Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Disability and the Immigrant Health Paradox: Gender and Timing of Migration

Although research has documented better health and longer life expectancy among the foreign-born relative to their U.S.-born counterparts, the U.S. Mexican-origin immigrant population is diverse and the healthy immigrant effect likely varies by key structural and demographic factors such as gender, migration history, and duration in the United States. Using a life course framework, we use data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly (H-EPESE 1993–2013) which includes Mexican-American individuals aged 65 and older to assess the heterogeneity in the immigrant health advantage by age of migration and gender. We find that age of migration is an important delineating factor for disability among both men and women. The healthy immigrant hypothesis is only observable among mid- and late-life migrant men for ADL disability. While among immigrant women, late-life migrants are more likely to have an IADL disability putting them at a health disadvantage. These findings illustrate that Mexican immigrants are not a homogeneous group and migrant health selectivity depends on both gender and when migrants arrived in the United States

Moths Behaving like Butterflies. Evolutionary Loss of Long Range Attractant Pheromones in Castniid Moths: A Paysandisia archon Model

Background: In the course of evolution butterflies and moths developed two different reproductive behaviors. Whereas butterflies rely on visual stimuli for mate location, moths use the"female calling plus male seduction" system, in which females release long-range sex pheromones to attract conspecific males. There are few exceptions from this pattern but in all cases known female moths possess sex pheromone glands which apparently have been lost in female butterflies. In the day-flying moth family Castniidae ("butterfly-moths"), which includes some important crop pests, no pheromones have been found so far. Methodology/Principal Findings: Using a multidisciplinary approach we described the steps involved in the courtship of P. archon, showing that visual cues are the only ones used for mate location; showed that the morphology and fine structure of the antennae of this moth are strikingly similar to those of butterflies, with male sensilla apparently not suited to detect female-released long range pheromones; showed that its females lack pheromone-producing glands, and identified three compounds as putative male sex pheromone (MSP) components of P. archon, released from the proximal halves of male forewings and hindwings. Conclusions/Significance: This study provides evidence for the first time in Lepidoptera that females of a moth do not produce any pheromone to attract males, and that mate location is achieved only visually by patrolling males, which may release a pheromone at short distance, putatively a mixture of Z,E-farnesal, E,E-farnesal, and (E,Z)-2,13-octadecadienol. The outlined behavior, long thought to be unique to butterflies, is likely to be widespread in Castniidae implying a novel, unparalleled butterfly-like reproductive behavior in moths. This will also have practical implications in applied entomology since it signifies that the monitoring/control of castniid pests should not be based on the use of female-produced pheromones, as it is usually done in many moths

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

Functional Characterization of MODY2 Mutations Highlights the Importance of the Fine-Tuning of Glucokinase and Its Role in Glucose Sensing

Glucokinase (GK) acts as a glucose sensor in the pancreatic beta-cell and regulates insulin secretion. Heterozygous mutations in the human GK-encoding GCK gene that reduce the activity index increase the glucose-stimulated insulin secretion threshold and cause familial, mild fasting hyperglycaemia, also known as Maturity Onset Diabetes of the Young type 2 (MODY2). Here we describe the biochemical characterization of five missense GK mutations: p.Ile130Thr, p.Asp205His, p.Gly223Ser, p.His416Arg and p.Ala449Thr. The enzymatic analysis of the corresponding bacterially expressed GST-GK mutant proteins show that all of them impair the kinetic characteristics of the enzyme. In keeping with their position within the protein, mutations p.Ile130Thr, p.Asp205His, p.Gly223Ser, and p.His416Arg strongly decrease the activity index of GK, affecting to one or more kinetic parameters. In contrast, the p.Ala449Thr mutation, which is located in the allosteric activator site, does not affect significantly the activity index of GK, but dramatically modifies the main kinetic parameters responsible for the function of this enzyme as a glucose sensor. The reduced Kcat of the mutant (3.21±0.28 s−1 vs 47.86±2.78 s−1) is balanced by an increased glucose affinity (S0.5 = 1.33±0.08 mM vs 7.86±0.09 mM) and loss of cooperativity for this substrate. We further studied the mechanism by which this mutation impaired GK kinetics by measuring the differential effects of several competitive inhibitors and one allosteric activator on the mutant protein. Our results suggest that this mutation alters the equilibrium between the conformational states of glucokinase and highlights the importance of the fine-tuning of GK and its role in glucose sensing

Right ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity and functional class

BACKGROUND: Abnormalities in right ventricular function are known to occur in patients with pulmonary arterial hypertension. OBJECTIVE: Test the hypothesis that chronic elevation in pulmonary artery systolic pressure delays mechanical activation of the right ventricle, termed dyssynchrony, and is associated with both symptoms and right ventricular dysfunction. METHODS: Fifty-two patients (mean age 46 ± 15 years, 24 patients with chronic pulmonary hypertension) were prospectively evaluated using several echocardiographic parameters to assess right ventricular size and function. In addition, tissue Doppler imaging was also obtained to assess longitudinal strain of the right ventricular wall, interventricular septum, and lateral wall of the left ventricle and examined with regards to right ventricular size and function as well as clinical variables. RESULTS: In this study, patients with chronic pulmonary hypertension had statistically different right ventricular fractional area change (35 ± 13 percent), right ventricular end-systolic area (21 ± 10 cm(2)), right ventricular Myocardial Performance Index (0.72 ± 0.34), and Eccentricity Index (1.34 ± 0.37) than individuals without pulmonary hypertension (51 ± 5 percent, 9 ± 2 cm(2), 0.27 ± 0.09, and 0.97 ± 0.06, p < 0.005, respectively). Furthermore, peak longitudinal right ventricular wall strain in chronic pulmonary hypertension was also different -20.8 ± 9.0 percent versus -28.0 ± 4.1 percent, p < 0.01). Right ventricular dyssynchrony correlated very well with right ventricular end-systolic area (r = 0.79, p < 0.001) and Eccentricity Index (r = 0.83, p < 0.001). Furthermore, right ventricular dyssynchrony correlates with pulmonary hypertension severity index (p < 0.0001), World Health Organization class (p < 0.0001), and number of hospitalizations (p < 0.0001). CONCLUSION: Lower peak longitudinal right ventricular wall strain and significantly delayed time-to-peak strain values, consistent with right ventricular dyssynchrony, were found in a small heterogeneous group of patients with chronic pulmonary hypertension when compared to individuals without pulmonary hypertension. Furthermore, right ventricular dyssynchrony was associated with disease severity and compromised functional class

The effect of social relationships on survival in elderly residents of a Southern European community: a cohort study

<p>Abstract</p> <p>Background</p> <p>Comparative evidence regarding the effects of social relationships on mortality in Mediterranean communities will increase our knowledge of their strengths and the ways in which they influence longevity across cultures. Men and women may benefit differently from social relationships because of cultural differences in gender roles. Psychosocial mechanisms such as social support, which may explain the effects of social networks, may also vary by culture.</p> <p>Methods</p> <p>Detailed information on the social relationships of a representative sample of 1,174 community-dwelling older adults was collected in Leganés, a city in central Spain. Mortality over a 6-year follow-up period was ascertained. Information on socio-demographic, health and disability variables was also collected. Cox proportional hazards models were fitted separately for men and women and for the combined sample.</p> <p>Results</p> <p>Having a confidant was associated with a 25% (95% CI 5–40%) reduction in the mortality risk. The hazard ratio for lack of social participation was 1.5 (95% CI 1.3–1.7). Being engaged in meaningful roles protected against mortality, while receipt of emotional support did not affect survival. These results were comparable for men and women. Having contact with all family ties was associated with reduced mortality only in men. Structural aspects of social networks make a unique contribution to survival, independently of emotional support and the role played in the lives of significant others.</p> <p>Conclusion</p> <p>In this elderly Southern European population, the beneficial effects of social networks, social participation, engagement in the life of significant others and having a confidant call for public policies that foster intergenerational and community exchanges.</p

Utility of a thematic network in primary health care: a controlled interventional study in a rural area

BACKGROUND: UniNet is an Internet-based thematic network for a virtual community of users (VCU). It supports a virtual multidisciplinary community for physicians, focused on the improvement of clinical practice. This is a study of the effects of a thematic network such as UniNet on primary care medicine in a rural area, specifically as a platform of communication between specialists at the hospital and doctors in the rural area. METHODS: In order to study the effects of a thematic network such as UniNet on primary care medicine in a rural area, we designed an interventional study that included a control group. The measurements included the number of patient displacements due to disease, number of patient hospital stays and the number of prescriptions of drugs of low therapeutic utility and generic drug prescriptions by doctors. These data were analysed and compared with those of the control center. RESULTS: Our study showed positive changes in medical practice, reflected in the improvement of the evaluated parameters in the rural health area where the interventional study was carried out, compared with the control area. We discuss the strengths and weaknesses of UniNet as a potential medium to improve the quality of medical care in rural areas. CONCLUSION: The rural doctors had an effective, useful, user-friendly and cheap source of medical information that may have contributed to the improvement observed in the medical quality indices

Twelve experiments in restorative justice: the Jerry Lee program of randomized trials of restorative justice conferences

Objectives: We conducted and measured outcomes from the Jerry Lee Program of 12 randomized trials over two decades in Australia and the United Kingdom (UK), testing an identical method of restorative justice taught by the same trainers to hundreds of police officers and others who delivered it to 2231 offenders and 1179 victims in 1995–2004. The article provides a review of the scientific progress and policy effects of the program, as described in 75 publications and papers arising from it, including previously unpublished results of our ongoing analyses. Methods: After random assignment in four Australian tests diverting criminal or juvenile cases from prosecution to restorative justice conferences (RJCs), and eight UK tests of supplementing criminal or juvenile proceedings with RJCs, we followed intention-to-treat group differences between offenders for up to 18 years, and for victims up to 10 years. Results: We distil and modify prior research reports into 18 updated evidence-based conclusions about the effects of RJCs on both victims and offenders. Initial reductions in repeat offending among offenders assigned to RJCs (compared to controls) were found in 10 of our 12 tests. Nine of the ten successes were for crimes with personal victims who participated in the RJCs, with clear benefits in both short- and long-term measures, including less prevalence of post-traumatic stress symptoms. Moderator effects across and within experiments showed that RJCs work best for the most frequent and serious offenders for repeat offending outcomes, with other clear moderator effects for poly-drug use and offense seriousness. Conclusions: RJ conferences organized and led (most often) by specially-trained police produced substantial short-term, and some long-term, benefits for both crime victims and their offenders, across a range of offense types and stages of the criminal justice processes on two continents, but with important moderator effects. These conclusions are made possible by testing a new kind of justice on a programmatic basis that would allow prospective meta-analysis, rather than doing one experiment at a time. This finding provides evidence that funding agencies could get far more evidence for the same cost from programs of identical, but multiple, RCTs of the identical innovative methods, rather than funding one RCT at a time

Gait kinematic analysis in patients with a mild form of central cord syndrome

<p>Abstract</p> <p>Background</p> <p>Central cord syndrome (CCS) is considered the most common incomplete spinal cord injury (SCI). Independent ambulation was achieved in 87-97% in young patients with CCS but no gait analysis studies have been reported before in such pathology. The aim of this study was to analyze the gait characteristics of subjects with CCS and to compare the findings with a healthy age, sex and anthropomorphically matched control group (CG), walking both at a self-selected speed and at the same speed.</p> <p>Methods</p> <p>Twelve CCS patients and a CG of twenty subjects were analyzed. Kinematic data were obtained using a three-dimensional motion analysis system with two scanner units. The CG were asked to walk at two different speeds, at a self-selected speed and at a slower one, similar to the mean gait speed previously registered in the CCS patient group. Temporal, spatial variables and kinematic variables (maximum and minimum lower limb joint angles throughout the gait cycle in each plane, along with the gait cycle instants of occurrence and the joint range of motion - ROM) were compared between the two groups walking at similar speeds.</p> <p>Results</p> <p>The kinematic parameters were compared when both groups walked at a similar speed, given that there was a significant difference in the self-selected speeds (p < 0.05). Hip abduction and knee flexion at initial contact, as well as minimal knee flexion at stance, were larger in the CCS group (p < 0.05). However, the range of knee and ankle motion in the sagittal plane was greater in the CG group (p < 0.05). The maximal ankle plantar-flexion values in stance phase and at toe off were larger in the CG (p < 0.05).</p> <p>Conclusions</p> <p>The gait pattern of CCS patients showed a decrease of knee and ankle sagittal ROM during level walking and an increase in hip abduction to increase base of support. The findings of this study help to improve the understanding how CCS affects gait changes in the lower limbs.</p