Kinase independent oncogenic cyclin D1.

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Nanoarrays for the generation of complex optical wave-forms

Light beams with unusual forms of wavefront offer a host of useful features to extend the repertoire of those developing new optical techniques. Complex, non-uniform wavefront structures offer a wide range of optomechanical applications, from microparticle rotation, traction and sorting, through to contactless microfluidic motors. Beams combining transverse nodal structures with orbital angular momentum, or vector beams with novel polarization profiles, also present new opportunities for imaging and the optical transmission of information, including quantum entanglement effects. Whilst there are numerous well-proven methods for generating light with complex wave-forms, most current methods work on the basis of modifying a conventional Hermite-Gaussian beam, by passage through suitably tailored optical elements. It has generally been considered impossible to directly generate wave-front structured beams either by spontaneous or stimulated emission from individual atoms, ions or molecules. However, newly emerged principles have shown that emitter arrays, cast in an appropriately specified geometry, can overcome the obstacles: one possibility is a construct based on the electronic excitation of nanofabricated circular arrays. Recent experimental work has extended this concept to a phase-imprinted ring of apertures holographically encoded in a diffractive mask, generated by a programmed spatial light modulator. These latest advances are potentially paving the way for creating new sources of structured light

Fracture Blisters

Fracture blisters are a relatively uncommon complication of fractures in locations of the body, such as the ankle, wrist elbow and foot, where skin adheres tightly to bone with little subcutaneous fat cushioning. The blister that results resembles that of a second degree burn

Impact of postharvest osmodehydration treatments and drying processes on the nutritional quality, bioactive compounds and preservation of leaf amaranth (Amaranthus cruentus)

Amaranth leaves are rich in micronutrients and health-promoting secondary metabolites, but highly perishable. The effect of osmodehydration and drying on nutritional quality, health-promoting compounds and their postharvest preservation in Amaranthuscruentus leaves was investigated. The experimental set up consisted of four treatment variants with different levels of osmotic solution (NaCl) concentration, temperature and immersion time, i.e.; variant 1 (2.5%, 20 °C, 60 min), variant 2 (10%, 20°C, 60 min), variant 3 (10%, 40°C, 60 min), and variant 4 (10%, 40°C, 180 min). Osmodehydrated leaves were oven-dried at 30°C or 60°C, freeze-dried or stored at ambient temperature for 3 days, with non-osmodehydrated leaves as control. Results showed that proteins,minerals (Ca, Mg, Fe, Zn), carotenoids, flavonoids, and phenolic acids were preserved in osmodehydrated leaves with no significant changes, except proteins in freeze-dried and a significantly decreased chlorophyll content in both freeze- and oven-dried leaves of variant 4, corresponding to higher osmotic solution concentration, temperature and longer immersion time. During shelf-life, most nutrients and secondary metabolites were maintained with no significant changes, except protein that significantly increased while ascorbic acid and chlorophylls in both osmodehydrated and control leaves significantly decreased. Lower-temperature and shorter-time immersion resulted in better quality preservation

Next Generation Lightweight Mirror Modeling Software

The advances in manufacturing techniques for lightweight mirrors, such as EXELSIS deep core low temperature fusion, Corning's continued improvements in the Frit bonding process and the ability to cast large complex designs, combined with water-jet and conventional diamond machining of glasses and ceramics has created the need for more efficient means of generating finite element models of these structures. Traditional methods of assembling 400,000 + element models can take weeks of effort, severely limiting the range of possible optimization variables. This paper will introduce model generation software developed under NASA sponsorship for the design of both terrestrial and space based mirrors. The software deals with any current mirror manufacturing technique, single substrates, multiple arrays of substrates, as well as the ability to merge submodels into a single large model. The modeler generates both mirror and suspension system elements, suspensions can be created either for each individual petal or the whole mirror. A typical model generation of 250,000 nodes and 450,000 elements only takes 5-10 minutes, much of that time being variable input time. The program can create input decks for ANSYS, ABAQUS and NASTRAN. An archive/retrieval system permits creation of complete trade studies, varying cell size, depth, and petal size, suspension geometry with the ability to recall a particular set of parameters and make small or large changes with ease. The input decks created by the modeler are text files which can be modified by any editor, all the key shell thickness parameters are accessible and comments in deck identify which groups of elements are associated with these parameters. This again makes optimization easier. With ANSYS decks, the nodes representing support attachments are grouped into components; in ABAQUS these are SETS and in NASTRAN as GRIDPOINT SETS, this make integration of these models into large telescope or satellite models easier

Real World Clinicopathologic Observations of Patients with Metastatic Solid Tumors Receiving Immune Checkpoint Inhibitor Therapy: Analysis from Kentucky Cancer Registry

The state of Kentucky has the highest cancer incidence and mortality in the United States. High‐risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate‐high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high‐TMB cohort compared to low‐intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real‐world data publications which might help determine biomarkers that could benefit specific populations

Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis

Using Resonances to Control Chaotic Mixing within a Translating and Rotating Droplet

Enhancing and controlling chaotic advection or chaotic mixing within liquid droplets is crucial for a variety of applications including digital microfluidic devices which use microscopic ``discrete'' fluid volumes (droplets) as microreactors. In this work, we consider the Stokes flow of a translating spherical liquid droplet which we perturb by imposing a time-periodic rigid-body rotation. Using the tools of dynamical systems, we have shown in previous work that the rotation not only leads to one or more three-dimensional chaotic mixing regions, in which mixing occurs through the stretching and folding of material lines, but also offers the possibility of controlling both the size and the location of chaotic mixing within the drop. Such a control was achieved through appropriate tuning of the amplitude and frequency of the rotation in order to use resonances between the natural frequencies of the system and those of the external forcing. In this paper, we study the influence of the orientation of the rotation axis on the chaotic mixing zones as a third parameter, as well as propose an experimental set up to implement the techniques discussed.Comment: 15 pages, 6 figure

Next-Generation Lightweight Mirror Modeling Software

The advances in manufacturing techniques for lightweight mirrors, such as EXELSIS deep core low temperature fusion, Corning's continued improvements in the Frit bonding process and the ability to cast large complex designs, combined with water-jet and conventional diamond machining of glasses and ceramics has created the need for more efficient means of generating finite element models of these structures. Traditional methods of assembling 400,000 + element models can take weeks of effort, severely limiting the range of possible optimization variables. This paper will introduce model generation software developed under NASA sponsorship for the design of both terrestrial and space based mirrors. The software deals with any current mirror manufacturing technique, single substrates, multiple arrays of substrates, as well as the ability to merge submodels into a single large model. The modeler generates both mirror and suspension system elements, suspensions can be created either for each individual petal or the whole mirror. A typical model generation of 250,000 nodes and 450,000 elements only takes 5-10 minutes, much of that time being variable input time. The program can create input decks for ANSYS, ABAQUS and NASTRAN. An archive/retrieval system permits creation of complete trade studies, varying cell size, depth, and petal size, suspension geometry with the ability to recall a particular set of parameters and make small or large changes with ease. The input decks created by the modeler are text files which can be modified by any editor, all the key shell thickness parameters are accessible and comments in deck identify which groups of elements are associated with these parameters. This again makes optimization easier. With ANSYS decks, the nodes representing support attachments are grouped into components; in ABAQUS these are SETS and in NASTRAN as GRIDPOINT SETS, this make integration of these models into large telescope or satellite models possibl

Comprehensive Genomic Profiling in Routine Clinical Practice Leads to a Low Rate of Benefit from Genotype-Directed Therapy

Background: Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. Methods: Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. Results: A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2–3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. Conclusions: CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT