Dendritic cells process synthetic long peptides better than whole protein,improving antigen presentation and T‐cell activation

The efficiency of antigen (Ag) processing by dendritic cells (DCs) is vital for the strength of the ensuing T‐cell responses. Previously, we and others have shown that in comparison to protein vaccines, vaccination with synthetic long peptides (SLPs) has shown more promising (pre‐)clinical results. Here, we studied the unknown mechanisms underlying the observed vaccine efficacy of SLPs. We report an in vitro processing analysis of SLPs for MHC class I and class II presentation by murine DCs and human monocyte‐derived DCs. Compared to protein, SLPs were rapidly and much more efficiently processed by DCs, resulting in an increased presentation to CD4⁺ and CD8⁺ T cells. The mechanism of access to MHC class I loading appeared to differ between the two forms of Ag. Whereas whole soluble protein Ag ended up largely in endolysosomes, SLPs were detected very rapidly outside the endolysosomes after internalization by DCs, followed by proteasome‐ and transporter associated with Ag processing‐dependent MHC class I presentation. Compared to the slower processing route taken by whole protein Ags, our results indicate that the efficient internalization of SLPs, accomplished by DCs but not by B or T cells and characterized by a different and faster intracellular routing, leads to enhanced CD8⁺ T‐cell activation.     

Photochromic organic solar cells based on diarylethenes

Photovoltaic devices that switch color depending on illumination conditions may find application in future smart window applications. Here a photochromic diarylethene molecule is used as sensitizer in a ternary bulk heterojunction blend, employing poly(4-butylphenyldiphenylamine) (poly-TPD) and [6,6]-phenyl-C₆₁-butyric acid methyl ester (PC₆₁BM) for the transport of holes and electrons, respectively. Sandwiched between two electrodes, the blend creates a photochromic photovoltaic device that changes color, light absorption, and photon-to-electron conversion efficiency in the visible spectral range after having been illuminated with UV light.

A diarylethene dye that reversibly changes color upon illumination is used in a switchable photochromic organic solar cell.     

Previously identified patellar tendinopathy risk factors differ between elite and sub‐elite volleyball players

Patellar tendinopathy is the most common knee injury incurred in volleyball, with its prevalence in elite athletes more than three times that of their sub‐elite counterparts. The purpose of this study was to determine whether patellar tendinopathy risk factors differed between elite and sub‐elite male volleyball players. Nine elite and nine sub‐elite male volleyball players performed a lateral stop–jump block movement. Maximum vertical jump, training history, muscle extensibility and strength, three‐dimensional landing kinematics (250 Hz), along with lower limb neuromuscular activation patterns (1500 Hz), and patellar tendon loading were collected during each trial. Multivariate analyses of variance (P < 0.05) assessed for between‐group differences in risk factors or patellar tendon loading. Significant interaction effects were further evaluated using post‐hoc univariate analysis of variance tests. Landing kinematics, neuromuscular activation patterns, patellar tendon loading, and most of the previously identified risk factors did not differ between the elite and sub‐elite players. However, elite players participated in a higher training volume and had less quadriceps extensibility than sub‐elite players. Therefore, high training volume is likely the primary contributor to the injury discrepancy between elite and sub‐elite volleyball players. Interventions designed to reduce landing frequency and improve quadriceps extensibility are recommended to reduce patellar tendinopathy prevalence in volleyball players.     

2015 Marshall Urist Young Investigator Award: Prognostication in Patients With Long Bone Metastases: Does a Boosting Algorithm Improve Survival Estimates?

Background

Survival estimation guides surgical decision-making in metastatic bone disease. Traditionally, classic scoring systems, such as the Bauer score, provide survival estimates based on a summary score of prognostic factors. Identification of new factors might improve the accuracy of these models. Additionally, the use of different algorithms—nomograms or boosting algorithms—could further improve accuracy of prognostication relative to classic scoring systems. A nomogram is an extension of a classic scoring system and generates a more-individualized survival probability based on a patient’s set of characteristics using a figure. Boosting is a method that automatically trains to classify outcomes by applying classifiers (variables) in a sequential way and subsequently combines them. A boosting algorithm provides survival probabilities based on every possible combination of variables.

Questions/purposes

We wished to (1) assess factors independently associated with decreased survival in patients with metastatic long bone fractures and (2) compare the accuracy of a classic scoring system, nomogram, and boosting algorithms in predicting 30-, 90-, and 365-day survival.

Methods

We included all 927 patients in our retrospective study who underwent surgery for a metastatic long bone fracture at two institutions between January 1999 and December 2013. We included only the first procedure if patients underwent multiple surgical procedures or had more than one fracture. Median followup was 8 months (interquartile range, 3-25 months); 369 of 412 (90%) patients who where alive at 1 year were still in followup. Multivariable Cox regression analysis was used to identify clinical and laboratory factors independently associated with decreased survival. We created a classic scoring system, nomogram, and boosting algorithms based on identified variables. Accuracy of the algorithms was assessed using area under the curve analysis through fivefold cross validation.

Results

The following factors were associated with a decreased likelihood of survival after surgical treatment of a metastatic long bone fracture, after controlling for relevant confounding variables: older age (hazard ratio [HR], 1.0; 95% CI, 1.0–1.0; p < 0.001), additional comorbidity (HR, 1.2; 95% CI, 1.0–1.4; p = 0.034), BMI less than 18.5 kg/m² (HR, 2.0; 95% CI, 1.2–3.5; p = 0.011), tumor type with poor prognosis (HR, 1.8; 95% CI, 1.6–2.2; p < 0.001), multiple bone metastases (HR, 1.3; 95% CI, 1.1–1.6; p = 0.008), visceral metastases (HR, 1.6; 95% CI, 1.4–1.9; p < 0.001), and lower hemoglobin level (HR, 0.91; 95% CI, 0.87–0.96; p < 0.001). The survival estimates by the nomogram were moderately accurate for predicting 30-day (area under the curve [AUC], 0.72), 90-day (AUC, 0.75), and 365-day (AUC, 0.73) survival and remained stable after correcting for optimism through fivefold cross validation. Boosting algorithms were better predictors of survival on the training datasets, but decreased to a performance level comparable to the nomogram when applied on testing datasets for 30-day (AUC, 0.69), 90-day (AUC, 0.75), and 365-day (AUC, 0.72) survival prediction. Performance of the classic scoring system was lowest for all prediction periods.

Conclusions

Comorbidity status and BMI are newly identified factors associated with decreased survival and should be taken into account when estimating survival. Performance of the boosting algorithms and nomogram were comparable on the testing datasets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision making in clinical practice.

Level of Evidence

Level III, prognostic study.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-015-4446-z) contains supplementary material, which is available to authorized users.     

Inhibitory receptor molecules in chronic hepatitis B and C infections: novel targets for immunotherapy?

Chronic HBV and HCV infections are the leading cause of liver‐related morbidity and mortality. For effective antiviral immunity, virus‐specific T cells are required, but these cells have been shown to be weak or absent in chronic HBV and HCV patients. One of the mechanisms that underlies the impaired T‐cell response is the result of the continuously high viral load that causes HBV‐specific and HCV‐specific T cells to become exhausted, which is characterized by impaired proliferation, cytokine production and cytotoxic activity of T cells as well as high susceptibility to apoptosis. In vitro studies from chronic HBV and HCV patients as well as in vivo studies in animal models demonstrated a reversible state of T‐cell exhaustion, which can be manipulated to reinvigorate the specific antiviral immune responses. In chronic HCV infection, this concept has been explored in clinical trials by administration of specific antibody to block the inhibitory pathways. The manipulation of inhibitory receptors is a promising and potential strategy for immunotherapeutic interventions in chronic HBV and HCV patients to facilitate complete elimination of the viruses or sustained viral control. Copyright © 2013 John Wiley & Sons, Ltd.     

Correlates of 15-Year Maintenance of Physical Activity in Middle-Aged Women

Background

Interventions to increase sustained physical activity are needed and should be based on proven theories.

Purpose

To gain a better understanding of the correlates of sustained physical activity in midlife women, we used longitudinal epidemiologic data to investigate links between sustained physical activity and constructs advocated by three basic behavioral and social science theories: (1) self-determination, (2) social cognitive, and (3) social networks. A random sample of 90 midlife women, stratified by level of physical activity over 15 years, was selected from the Chicago cohort of the Longitudinal Study of Women’s Health Across the Nation (SWAN).

Methods

Using data on self-reported physical activity collected over 15 years, women were categorized into consistently active, sporadically active, and sedentary. New data were collected on theory-relevant constructs, i.e., autonomous motivation (assessed by the Treatment Self-Regulation Questionnaire) and self-efficacy (assessed by the Self-Efficacy and Exercise Habits Survey). Every SWAN woman identified a close female friend who also completed the physical activity questionnaire.

Results

SWAN women with higher autonomous motivation (p?=?0.002) and higher self-efficacy (p?<?0.001) were more likely to be consistently physically active in analyses adjusted for age, race, and socioeconomic status. Sixty-one percent of SWAN women with a history of consistent physical activity had a friend who is currently highly active, versus 38 and 23 % for sporadically active and sedentary women, respectively (test for trend p?=?0.008).

Conclusion

In midlife women, constructs advocated by basic behavioral and social science theories were consistent with long-term patterns of physical activity behavior. Special focus should be given to these basic theories in the design of interventions to promote sustained physical activity in mid-life women.