Short and Intermediate Term Outcomes of the Convergent Procedure: Initial Experience in a Tertiary Referral Center

PURPOSE: The Convergent procedure is a hybrid, multidisciplinary treatment for symptomatic atrial fibrillation (AF) consisting of minimally invasive surgical epicardial ablation and percutaneous/catheter endocardial ablation. We investigated outcomes following introduction of the Convergent procedure at our institution. METHODS: Retrospective study examining single-center outcomes. Demographic, procedural, and post-procedural variables were collected with follow-up data obtained at 3, 6, and 12 months. RESULTS: In all, 36 patients with paroxysmal (11%) or persistent/long-standing persistent (89%) AF underwent the Convergent procedure. 36% also underwent concomitant left atrial appendage (LAA) exclusion by thoracoscopic placement of an epicardial clip. Mean age 60.6 ± 8.0 years with mean arrhythmia burden of 3.9 ± 2.7 years. All patients had failed prior attempts at medical management, 81% had failed prior cardioversion, and 17% had failed prior catheter ablation. Convergent was performed successfully in all patients with no peri-procedural deaths or major complications. At 3 and 12 months, 77.8% and 77.3% of patients, respectively, were free from symptomatic arrhythmia. 65.8% were off anti-arrhythmic medication at 12 months. CONCLUSIONS: The Convergent procedure is safe and has good short- and intermediate-term clinical success rates. This unique hybrid approach combines strengths of surgical and catheter ablation and should be part of any comprehensive AF treatment program

Identifying unmet training needs for postgraduate research students in the biomedical sciences through audit of examiners' reports

Aim/Purpose: Understanding the educational needs of postgraduate research candidates (PGRs) is essential to facilitate development, support attainment, and maintain graduate quality. Background: The production and effective defence of the research thesis are the summative assessment tools used in postgraduate research education. Examiners’ reports provide a rich source of feedback and indicate the gap between the candidate’s level of performance and that expected for the award. This provides a lens through which to view the unmet training needs of PGR cohorts. Methodology: Following a review of all examiner reports for PGR assessments held over a 12 month period, we explored the quantitative and qualitative dimension data in context in order to identify common training needs for our PGR students. Utilising this theoretical framework and standard thematic analysis, we identified recurring themes and were able to determine key areas for future focus. Contribution: This study utilises independent comment from postgraduate research candidate thesis and oral examination assessment to identify unmet core research training needs. Findings: We recognised seven key areas identified by the examiners for improvement: i) quality of scientific writing, ii) general presentation of thesis, iii) statistics /data analysis, iv) understanding / critical appraisal, v) experimental design, vi) English language and vii) supervision. Academic literacy and numeracy stood out as key areas for future training focus. The results highlight areas for future focus in educational provision and targeted training for PGRs undertaking biomedical and life sciences research within our faculty. Recommendations for Practitioners: Evaluation of postgraduate research programmes should include feedback from a variety of sources and not rely solely on employability and completion rates as measures of success. The examination committees are an important source of feedback on the individual and the programme with regard to attainment of core research skills. Recommendation for Researchers: Regular and wide reaching evaluation of postgraduate research programmes and support available is required to ensure the sector can meet the changing needs of our PGR cohorts. Impact on Society: Doctoral graduates are entering increasingly diverse employment fields. Ensuring the quality of graduates and supporting their journey through candidature ensures the greatest value for society once in the work place. Future Research: This study highlights unmet training needs of PGRs as identified by an inde-pendent expert. The impact of engagement with training and the importance of prior experience are not explored in this study, nor is the student perspective on the process. These will reveal additional dimensions to the evaluation process. </jats:p

A Brake Becomes an Accelerator: PTP1B-A New Therapeutic Target for Breast Cancer

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer

Deformation and spallation of shocked Cu bicrystals with Σ3 coherent and symmetric incoherent twin boundaries

We perform molecular dynamics simulations of Cu bicrystals with two important grain boundaries (GBs), Σ3 coherent twin boundaries (CTB), and symmetric incoherent twin boundaries (SITB) under planar shock wave loading. It is revealed that the shock response (deformation and spallation) of the Cu bicrystals strongly depends on the GB characteristics. At the shock compression stage, elastic shock wave can readily trigger GB plasticity at SITB but not at CTB. The SITB can induce considerable wave attenuation such as the elastic precursor decay via activating GB dislocations. For example, our simulations of a Cu multilayer structure with 53 SITBs (∼1.5-μm thick) demonstrate a ∼80% elastic shock decay. At the tension stage, spallation tends to occur at CTB but not at SITB due to the high mobility of SITB. The SITB region transforms into a threefold twin via a sequential partial dislocation slip mechanism, while CTB preserves its integrity before spallation. In addition, deformation twinning is a mechanism for inducing surface step during shock tension stage. The drastically different shock response of CTB and SITB could in principle be exploited for, or benefit, interface engineering and materials design

Left-right loading dependence of shock response of (111)//(112) Cu bicrystals: Deformation and spallation

We investigate with molecular dynamics the dynamic response of Cu bicrystals with a special asymmetric grain boundary (GB), (111)//(112)〈110〉, and its dependence on the loading directions. Shock loading is applied along the GB normal either from the left or right to the GB. Due to the structure asymmetry, the bicrystals demonstrate overall strong left-right loading dependence of its shock response, including compression wave features, compression and tensile plasticity, damage characteristics (e.g., spall strength), effective wave speeds and structure changes, except that spallation remains dominated by the GB damage regardless of the loading directions. The presence or absence of transient microtwinning also depends on the loading directions

Dynamic response of phenolic resin and its carbon-nanotube composites to shock wave loading

We investigate with nonreactive molecular dynamics simulations the dynamic response of phenolic resin and its carbon-nanotube (CNT) composites to shock wave compression. For phenolic resin, our simulations yield shock states in agreement with experiments on similar polymers except the “phase change” observed in experiments, indicating that such phase change is chemical in nature. The elastic–plastic transition is characterized by shear stress relaxation and atomic-level slip, and phenolic resin shows strong strain hardening. Shock loading of the CNT-resin composites is applied parallel or perpendicular to the CNT axis, and the composites demonstrate anisotropy in wave propagation, yield and CNT deformation. The CNTs induce stress concentrations in the composites and may increase the yield strength. Our simulations suggest that the bulk shock response of the composites depends on the volume fraction, length ratio, impact cross-section, and geometry of the CNT components; the short CNTs in current simulations have insignificant effect on the bulk response of resin polymer

Shock compression and spallation of single crystal tantalum

We present molecular dynamics simulations of shock-induced plasticity and spall damage in single crystal Ta described by a recently developed embedded-atom-method (EAM) potential and a volumedependent qEAM potential. We use impact or Hugoniotstat simulations to investigate the Hugoniots, deformation and spallation. Both EAM and qEAM are accurate in predicting, e.g., the Hugoniots and γ - surfaces. Deformation and spall damage are anisotropic for Ta single crystals. Our preliminary results show that twinning is dominant for [100] and [110] shock loading, and dislocation, for [111]. Spallation initiates with void nucleation at defective sites from remnant compressional deformation or tensile plasticity. Spall strength decreases with increasing shock strength, while its rate dependence remains to be explored

Homophilic binding of PTP mu, a receptor-type protein tyrosine phosphatase, can mediate cell-cell aggregation

The receptor-like protein tyrosine phosphatase, PTPmu, displays structural similarity to cell-cell adhesion molecules of the immunoglobulin superfamily. We have investigated the ability of human PTPmu to function in such a capacity. Expression of PTPmu, with or without the PTPase domains, by recombinant baculovirus infection of Sf9 cells induced their aggregation. However, neither a chimeric form of PTPmu, containing the extracellular and transmembrane segments of the EGF receptor and the intracellular segment of PTPmu, nor the intracellular segment of PTPmu expressed as a soluble protein induced aggregation. PTPmu mediates aggregation via a homophilic mechanism, as judged by lack of incorporation of uninfected Sf9 cells into aggregates of PTPmu-expressing cells. Homophilic binding has been demonstrated between PTPmu-coated fluorescent beads (Covaspheres) and endogenously expressed PTPmu on MvLu cells. Additionally the PTPmu-coated beads specifically bound to a bacterially expressed glutathione-S-transferase fusion protein containing the extracellular segment of PTPmu (GST/PTPmu) adsorbed to petri dishes. Covaspheres coated with the GST/PTPmu fusion protein aggregated in vitro and also bound to PTPmu expressed endogenously on MvLu cells. These results suggest that the ligand for this transmembrane PTPase is another PTPmu molecule on an adjacent cell. Thus homophilic binding interactions may be an important component of the function of PTPmu in vivo

Kinetics and Mechanism of Indene C–H Bond Activation by [(COD)Ir(μ_2-OH)]_2

The hydroxy-bridged dimer [(COD)Ir(μ_2-OH)]_2 (COD = 1,5-cyclooctadiene) cleanly cleaves C–H bonds in indene and cyclopentadiene to produce (COD)Ir(η^3-indenyl) and (COD)Ir(η^5-C_(5)H_5), respectively. The kinetics of the formation of (COD)Ir(η^3-indenyl) are consistent with a mechanism that involves coordination of indene to [(COD)Ir(μ_2-OH)]_2 followed by rate-determining C–H activation from the iridium dimer–indene unit. Transition-state analysis of the Ir and Rh hydroxy dimers indicates that the C–H activation proceeds through a direct deprotonation of indene by the M–OH unit rather than a stepwise oxidative addition/reductive elimination mechanism. The crystal structure of [(COD)Ir]_5(μ_4-O)(μ_3-O)(μ_2-OH), a dehydration product of [(COD)Ir(μ_2-OH)]_2, is presented

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer