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Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600Einhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to the chondroitin sulfate proteoglycan 4 (CSPG4) melanoma marker. After evaluation in vitro, the efficacy of this treatment was evaluated through an in vivoexperiment using mice bearing resistant human melanoma. The co-administration of miR126 and the PI3K/AKT inhibitor in these experiments significantly reduced tumor growth and inhibited the formation of liver and lung metastases. These results provide evidence for a strategy to target an oncosuppressive nucleic acid sequence to tumor cells while simultaneously protecting it from plasma degradation. The system described in this study exhibits encouraging potential for the effective treatment of therapy-resistant metastatic melanoma while also presenting a prospective approach for other forms of cancer.

We present NG-DBSCAN, an approximate density-based clustering algorithm that operates on arbitrary data and any symmetric distance measure. The distributed design of our algorithm makes it scalable to very large datasets; its approximate nature makes it fast, yet capable of producing high quality clustering results. We provide a detailed overview of the steps of NG-DBSCAN, together with their analysis. Our results, obtained through an extensive experimental campaign with real and synthetic data, substantiate our claims about NG-DBSCAN's performance and scalability.

Vegetatively propagated warm-season turfgrasses are established with methods that rely on large quantities of propagation material and subsequent plant growth support. The precision seeding adopted for some seed propagated crops controls the depth and spacing at which seeds are placed in the soil. Sprigs that are reduced in length could potentially be suitable for existing machinery, and precision planting could enhance the efficiency of use of the propagation material. The aim of the present study was to carry out a preliminary screening on products known to act as plant growth regulators to explore their potential use for controlling stolon development and elongation of 'Patriot' hybrid bermudagrass (Cynodon dactylon × C. transvaalensis) grown in pots for propagation purposes. Trinexapac-ethyl (TE), chlormequat chloride (CM), paclobutrazol (PB), propiconazole (PPC), diquat (DQ), flazasulfuron (FS), glyphosate (GP), ethephon (EP), and gibberellic acid (GA) were applied to pot-grown 'Patriot' hybrid bermudagrass turf in eight different application rates, ranging for each product from the minimum expected effective rate to a potentially harmful rate. Of the tested treatments, TE applied at 2.0 kg·ha-1 and PB applied at 1.0 kg·ha-1 reduced stolon and internode length without causing a reduction in the stolon number or turf quality. PPC was also effective in reducing stolon length, but the effect on internode length was not statistically significant. Stolon length was unaffected by CM, while DQ and GP induced stolon elongation. FS, EP, and GA affected stolon length without a consistent relation between stolon length and application rate. The chemical suppression of stolon elongation in pot-grown 'Patriot' hybrid bermudagrass can contribute to controlling sprig size for use with precision seeding machinery. [ABSTRACT FROM AUTHOR]

Many early spring bulb species are naturally found in grassy areas such as meadows or lawns. However, few studies have been conducted to define this concept in maintained lawns, especially warm-season lawns such as zoysiagrass (Zoysia japonica) or bermudagrass (Cynodon dactylon). Four early spring bulb species, including two crocus species (Crocus tommasinianus 'Ruby Giant' and Crocus chrysantbus 'Goldilocks'), reticulated iris (Iris reticulata 'Cantab'), and snowdrop (Galanthus ehvesii) were established in a zoysiagrass lawn site in Fall 2010. In Spring 2011 and 2012, five common preemergence herbicides used on lawns were applied across the plots to determine phytotoxicity. In addition, mowing treatments were started on plots at two timings (15 Mar. and 15 Apr.) to determine how mowing might affect survival and performance of the bulb species. Early performance was good for all bulb species and greater than 50% flower production was observed in the first spring (2011) after planting. However, in the subsequent 3 years (2012-14), the only species that persisted and continued to flower adequately each spring was 'Ruby Giant' crocus. Herbicides and mowing did not affect bulb survival or performance in the trial, suggesting that typical lawn management practices will not be deleterious to the bulbs. These results demonstrate that early spring bulbs may be incorporated into dormant, warm-season lawns, but species and cultivar selection will be crucial for long-term performance. [ABSTRACT FROM AUTHOR]

Synthetic sports surfaces are increasingly subject to standardization of athlete-surface and ball-surface interactions (playability parameters). Such standardizations have led to an increase in the level of the engineering and predictability of these surfaces, and as such may be beneficial also for natural turf. In warm and temperate climates, many natural turf sports surfaces are established with warm-season (C4) turfgrass species due to their suitability to the environment in such areas. This study was aimed at evaluating the Féderation Internationale de Football Association (FIFA)-standard playing characteristics of different sports turf surfaces obtained from three commonly used C4 turfgrass species: 1) 'Tifway 419' hybrid bermudagrass (Cynodon dactylon var. dactylon × C. transvaalensis), 2) 'Zeon' manilagrass (Zoysia matrella), and 3) 'Salam' seashore paspalum (Paspalum vaginatum) for factors concerning leaf tissue (silica, lignin, water content) and canopy structure (shoot density, leaf architecture, stolon density, etc.). Results showed that surfaces of different C4 turfgrass species generate different playability parameters, with seashore paspalum being a harder faster surface, manilagrass being a softer slower surface, and hybrid bermudagrass showing intermediate characteristics. These playing quality results were associated with certain specific canopy biometrical/morphological parameters such as shoot density, horizontal stem density (HSD), leaf section, and, to a lesser extent, to certain plant tissue compounds (lignin, silica). [ABSTRACT FROM AUTHOR]

Excessive exposure to solar UVA and UVB radiation is widely considered to cause skin cancers such as squamous cell carcinoma and basalioma. Direct UVB damage to skin cell DNA as well as UV-induced chronic skin inflammation, accelerated keratinocyte proliferation, inhibited apoptosis, and immunosuppression seem to underlie the UV-induced carcinogenesis. Also, UVB induces cytochrome P450 subfamilies (CYP1A1 and CYP1B1) involved in metabolic activation of organic pro-carcinogens and their conversion to ultimate carcinogens. Here, the effects of several glycosylated and non-glycosylated plant polyphenols (verbascoside, resveratrol, polydatin, rutin, and quercetin) on the inflammatory, apoptotic, metabolic, and proliferative responses of cultured human epidermal keratinocytes (HEK) to non-cytotoxic doses of solar-simulated UVA+UVB and chemical mediators of UV signalling in HEK, 6- formylindolo[3,2-b]carbazole and squalene isolated from photo-oxidized skin surface lipids (SSL), were evaluated. We showed that the stilbenes and quercetin being exposed to UV were photo-destroyed within a short period of time, while verbascoside and rutin were photo-stable. When SSL were exposed to UV, the stilbenes and quercetin remarkably accelerated photo-oxidation of alpha-tocopherol, squalene, and cholesterol fractions, whilst verbascoside protected them. Verbascoside invariably inhibited molecular pathways in HEK leading to inflammatory cytokine expression (NFkappaB and EGFR/ERK phosphorylation), and cell proliferation (EGFR nuclear translocation), and displayed a stimulus-specific effect on the metabolic axis aryl hydrocarbon receptor (AhR)-CYP1A1/CYP1B1. By contrast, the stilbenes inhibited UV-connected inflammatory cytokines excluding IL-8, but they prevalently stimulated NFkappaB, EGFR nuclear translocation and the AhR-CYP pathway. We conclude that, among the PPs investigated, verbascoside does interfere with multiple UV-sensitive signalling in HEK in a way that it could have a major impact on skin cancer chemoprevention.

Airlines need to pay special attention to flights that may be liable to produce undesired downstream effects if subjected to delay. A mathematical formulation is proposed to identify these critical flights by defining a set of temporal intervals, called time window, which must be met during the flight execution. The width of the time window is variable because it reflects all known constraints on runway capacities or on congested en route sectors that the flight will go through, or both. The set of optimal time window that maximizes their overall width was chosen, thus providing airline operators with the largest degree of flexibility to perform their flights. Three possible approaches are presented to compute the utilization of the system capacity. By means of a computational analysis, it is shown that the solution of the time window model is insensitive about the formulation used for the capacity constraints.

Third-generation artificial-turf pitches are often criticized because of their high abrasiveness when athletes fall on the surface, the high temperatures recorded in summer periods, and their unpleasant rubber odour. On the other hand, natural-turf pitches are not able to withstand the high play volumes currently associated with modern high-profile and community sports pitches. Hybrid systems with a varying presence of artificial fibres and reinforcements have long been tested and installed, without providing a definitive answer to the above-mentioned problems of natural turf.The aim of this study was to evaluate the playing characteristics and the wear resistance of a newly patented hybrid natural-artificial sports pitch construction system after rugby and football play for 2 months and 5 months. This hybrid system consists of a modified third-generation artificial grass with organic infill, on which natural grass was allowed to grow.A 11300 m2experimental pitch was constructed in Pisa (Italy) in the summer of 2007 and tested during 2007–2008 following football and rugby union play for an average of 8–9 h/week. The hybrid pitch showed a total absence of rubber odour, summer temperatures similar to those of natural-turf pitches, wear resistance superior to that of natural-turf pitches, abrasiveness similar to that of natural-turf pitches, and good infill particle size stability. Most playing-quality parameters fell within both the Fédération Internationale de Football Association (FIFA) Recommended 2-Star Standard requirements for artificial turf and generally accepted playing-quality parameters for natural turf. Since then more pitches as described herein have been constructed and witnessed international match play, while FIFA has classified the system as a reinforced natural-grass pitch.

In this work under-mask penetration of Al+ ions implanted in 4H-SiC is investigated by computer simulation based on the Monte-Carlo binary collision approximation (MC–BCA). Results indicate that a small fraction of ions, implanted normal to a (0001) 4H-SiC wafer (8° off-axis towards the {11-20}), is scattered and become channeled in the <1120> directions perpendicular to the <0001> axis. Due to this phenomenon, doped regions with concentration ≤ 10− 4 of the peak value, may extend laterally for a few µm below the edge of a SiO2 mask.

We report on a 3yearold boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II MOPD II syndrome. Western blot analysis of the patients lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion c.15271528insA in exon 10 of the PCNTgene, which leads to a frameshift Treo510fs and to premature protein truncation. PCNTmutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested. © 2009 WileyLiss, Inc.

We have identified previously a destabilizing adenine- and uracil-rich element (ARE) in the 3'-UTR of bcl-2 mRNA that interacted with ARE-binding proteins to down-regulate bcl-2 gene expression in response to apoptotic stimuli. We have also described three contiguous 2'-O-methyl oligoribonucleotides (ORNs) in both sense and antisense orientation with respect to the bcl-2 ARE that are able to regulate the bcl-2 mRNA half-life and Bcl-2 protein level in two different cell lines. Here we show that treatment of neuronal cell line (SHSY-5Y) with antisense ORNs targeting the bcl-2 ARE (bcl-2 ARE asORNs) prevents bcl-2 down-regulation in response to apoptotic stimuli with glucose/growth factor starvation (Locke medium) or oxygen deprivation and enhances the apoptotic threshold as evaluated by time-lapse videomicroscopy, fluorescence-activated cell sorting analysis, and caspase-3 activation. Additional effects of bcl-2 ARE asORNs included inhibition of cell cycle entry and a marked increase of cellular neurite number and length, a hallmark of neuronal differentiation resulting from bcl-2 up-regulation. The ability of bcl-2 ARE asORNs to enhance the apoptotic threshold and to induce neuronal differentiation implies their potential application as a novel informational tool to protect cells from ischemic damage and to prevent neuronal degeneration.

Autologous fat transplantation (or lipofilling) is an excellent technique for correction of cosmetic defects. The success of the procedure relies strongly on the techniques of harvesting and transferring viable adipocytes. The purpose of this study was to evaluate effects of two harvesting methods and coenzyme Q10on the viability and apoptotic death of adipocytes collected for autologous lipofilling.

Postnatal CD34+cells expressing vascular endothelial growth factor receptor 2 (KDR) generate hematopoietic or endothelial progeny in different in vitro and in vivo assays. Hypothetically, CD34+KDR+cells may comprise hemangioblasts bipotent for both lineages. This hypothesis is consistent with 2 series of experiments. In the first series, in clonogenic culture permissive for hematopoietic and endothelial cell growth, CD34+KDR+cells generate large hemato-endothelial (Hem-End) colonies (5% of seeded cells), whereas CD34+KDR−cells do not. Limiting-dilution analysis indicates that Hem-End colonies are clonally generated by single hemangioblasts. Sibling cells generated by a hemangioblast, replated in unicellular culture, produce either hematopoietic or Hem-End colonies, depending on the specific culture conditions. Identification of endothelial cells was based on the expression of VE-cadherin and endothelial markers and with lack of CD45 and hematopoietic molecules, as evaluated by immunofluorescence, immunocytochemistry, and reverse transcription–polymerase chain reaction. Furthermore, endothelial cells were functionally identified using low-density lipoprotein (LDL) uptake and tube-formation assays. In the second series, to evaluate the self-renewal capacity of hemangioblasts, single CD34+KDR+cells were grown in 3-month extended long-term culture (ELTC) through 3 serial culture rounds—that is, blast cells generated in unicellular ELTC were reseeded for a subsequent round of unicellular ELTC. After 9 months, 10% blasts from tertiary ELTC functioned as hemangioblasts and generated macroscopic Hem-End colonies in clonogenic culture. These studies identified postnatal hemangioblasts in a CD34+KDR+cell subset, endowed with long-term proliferative potential and bilineage differentiation capacity. Although exceedingly rare, hemangioblasts may represent the lifetime source/reservoir for primitive hematopoietic and endothelial progenitors.

We describe a genetic algorithm approach to solve an inverse problem in optics, which determines the characteristics of a fiber Bragg grating from its reflected spectrum. The validity of the proposed method is demonstrated by use of a Bragg sensor for the measurement of nonlinear strain acting on a uniaxial aluminum test specimen.

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ABSTRACTHuman proerythroblasts and early erythroblasts, generated in vitro by normal adult progenitors, contain a pentamer protein complex comprising the tal-1 transcription factor heterodimerized with the ubiquitous E2A protein and linked to Lmo2, Ldb1, and retinoblastoma protein (pRb). The pentamer can assemble on a consensus tal-1 binding site. In the pRb-SAOS-2 cell line transiently transfected with a reporter plasmid containing six tal-1 binding site, pRb enhances the transcriptional activity of tal-1–E12–Lmo2 and tal-1–E12–Lmo2–Ldb1 complexes but not that of a tal-1–E12 heterodimer. We explored the functional significance of the pentamer in erythropoiesis, specifically, its transcriptional effect on the c-kit receptor, a tal-1 target gene stimulating early hematopoietic proliferation downmodulated in erythroblasts. In TF1 cells, the pentamer decreased the activity of the reporter plasmid containing the c-kit proximal promoter with two inverted E box-2 type motifs. In SAOS-2 cells the pentamer negatively regulates (i) the activity of the reporter plasmid containing the proximal human c-kit promoter and (ii) endogenous c-kit expression. In both cases pRb significantly potentiates the inhibitory effect of the tal-1–E12–Lmo2–Ldb1 tetramer. These data indicate that this pentameric complex assembled in maturing erythroblasts plays an important regulatory role in c-kit downmodulation; hypothetically, the complex may regulate the expression of other critical erythroid genes.