High Acute Myeloid Leukemia derived VEGFA levels are associated with a specific vascular morphology in the leukemic bone marrow

Acute Myeloid Leukemia (AML) bone marrow biopsies at diagnosis display enhanced angiogenesis and increased VEGFA expression. In a xenograft mouse model it was described that availability of free VEGFA versus bound VEGFA is related to different vascular morphology. In this study we investigate the relationship between vascular morphology within AML bone marrow biopsies and AML derived VEGFA levels. Vessel count and surface area (Chalkley count) were calculated in AML bone marrow biopsies at diagnosis (n = 32), at remission (n = 8) and Normal Bone Marrow (n = 32) using immunohistochemical staining for FVIII, CD31, CTIV, SMA and VEGFA. VEGFA protein levels were measured. High vessel count was associated with an immature vessel status. Combining vessel count and Chalkley count different vessel morphology patterns were quantified within AML bone marrow biopsies. Three different subgroups could be distinguished. The subgroup (37.5% of the samples) exhibiting a high vessel count and vessels with predominantly large lumen (normal Chalkley count) was associated with high secreted VEGFA protein levels. Different vasculature patterns are seen in AML bone marrow biopsies, defined by combining number and size of vessel. These quantified morphology patterns, combined with VEGFA levels, might be of value in the success of VEGF/VEGFR-signaling interference approaches

Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas

HER-2/neu gene amplification and cell surface overexpression are important factors in breast cancer for prognosis and prediction of sensitivity to anti-HER-2/neu monoclonal antibody therapy. In lung cancer, the clinical significance of HER-2/neu expression is currently under evaluation. We investigated 238 non-small lung carcinomas for HER-2/neu protein overexpression by immunohistochemistry using the HercepTest. We found 2+ or 3+ overexpression in 39 patients (16%), including 35% in adenocarcinomas and 20% in large cell carcinomas, but only 1% of squamous cell carcinomas. Marked (3+) overexpression was uncommon (4%). The association between protein expression and gene copy number per cell, as determined by fluorescence in situ hybridisation assay, was investigated in 51 of these NSCLC tumours. Twenty-seven tumours (53%) were negative by both tests. Marked (3+) protein expression and gene amplification were present in only 4% of samples. In 11 tumours (21%), gene gain was accompanied by chromosomal aneusomy and did not result in high protein levels while in 7 (14%) the score 2+ was associated with maximum number of signals per cell <9. The prognostic implication of HER-2/neu protein expression was studied in 187 surgically resected tumours. No statistical difference in survival was observed comparing patients with positive (2+/3+) and negative tumours (0/1+), although 3+ patients showed a tendency to shorter survival. The therapeutic implications of protein expression and gene amplification in lung cancer need to be examined in prospective clinical trials

Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes

Triglycerides have a limited solubility, around 3%, in phosphatidylcholine lipid bilayers. Using millisecond-scale course grained molecular dynamics simulations, we show that the model lipid bilayer can accommodate a higher concentration of triolein (TO) than earlier anticipated, by sequestering triolein molecules to the bilayer center in the form of a disordered, isotropic, mobile neutral lipid aggregate, at least 17 nm in diameter, which forms spontaneously, and remains stable on at least the microsecond time scale. The results give credence to the hotly debated existence of mobile neutral lipid aggregates of unknown function present in malignant cells, and to the early biogenesis of lipid droplets accommodated between the two leaflets of the endoplasmic reticulum membrane. The TO aggregates give the bilayer a blister-like appearance, and will hinder the formation of multi-lamellar phases in model, and possibly living membranes. The blisters will result in anomalous membrane probe partitioning, which should be accounted for in the interpretation of probe-related measurements

Models of care for musculoskeletal health: A cross-sectional qualitative study of Australian stakeholders' perspectives on relevance and standardised evaluation

Background: The prevalence and impact of musculoskeletal conditions are predicted to rapidly escalate in the coming decades. Effective strategies are required to minimise 'evidence-practice', 'burden-policy' and 'burden-service' gaps and optimise health system responsiveness for sustainable, best-practice healthcare. One mechanism by which evidence can be translated into practice and policy is through Models of Care (MoCs), which provide a blueprint for health services planning and delivery. While evidence supports the effectiveness of musculoskeletal MoCs for improving health outcomes and system efficiencies, no standardised national approach to evaluation in terms of their 'readiness' for implementation and 'success' after implementation, is yet available. Further, the value assigned to MoCs by end users is uncertain. This qualitative study aimed to explore end users' views on the relevance of musculoskeletal MoCs to their work and value of a standardised evaluation approach. Methods: A cross-sectional qualitative study was undertaken. Subject matter experts (SMEs) with health, policy and administration and consumer backgrounds were drawn from three Australian states. A semi-structured interview schedule was developed and piloted to explore perceptions about musculoskeletal MoCs including: i) aspects important to their work (or life, for consumers) ii) usefulness of standardised evaluation frameworks to judge 'readiness' and 'success' and iii) challenges associated with standardised evaluation. Verbatim transcripts were analysed by two researchers using a grounded theory approach to derive key themes. Results: Twenty-seven SMEs (n = 19; 70.4 % female) including five (18.5 %) consumers participated in the study. MoCs were perceived as critical for influencing and initiating changes to best-practice healthcare planning and delivery and providing practical guidance on how to implement and evaluate services. A 'readiness' evaluation framework assessing whether critical components across the health system had been considered prior to implementation was strongly supported, while 'success' was perceived as an already familiar evaluation concept. Perceived challenges associated with standardised evaluation included identifying, defining and measuring key 'readiness' and 'success' indicators; impacts of systems and context changes; cost; meaningful stakeholder consultation and developing a widely applicable framework. Conclusions: A standardised evaluation framework that includes a strong focus on 'readiness' is important to ensure successful and sustainable implementation of musculoskeletal MoCs

On shape dependence of holographic entanglement entropy in AdS4/CFT3

We study the finite term of the holographic entanglement entropy of finite domains with smooth shapes and for four dimensional gravitational backgrounds. Analytic expressions depending on the unit vectors normal to the minimal area surface are obtained for both stationary and time dependent spacetimes. The special cases of AdS4, asymptotically AdS4 black holes, domain wall geometries and Vaidya-AdS backgrounds have been analysed explicitly. When the bulk spacetime is AdS4, the finite term is the Willmore energy of the minimal area surface viewed as a submanifold of the three dimensional flat Euclidean space. For the static spacetimes, some numerical checks involving spatial regions delimited by ellipses and non convex domains have been performed. In the case of AdS4, the infinite wedge has been also considered, recovering the known analytic formula for the coefficient of the logarithmic divergence