all-cause death, Q-wave myocardial infarction, and target lesion revascularization up to 3 years. RESULTS: The overall MACE rates were significantly higher for both BMS and SES, but not E-ZES, when compared with EES (EES vs. BMS: HR 2.68, 95% CI 1.91-3.78, P <0.001; EES vs. SES: HR 1.75, 95% CI 1.24-2.47, P = 0.001 and EES vs. E-ZES: HR 1.08, 95% CI 0.65-1.77, P = 0.72). Stent thrombosis rates were similar for EES, E-ZES, and BMS but higher for SES throughout the 3-year follow-up (EES vs. BMS: HR 1.02, 95% CI: 0.31-3.35, P = 0.973; EES vs. SES: HR 4.90, 95% CI: 1.75-13.69, P = 0.002 and EES vs. E-ZES: HR 1.63, 95% CI 0.37-7.31, P = 0.449). CONCLUSIONS: There was an improvement in the long-term outcome for MACE with EES when compared to earlier-generation stents, but this was comparable with the 2nd-generation E-ZES. There was no additional risk of early or late stent thrombosis in EES when compared with BMS.

Intravascular ultrasound analysis to determine the relationship between high-density lipoprotein cholesterol and lesion characteristics in patients with coronary artery disease.

OBJECTIVES: This study utilized grayscale intravascular ultrasound (IVUS) to explore the relationship between high-density lipoprotein cholesterol (HDL-C) levels and culprit lesion characteristics in patients with coronary artery disease. BACKGROUND: Low HDL-C is associated with an increased risk of cardiovascular events. Previous IVUS studies have suggested a significant association between lesion characteristics and cardiovascular events. METHODS: According to HDL-C levels, 120 patients who underwent IVUS for native, de novo coronary lesions before any intervention were divided into a low HDL-C group (<40 mg/dL, n = 60) and a high HDL-C group (≥40 mg/dL, n = 60). Quantitative and qualitative IVUS analyses were performed to compare lesion characteristics. RESULTS: Quantitative IVUS measurements showed no significant differences between the 2 groups. HDL-C level was not significantly correlated with remodeling index (r = 0.03, P = 0.78). However, attenuated plaque was more frequent in the low HDL-C group (48.3% vs. 28.3%, P = 0.02) and a greater percentage of attenuated plaque was found in this group (32.5 ± 21.3% vs. 21.0 ± 11.0%, P = 0.02). Moreover, when categorized into 4 groups according to HDL-C levels, the proportion of attenuated plaque (64.7% in group with <30 mg/dL, 41.9% in group with 30-39 mg/dL, 36.4% in group with 40-59 mg/dL, and 6.3% in group with ≥60 mg/dL; P = 0.001 for trend) was significantly different among groups. On multivariate analysis, only HDL-C and male gender were independently associated with the presence of attenuated plaque at the culprit lesions. CONCLUSIONS: Patients with low levels of HDL-C may be at increased risk of having a higher incidence of attenuated plaques.

Engineered Immunomodulatory Nanoparticles Inhibit Root Resorption and Ankylosis.

INTRODUCTION: External root resorption following avulsion injury is a complex process wherein differentiation of Macrophages (Mφ) to multinucleated osteoclasts is temporally regulated by resident periodontal fibroblasts (PDLF). The current study aims to assess the effect of engineered bioactive chitosan nanoparticles (CSNP), sustained released Dexamethasone conjugated CSNP (CS-DEX) and CSNP functionalised with photosensitizer Rose Bengal (CSRB) for application in root resorption using an in-vitro PDLF-Mφ direct coculture model, and in-vivo delayed reimplantation model. METHODS: PDLF-Mφ direct coculture system was exposed to LPS, MCSF, RANKL with or without CSNP/CS-DEX for 7 days. Clastic differentiation was assessed by tartrate resistant acid phosphatase (TRAP) staining on day 7. On day 2 and 7, immunofluorescence analysis was done to assess the expression of Mφ polarization markers (CD80, CD206), multinucleation markers (NFATc1, STAT6) in Mφ and matricellular protein periostin in PDLF and cytokine profiling in cell culture supernatants. Delayed replantation model with extraoral air dry / LPS exposure for 1h followed by root surface treatment with CS-DEX/CSRB was used in Wistar rats. After 21 days, rats were euthanized for histological and immunofluorescence analysis. Statistical analysis One-way ANOVA with Tukey's multiple comparisons was used to analyze the data (p<0.05). RESULTS: CS-DEX significantly reduced TRAP+ multinucleated cells and CSNP treatment showed no TRAP+ cells. Immunofluorescence analysis showed that CSNP/CS-DEX reduced CD80, NFATc1 and STAT6 expression and increased periostin as expressed by fluorescence intensity. CSNP/CS-DEX significantly reduced TNFα, MMP9 and increased IL10, TGFß1. OPG was upregulated only by CSNP. Root surface treatment in delayed replantation model showed that CS-DEX and CSRB substantially reduced the degree of resorption and ankylosis. Further, CD80, CD206, MMP2 expression in groups with root surface treatment with CS-DEX and CSRB was lower than airdry/ LPS group and similar to healthy control and NFATc1, STAT6, MMP9 expression were lower than healthy control. CONCLUSION: The engineered nanosized immunomodulatory bioactive materials chitosan nanoparticles functionalised with photosensitizer and dexamethasone effectively reduced the clastic differentiation of Mφ in in-vitro coculture and minimized the resorption and ankylosis in a delayed reimplantation model. These biomaterials have the potential to serve as root modification agents, promoting favourable healing outcomes in cases of dental avulsion.

SMARCB1 (INI1)-deficient sinonasal carcinoma manifesting as oral lesions: A report of two cases.

BACKGROUND: Sinonasal carcinomas represent a rare group of malignancies, accounting for less than 5% of all head and neck cancers and a worldwide incidence of less than 1 case per 100 000 inhabitants annually. Despite the restricted anatomical location, sinonasal carcinomas harbor some of the most histologically and molecularly diverse groups of tumors. SMARCB1 (INI1)-deficient sinonasal carcinomas are locally aggressive tumors commonly detected late, leading to devastating morbidity and mortality. CASE REPORT: We present two cases of SMARCB1-deficient sinonasal carcinoma involving the oral cavity and presenting as progressive radiolucent lesions with local swelling associated with maxillary dentition and alveolar bone. Both cases were initially considered odontogenic in origin and involved the destruction of the left anterior maxilla. CONCLUSION: Given the rarity and the variable presentation of these tumors, they pose a challenge for head and neck surgeons, dentists, and pathologists due to the potential overlapping features with odontogenic and non-odontogenic inflammatory and neoplastic lesions. These cases highlight the importance of a multidisciplinary team and include SMARCB1-deficient sinonasal carcinomas in the differential diagnosis of destructive lesions of the maxilla.

Salivary exosomal microRNA profile as biomonitoring tool for diagnosis and prognosis of patients with head and neck squamous cell carcinoma: a systematic review.

OBJECTIVE: Exosomes are extracellular vesicles found in saliva and other body fluids. These vesicles range in size from 30 to 150 nm and play a crucial role in intercellular communication, transporting different biomolecules, actively targeting cells. These vesicles regulate both physiological and pathological processes within recipient cells. MicroRNAs (miRs) are transported within exosomes and are delivered to target cells where they influence signaling pathways, taking on a crucial regulatory role in oncogenesis; for example, they are implicated in progression and infiltration of various cancers, such as head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: A systematic literature search based on specific keywords, according to the PRISMA guidelines, was carried out on PubMed, Web of Science, Scopus, and Google Scholar. Only original articles were selected during this review. The risk of bias was assessed by QUADAS-2. RESULTS: At the end of the selection process 9 articles were included. In these studies, 41 miRs showed differential expression between healthy subjects and patient with HNSCC. The techniques varied among studies for the extraction and analysis of exosomal miRs. We presented also salivary exosomal miRs pathways, to give insights about pathogenetic mechanisms. CONCLUSIONS: Exosomal microRNA are promising biomarkers for HNSCC detection. MiR-10b-5p, miR-486-5p, miR-24-3p, miR-412-3p, and miR-512-3p are the most promising markers applicable to diagnostics, while miR-1307-5p and miR-519c-3p resulted overexpressed and correlated to worse survival outcomes.

Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop.

Directional cell migration is an essential requirement for efficient neutrophil translocation to sites of infection and requires the establishment of a polarized cell characterized by an actin-rich leading edge facing the chemoattractant gradient. The asymmetrical accumulation of phosphatidylinositol(3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] in the up-gradient leading edge is a hallmark of polarization and regulates the recruitment and localization of various effector proteins at the leading-edge plasma membrane. How shallow gradients of chemoattractants trigger and maintain a much steeper intracellular gradient of PtdIns(3,4,5)P(3) is a critical question in the study of leukocyte chemotaxis. Our data demonstrate that the migration of neutrophils toward the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine depends on the generation of reactive oxygen species by the phagocytic NADPH oxidase (NOX2) and subsequent oxidation and inhibition of phosphatase and tensin homolog. Moreover, we show that events downstream of PtdIns(3,4,5)P(3), including phosphorylation of AKT, Rac activation, uncapping of actin filaments, and directional migration, can be attenuated by ROS scavengers or genetic ablation of NOX2. Using Rac mutants that are defective in their ability to activate NOX2, we show that Rac regulates a redox-mediated feedback loop that mediates directional migration of neutrophils.

Transcatheter aortic valve implantation through a diseased left common carotid artery: combined approach with endarterectomy and left carotid-subclavian bypass.

We report a case of transcatheter aortic valve implantation (TAVI) with the self-expanding Medtronic CoreValve bioprosthesis (Medtronic, Minneapolis, MI) through a diseased left common carotid (LCC) artery. This 81-year-old male patient presented with heart failure due to a severe degenerative aortic valve stenosis. Comorbidities included diabetes, hypertension, and dyslipidemia as well as peripheral and coronary artery disease, resulting in a logistic EuroScore II of 25.9%. Consequently, he was rejected to undergo surgery and a transcatheter approach was planned. Due to severe peripheral vascular disease with iliofemoral lesions, significant calcifications and unfavourable angulations of the innominate artery as well as prior bypass surgery precluding a direct aortic and subclavian approach, none of the established access sites were suitable. Therefore, we considered a left carotid access, which had to be combined with a surgical endarterectomy for treatment of a significant common carotid bifurcation stenosis and left subclavian-LCC permanent tunnel bypass graft. The procedure was successful without cardiac, cerebrovascular, or access complications. This case illustrates a true heart team approach, establishing a unique access for TAVI for patients without regular access options.