Mechanics of Intact Bone Marrow

The current knowledge of bone marrow mechanics is limited to its viscous properties, neglecting the elastic contribution of the extracellular matrix. To get a more complete view of the mechanics of marrow, we characterized intact yellow porcine bone marrow using three different, but complementary techniques: rheology, indentation, and cavitation. Our analysis shows that bone marrow is elastic, and has a large amount of intra- and inter-sample heterogeneity, with an effective Young’s modulus ranging from 0.25-24.7 kPa at physiological temperature. Each testing method was consistent across matched tissue samples, and each provided unique benefits depending on user needs. We recommend bulk rheology to capture the effects of temperature on tissue elasticity and moduli, indentation for quantifying local tissue heterogeneity, and cavitation rheology for mitigating destructive sample preparation. We anticipate the knowledge of bone marrow elastic properties for building in vitro models will elucidate mechanisms involved in disease progression and regenerative medicin

Cross-Platform Mechanical Characterization of Lung Tissue

Published data on the mechanical strength and elasticity of lung tissue is widely variable, primarily due to differences in how testing was conducted across individual studies. This makes it extremely difficult to find a benchmark modulus of lung tissue when designing synthetic extracellular matrices (ECMs). To address this issue, we tested tissues from various areas of the lung using multiple characterization techniques, including micro-indentation, small amplitude oscillatory shear (SAOS), uniaxial tension, and cavitation rheology. We report the sample preparation required and data obtainable across these unique but complimentary methods to quantify the modulus of lung tissue. We highlight cavitation rheology as a new method, which can measure the modulus of intact tissue with precise spatial control, and reports a modulus on the length scale of typical tissue heterogeneities. Shear rheology, uniaxial, and indentation testing require heavy sample manipulation and destruction; however, cavitation rheology can be performed in situ across nearly all areas of the lung with minimal preparation. The Young’s modulus of bulk lung tissue using micro-indentation (1.4±0.4 kPa), SAOS (3.3±0.5 kPa), uniaxial testing (3.4±0.4 kPa), and cavitation rheology (6.1±1.6 kPa) were within the same order of magnitude, with higher values consistently reported from cavitation, likely due to our ability to keep the tissue intact. Although cavitation rheology does not capture the non-linear strains revealed by uniaxial testing and SAOS, it provides an opportunity to measure mechanical characteristics of lung tissue on a microscale level on intact tissues. Overall, our study demonstrates that each technique has independent benefits, and each technique revealed unique mechanical features of lung tissue that can contribute to a deeper understanding of lung tissue mechanics

The Long-Term Consequences of the Global 1918 Influenza Pandemic: A Systematic Analysis of 117 IPUMS International Census Data Sets

Several country-level studies, including a prominent one for the United States, have identified long-term effects of in-utero exposure to the 1918 influenza pandemic (also known as the Spanish Flu) on economic outcomes in adulthood. In-utero conditions are theoretically linked to adult health and socioeconomic status through the fetal origins or Barker hypothesis. Historical exposure to the Spanish Flu provides a natural experiment to test this hypothesis. Although the Spanish Flu was a global phenomenon, with around 500 million people infected worldwide, there exists no comprehensive global study on its long-term economic effects. We attempt to close this gap by systematically analyzing 117 Census data sets provided by IPUMS International. We do not find consistent global long-term effects of influenza exposure on education, employment and disability outcomes. A series of robustness checks does not alter this conclusion. Our findings indicate that the existing evidence on long-term economic effects of the Spanish Flu is likely a consequence of publication bias

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

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

High Strength Reversible Adhesive Closures

Closures such as buttons, clasps, zippers, and hook-and-loops find widespread use in daily life, and all work by mechanical interlocking. However, these traditional closures are often rigid, lose performance with age, and can produce a harsh sound during use. Here high strength (> 50 N cm(-2)), reusable, and nearly silent closure devices are fabricated based on recently developed fibril-less gecko-inspired adhesives. Guided by a reversible adhesion scaling law, the closure force capacity is tuned by modifying the closure materials and geometry. A simple analytical model is presented which accurately predicts system performance, based on the reversible adhesion scaling parameter. The force capacity of these adhesive closures is measured and compared to commercially-available hook-and-loop closures, and it is found that the adhesive closures sustain forces that are 4.4 times greater for comparable geometry. The sound of release is also quantified and shown to be minimal for adhesive closures. This work provides motivation to develop new high strength, reusable closures for commercial and industrial applications

Scaling Normal Adhesion Force Capacity with a Generalized Parameter

The adhesive response of a rigid flat cylindrical indenter in contact with a compliant elastic layer of varying confinement is investigated experimentally and described analytically. Using a soft elastic gel with substrate thickness, <i>t</i>, and indenter radius, <i>a</i>, 28 unique combinations of the confinement parameter, <i>a</i>/<i>t</i>, are examined over a range of 0.016 < <i>a</i>/<i>t</i> < 7.2. Continuous force capacity predictions as a function of <i>a</i>/<i>t</i> and material properties are provided through a scaling theory and are found to agree well with the experimental data. We further collapse all of the data over orders of magnitude in adhesive force capacity onto a single line described by a generalized reversible adhesion scaling parameter, <i>A</i>/<i>C</i>, where <i>A</i> is the contact area and <i>C</i> is the compliance. As the scaling analysis does not assume a specific separation mechanism the adhesive force capacity is well described during both axisymmetric edge separation and during interfacial fingering and cavitation instabilities. We discuss how the geometry of the contact, specifically increasing the degree of confinement, allows reversible adhesive materials to be designed that are not “sticky” or “tacky”, yet can be very strong and provide high performance

Scaling Normal Adhesion Force Capacity with a Generalized Parameter

The adhesive response of a rigid flat cylindrical indenter in contact with a compliant elastic layer of varying confinement is investigated experimentally and described analytically. Using a soft elastic gel with substrate thickness, <i>t</i>, and indenter radius, <i>a</i>, 28 unique combinations of the confinement parameter, <i>a</i>/<i>t</i>, are examined over a range of 0.016 < <i>a</i>/<i>t</i> < 7.2. Continuous force capacity predictions as a function of <i>a</i>/<i>t</i> and material properties are provided through a scaling theory and are found to agree well with the experimental data. We further collapse all of the data over orders of magnitude in adhesive force capacity onto a single line described by a generalized reversible adhesion scaling parameter, <i>A</i>/<i>C</i>, where <i>A</i> is the contact area and <i>C</i> is the compliance. As the scaling analysis does not assume a specific separation mechanism the adhesive force capacity is well described during both axisymmetric edge separation and during interfacial fingering and cavitation instabilities. We discuss how the geometry of the contact, specifically increasing the degree of confinement, allows reversible adhesive materials to be designed that are not “sticky” or “tacky”, yet can be very strong and provide high performance

Mechanics of Intact Bone Marrow

The current knowledge of bone marrow mechanics is limited to its viscous properties, neglecting the elastic contribution of the extracellular matrix. To get a more complete view of the mechanics of marrow, we characterized intact yellow porcine bone marrow using three different, but complementary techniques: rheology, indentation, and cavitation. Our analysis shows that bone marrow is elastic, and has a large amount of intra- and inter-sample heterogeneity, with an effective Young’s modulus ranging from 0.25-24.7 kPa at physiological temperature. Each testing method was consistent across matched tissue samples, and each provided unique benefits depending on user needs. We recommend bulk rheology to capture the effects of temperature on tissue elasticity and moduli, indentation for quantifying local tissue heterogeneity, and cavitation rheology for mitigating destructive sample preparation. We anticipate the knowledge of bone marrow elastic properties for building in vitro models will elucidate mechanisms involved in disease progression and regenerative medicin