Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer

The targeting of oncogenic ‘driver’ kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.     

Microtubules and cyclic amp in human leukocytes: on the order of things

We have shown previously that the β-adrenergic agonist isoproterenol (2μM) and the phosphodiesterase inhibitor isobutylmethylxanthine (1 mM) produce a much greater increase in cyclic AMP in human leukocytes that have been pretreated with colchicine (or with other agents that affect microtubule assembly) than in control leukocytes. The effects of colchicines were both time- and dose-dependant. These and other data suggested that the generation of cyclic AMP is normally restricted by an intact system of cytoplasmic microtubules. If so, then the same time and dose dependencies might apply to other colchicines-induced changes in leukocyte function. We have now assayed the distribution of concanavalin A (Con A)-receptor complexes on the leukocyte membrane, taking into account that leukocytes competent to assemble microtubules show a uniform distribution of surface- bound Con A whereas microtubule-deficient cells accumulate Con A in surface caps. We have found that the effect of colchicine on capping is also both time- and dose dependent, and that the dose-response relationships conform to those required to increase cyclic AMP levels. These findings provide further evidence that both colchicine-induced Con-A capping and colchicine- induced cyclic AMP generation depend upon the relaxation of constraints normally imposed by cytoplasmic microtubules upon the plasma membrane, which limit, respectively, lateral mobility of the lectin-receptor complexes, and expression of hormone-sensitive adenylate cyclase. Moreover, colchicine-induced Con-A cap formation is not affected even by very large changes in leukocyte cyclic AMP levels. Thus, elevated cyclic AMP levels do not appear to promote the dissolution of microtubules; rather, the dissolution of microtubules permits the generation of increased amounts of cyclic AMP.     

Development of Trypanosoma (M.) theileri in Tabanids

Thus far the life cycle of Trypanosoma (Megatrypanum) theileri has not been studied. We collected tabanids during the mass hatching, when only few tabanids are infected with trypanosomes. Tabanids were caught immediately after attacking a bait cow to serve as controls or after they had been allowed to engorge on the Trypanosoma (M.) theileri-infected cow. Tabanids were kept in the laboratory and used to study the developmental cycle of T. (M.) theileri in the tabanid gut. From day 1 to day 10 the presumably unfed controls and the engorged tabanids were dissected and cytological smears made from the mid- and hindgut. In total 2.6% (1/38) of the controls and 39% (23/59) of the engorged tabanids were positive for trypanosomes in the 1991 season. From day 1 to day 4 after engorgement trypanosomes were found in the midgut. Epimastigotes with a length of 29 μm on day 1 after infection multiplied by inequal division to form smaller epimastigotes of 26 μm on day 3. On day 4 morphologically indistinguishable trypanosomes of 21 μm total length were found in both mid- and hindgut. From day 5 to day 10 trypanosomes were found only in the hindgut in which the transformation to metacyclics was demonstrated, i.e. epimastigotes transformed to amastigote stages of 5 μm in total length.     

Spatial variation in periphyton fatty acid composition in subtropical streams

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Cold-induced changes affect survival after exposure to vitrification solution during cryopreservation in the south-west Australian Mediterranean climate species Lomandra sonderi (Asparagaceae)

There is limited knowledge of the effects of exposure to low temperatures in the unique Mediterranean climate plant species of Western Australia. We have thus investigated the effect of low temperature on cryogenic tolerance in Lomandra sonderi, an endemic perennial species of southwest Western Australia. Lomandra sonderi plants were preconditioned in tissue culture at constant 23 °C (12 h light/dark cycle) or alternating 20/?1 °C (16 h light and 8 h dark cycle). Shoot tips from both conditions were analysed for their phospholipid, sterol and soluble sugar compositions. Shoot tips were also cryoexposed via a droplet-vitrification protocol. Survival in both preconditioning regimes for cryoexposed and non-cryoexposed samples was the same, but plants from the 20/?1 °C regime displayed an improved tolerance to the overall cryopreservation process in both cryoexposed and non-cryoexposed samples, thereby eliminating exposure to liquid nitrogen as a primary cause of reduced post-cryogenic viability. Preconditioning of in vitro shoots of L. sonderi at 20/?1 °C induced significant increases in phosphatidylcholine (from 7.30 ± 3.46 to 22.2 ± 7.80 ng mg^?1 FW) and increases in several soluble sugars (fructose, galactose, glucose, sucrose) compared to shoots incubated at 23 °C—changes consistent with known cold acclimation responses in plant species generally—but sterol content remained largely unchanged. Analysis of electrolyte leakage in shoot tips from both preconditioning regimes generated a significantly lower LT₅₀ value in the 20/?1 °C samples (?5.45 ± 0.53 °C) over the 23 °C samples (?2.5 ± 0.08 °C). Increased tolerance to cryoexposure in L. sonderi appears to lie mainly with acclimation-induced changes in membrane composition and promotion of membrane stability and hence increased resistance to freeze damage.     

Psychosocial Factors That Shape Patient and Carer Experiences of Dementia Diagnosis and Treatment: A Systematic Review of Qualitative Studies

Background

Early diagnosis and intervention for people with dementia is increasingly considered a priority, but practitioners are concerned with the effects of earlier diagnosis and interventions on patients and caregivers. This systematic review evaluates the qualitative evidence about how people accommodate and adapt to the diagnosis of dementia and its immediate consequences, to guide practice.

Methods and Findings

We systematically reviewed qualitative studies exploring experiences of community-dwelling individuals with dementia, and their carers, around diagnosis and the transition to becoming a person with dementia. We searched PubMed, PsychINFO, Embase, CINAHL, and the British Nursing Index (all searched in May 2010 with no date restrictions; PubMed search updated in February 2012), checked reference lists, and undertook citation searches in PubMed and Google Scholar (ongoing to September 2011). We used thematic synthesis to identify key themes, commonalities, barriers to earlier diagnosis, and support identified as helpful. We identified 126 papers reporting 102 studies including a total of 3,095 participants. Three overarching themes emerged from our analysis: (1) pathways through diagnosis, including its impact on identity, roles, and relationships; (2) resolving conflicts to accommodate a diagnosis, including the acceptability of support, focusing on the present or the future, and the use or avoidance of knowledge; and (3) strategies and support to minimise the impact of dementia. Consistent barriers to diagnosis include stigma, normalisation of symptoms, and lack of knowledge. Studies report a lack of specialist support particularly post-diagnosis.

Conclusions

There is an extensive body of qualitative literature on the experiences of community-dwelling individuals with dementia on receiving and adapting to a diagnosis of dementia. We present a thematic analysis that could be useful to professionals working with people with dementia. We suggest that research emphasis should shift towards the development and evaluation of interventions, particularly those providing support after diagnosis. Please see later in the article for the Editors'' Summary.     

Hematology and plasma biochemistry values for the giant garter snake (Thamnophis gigas) and valley garter snake (Thamnophis sirtalis fitchi) in the Central Valley of California

Hematology and plasma biochemistry parameters are useful in the assessment and management of threatened and endangered species. Although reference ranges are readily available for many mammalian species, reference ranges for snakes are lacking for most species. We determined hematology and plasma biochemistry reference ranges for giant garter snakes (Thamnophis gigas) and valley garter snakes (Thamnophis sirtalis fitchi) living in four management areas in the Central Valley of California. White blood cell, heterophil, lymphocyte, and azurophil counts in giant garter snakes were approximately twice the values of valley garter snakes. Statistically significant differences in aspartate aminotransferase, globulin, and potassium between the two species did not appear clinically significant. No significant differences were found in the measured parameters between male and female giant garter snakes. Some differences were found among collection sites. These reference ranges provide baseline data for comparisons over time and between collection sites.     

Lilac alcohol epoxide: a linalool derivative in Actinidia arguta flowers

Lilac alcohol epoxide (2-(5-methyl-5-(oxiran-2-yl)-tetrahydrofuran-2-yl)propan-1-ol), a previously unreported monoterpene, was identified in the solvent extract of the flowers of seven Actinidia arguta genotypes. The diastereomeric lilac alcohol epoxides co-occurred with the lilac aldehydes and alcohols. Another compound, the lilac diol (2-(5-(1-hydroxyethyl)-5-methyl-tetrahydrofuran-2-yl)propan-1-ol) was synthesised as part of our efforts to identify the lilac alcohol epoxide.