Dynamic Failure Properties of the Porcine Medial Collateral Ligament-Bone Complex for Predicting Injury in Automotive Collisions

The goal of this study was to model the dynamic failure properties of ligaments and their attachment sites to facilitate the development of more realistic dynamic finite element models of the human lower extremities for use in automotive collision simulations. Porcine medial collateral ligaments were chosen as a test model due to their similarities in size and geometry with human ligaments. Each porcine medial collateral ligament-bone complex (n = 12) was held in a custom test fixture placed in a drop tower to apply an axial impulsive impact load, applying strain rates ranging from 0.005 s-1 to 145 s-1. The data from the impact tests were analyzed using nonlinear regression to construct model equations for predicting the failure load of ligament-bone complexes subjected to specific strain rates as calculated from finite element knee, thigh, and hip impact simulations. The majority of the ligaments tested failed by tibial avulsion (75%) while the remaining ligaments failed via mid-substance tearing. The failure load ranged from 384 N to 1184 N and was found to increase with the applied strain rate and the product of ligament length and cross-sectional area. The findings of this study indicate the force required to rupture the porcine MCL increases with the applied bone-to-bone strain rate in the range expected from high speed frontal automotive collisions

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Drug discovery prospect from untapped species: Indications from approved natural product drugs

10.1371/journal.pone.0039782PLoS ONE77

The Ontario Mother and Infant Study (TOMIS) III: A multi-site cohort study of the impact of delivery method on health, service use, and costs of care in the first postpartum year

Abstract Background The caesarean section rate continues to rise globally. A caesarean section is inarguably the preferred method of delivery when there is good evidence that a vaginal delivery may unduly risk the health of a woman or her infant. Any decisions about delivery method in the absence of clear medical indication should be based on knowledge of outcomes associated with different childbirth methods. However, there is lack of sold evidence of the short-term and long-term risks and benefits of a planned caesarean delivery compared to a planned vaginal delivery. It also is important to consider the economic aspects of caesarean sections, but very little attention has been given to health care system costs that take into account services used by women for themselves and their infants following hospital discharge. Methods and design The Ontario Mother and Infant Study III is a prospective cohort study to examine relationships between method of delivery and maternal and infant health, service utilization, and cost of care at three time points during the year following postpartum hospital discharge. Over 2500 women were recruited from 11 hospitals across the province of Ontario, Canada, with data collection occurring between April 2006 and October 2008. Participants completed a self-report questionnaire in hospital and structured telephone interviews at 6 weeks, 6 months, and 12 months after discharge. Data will be analyzed using generalized estimating equation, a special generalized linear models technique. A qualitative descriptive component supplements the survey approach, with the goal of assisting in interpretation of data and providing explanations for trends in the findings. Discussion The findings can be incorporated into patient counselling and discussions about the advantages and disadvantages of different delivery methods, potentially leading to changes in preferences and practices. In addition, the findings will be useful to hospital- and community-based postpartum care providers, managers, and administrators in guiding risk assessment and early intervention strategies. Finally, the research findings can provide the basis for policy modification and implementation strategies to improve outcomes and reduce costs of care