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

Reconceptualizing Profit-Orientation in Management: A Karmic View on "Return on Investment" Calculations

From the perspective of the present day, Puritan-inspired capitalism seems to have succeeded globally, including in India. Connected to this, short-term profit-orientation in management seems to constrain the scope of different management approaches in a tight ideological corset. This article discusses the possibility of replacing this Puritan doctrine with the crucial elements of Indian philosophy: Karma and samsara. In doing so, the possibility of revising the guiding principles in capitalist management becomes conceivable, namely the monetary focus of profit-orientation and its short-term orientation. This perspective allows a detachment of the concept of profit from the realm of money, as the seemingly only objectifiable measure of profit. Furthermore it allows a removal of the expectation that every "investment" has to directly "pay off". A karmic view offers management a possible facility for being more caring about the needs and fates of other stakeholders, as profit-orientation would no longer be attached as a factual constraint to merely accumulate money. (author's abstract

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Assessing mechanical integrity of spinal fusion by in situ endochondral osteoinduction in the murine model

<p>Abstract</p> <p>Background</p> <p>Historically, radiographs, micro-computed tomography (micro-CT) exams, palpation and histology have been used to assess fusions in a mouse spine. The objective of this study was to develop a faster, cheaper, reproducible test to directly quantify the mechanical integrity of spinal fusions in mice.</p> <p>Methods</p> <p>Fusions were induced in ten mice spine using a previously described technique of in situ endochondral ossification, harvested with soft tissue, and cast in radiolucent alginate material for handling. Using a validated software package and a customized mechanical apparatus that flexed and extended the spinal column, the amount of intervertebral motion between adjacent vertebral discs was determined with static flexed and extended lateral spine radiographs. Micro-CT images of the same were also blindly reviewed for fusion.</p> <p>Results</p> <p>Mean intervertebral motion between control, non-fused, spinal vertebral discs was 6.1 ± 0.2° during spine flexion/extension. In fusion samples, adjacent vertebrae with less than 3.5° intervertebral motion had fusions documented by micro-CT inspection.</p> <p>Conclusions</p> <p>Measuring the amount of intervertebral rotation between vertebrae during spine flexion/extension is a relatively simple, cheap (<$100), clinically relevant, and fast test for assessing the mechanical success of spinal fusion in mice that compared favorably to the standard, micro-CT.</p

Habitat use at fine spatial scale: how does patch clustering criteria explain the use of meadows by red deer ?

Large mammalian herbivores are keystone species in different ecosystems. To mediate the effects of large mammalian herbivores on ecosystems, it is crucial to understand their habitat selection pattern. At finer scales, herbivore patch selection depends strongly on plant community traits and therefore its understanding is constrained by patch definition criteria. Our aim was to assess which criteria for patch definition best explained use of meadows by wild, free-ranging, red deer (Cervus elaphus) in a study area in Northeast Portugal. We used two clustering criteria types based on floristic composition and gross forage classes, respectively. For the floristic criteria, phytosociological approach was used to classify plant communities, and its objectivity evaluated with a mathematical clustering of the floristic relevés. Cover of dominant plant species was tested as a proxy for the phytosociological method. For the gross forage classes, the graminoids/forbs ratio and the percentage cover of legumes were used. For assessing deer relative use of meadows we used faecal accumulation rates. Patches clustered according to floristic classification better explained selection of patches by deer. Plant community classifications based on phytosociology, or proxies of this, used for characterizing meadow patches resulted useful to understand herbivore selection pattern at fine scales and thus potentially suitable to assist wildlife management decisions

Impact of resilience enhancing programs on youth surviving the Beslan school siege

The objective of this study was to evaluate a resilience-enhancing program for youth (mean age = 13.32 years) from Beslan, North Ossetia, in the Russian Federation. The program, offered in the summer of 2006, combined recreation, sport, and psychosocial rehabilitation activities for 94 participants, 46 of who were taken hostage in the 2004 school tragedy and experienced those events first hand. Self-reported resilience, as measured by the CD-RISC, was compared within subjects at the study baseline and at two follow-up assessments: immediately after the program and 6 months later. We also compared changes in resilience levels across groups that differed in their traumatic experiences. The results indicate a significant intra-participant mean increase in resilience at both follow-up assessments, and greater self-reported improvements in resilience processes for participants who experienced more trauma events

Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

Research articl

Importance of TP53 codon 72 and intron 3 duplication 16bp polymorphisms in prediction of susceptibility on breast cancer

<p>Abstract</p> <p>Background</p> <p><it>TP53 </it>is one of major tumour suppressor genes being essential in preservation of genome integrity. Two very common polymorphisms have been demonstrated to contribute to cancer susceptibility and tumour behaviour. The purpose of this study was to evaluate the role of <it>Arg72Pro </it>and <it>PIN3 Ins16bp </it>polymorphisms in <it>TP53 </it>gene as genetic susceptibility and predictive markers to breast cancer.</p> <p>Methods</p> <p>We analysed DNA samples from 264 breast cancer patients and 440 controls, for <it>TP53 Arg72Pro </it>and <it>PIN3 Ins16bp </it>polymorphisms using PCR-RFLP.</p> <p>Results</p> <p>We observed that women with <it>A2A2 </it>genotype have increased risk for developing breast cancer, either in women with or without familial history (FH) of the disease (OR = 4.40, 95% CI 1.60–12.0; p = 0.004; OR = 3.88, 95% CI 1.18–12.8; p = 0.026, respectively). In haplotype analysis, statistically significant differences were found between <it>TP53 Arg-A2 </it>haplotype frequencies and familial breast cancer cases and the respective control group (OR = 2.10, 95% CI 1.08–4.06; p = 0.028). Furthermore, both <it>TP53 </it>polymorphisms are associated with higher incidence of lymph node metastases.</p> <p>Conclusion</p> <p>Our findings suggest <it>TP53 PIN3 Ins16bp </it>polymorphism as a real risk modifier in breast cancer disease, either in sporadic and familial breast cancer. Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases.</p