Can multiple lifestyle behaviours be improved in people with familial hypercholesterolemia? Results of a parallel randomised controlled trial

Objective: To evaluate the efficacy of an individualised tailored lifestyle intervention on physical activity, dietary intake, smoking and compliance to statin therapy in people with Familial Hypercholesterolemia (FH). Methods: Adults with FH (n = 340) were randomly assigned to a usual care control group or an intervention group. The intervention consisted of web-based tailored lifestyle advice and face-to-face counselling. Physical activity, fat, fruit and vegetable intake, smoking and compliance to statin therapy were self-reported at baseline and after 12 months. Regression analyses were conducted to examine between-group differences. Intervention reach, dose and fidelity were assessed. Results: In both groups, non-significant improvements in all lifestyle behaviours were found. Post-hoc analyses showed a significant decrease in saturated fat intake among women in the intervention group (β = -1.03; CI -1.98/-0.03). In the intervention group, 95% received a log on account, of which 49% logged on and completed one module. Nearly all participants received face-to-face counselling and on average, 4.2 telephone booster calls. Intervention fidelity was low. Conclusions: Individually tailored feedback is not superior to no intervention regarding changes in multiple lifestyle behaviours in people with FH. A higher received dose of computer-tailored interventions should be achieved by uplifting the website and reducing the burden of screening questionnaires. Counsellor training should be more extensive. Trial Registration: Dutch Trial Register NTR1899. © 2012 Broekhuizen et al

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

On recent developments for high-speed atomic force microscopy

The atomic force microscope (AFM) is limited in imaging speed by the bandwidth and dynamic behavior of the actuators and mechanical parts. For high-speed imaging all AFM components have to be optimized in performance. Here, we present improvements of the force sensor, the scanner, the controller, and the data acquisition system. By combining all these improvements, the next generation AFMs will enable imaging speeds more than two orders of magnitude faster than current commercial AFM systems

Novel techniques for high-resolution functional imaging of trabecular bone

In current biological and biomedical research, quantitative endpoints have become an important factor of success. Classically, such endpoints were investigated with 2D imaging, which is usually destructive and the 3D character of tissue gets lost. 3D imaging has gained in importance as a tool for both, qualitative and quantitative assessment of biological systems. In this context synchrotron radiation based tomography has become a very effective tool for opaque 3D tissue systems. Results from a new device are presented enabling the 3D investigation of trabecular bone under mechanical load in a time-lapsed fashion. Using the highly brilliant X-rays from a synchrotron radiation source, bone microcracks and an indication for un-cracked ligament bridging are uncovered. 3D microcrack analysis proves that the classification of microcracks from 2D images is ambiguous. Fatigued bone was found to fail in burst-like fashion, whereas non-fatigued bone exhibited a distinct failure band. Additionally, a higher increase in microcrack volume was detected in fatigued in comparison to non-fatigued bone. Below the spatial resolution accessible with synchrotron radiation tomography we investigated native and fractured bone surfaces on the molecular scale with atomic force microscopy. The mineralized fibrils detected on fracture surfaces give rise to the assumption that the mineral-mineral interface is the weakest link in bone. The presented results show the power of functional micro-imaging, as well as the possibilities for AFM imaging (functional nano-imaging) in this context

Evidence that Collagen Fibrils in Tendons Are Inhomogeneously Structured in a Tubelike Manner

The standard model for the structure of collagen in tendon is an ascending hierarchy of bundling. Collagen triple helices bundle into microfibrils, microfibrils bundle into subfibrils, and subfibrils bundle into fibrils, the basic structural unit of tendon. This model, developed primarily on the basis of x-ray diffraction results, is necessarily vague about the cross-sectional organization of fibrils and has led to the widespread assumption of laterally homogeneous closepacking. This assumption is inconsistent with data presented here. Using atomic force microscopy and micromanipulation, we observe how collagen fibrils from tendons behave mechanically as tubes. We conclude that the collagen fibril is an inhomogeneous structure composed of a relatively hard shell and a softer, less dense core