Evaluation of Poly-Mechanistic Antiangiogenic Combinations to Enhance Cytotoxic Therapy Response in Pancreatic Cancer

Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). The present study investigated combinations of gemcitabine with antiangiogenic agents of various mechanisms for PDAC, including bevacizumab (Bev), sunitinib (Su) and EMAP II. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo experiments were performed via murine xenografts. Inhibition of in vitro proliferation of AsPC-1 PDAC cells by gemcitabine (10 µM), bevacizumab (1 mg/ml), sunitinib (10 µM) and EMAP (10 µM) was 35, 22, 81 and 6 percent; combination of gemcitabine with bevacizumab, sunitinib or EMAP had no additive effects. In endothelial HUVECs, gemcitabine, bevacizumab, sunitinib and EMAP caused 70, 41, 86 and 67 percent inhibition, while combination of gemcitabine with bevacizumab, sunitinib or EMAP had additive effects. In WI-38 fibroblasts, gemcitabine, bevacizumab, sunitinib and EMAP caused 79, 58, 80 and 29 percent inhibition, with additive effects in combination as well. Net in vivo tumor growth inhibition in gemcitabine, bevacizumab, sunitinib and EMAP monotherapy was 43, 38, 94 and 46 percent; dual combinations of Gem+Bev, Gem+Su and Gem+EMAP led to 69, 99 and 64 percent inhibition. Combinations of more than one antiangiogenic agent with gemcitabine were generally more effective but not superior to Gem+Su. Intratumoral proliferation, apoptosis and microvessel density findings correlated with tumor growth inhibition data. Median animal survival was increased by gemcitabine (26 days) but not by bevacizumab, sunitinib or EMAP monotherapy compared to controls (19 days). Gemcitabine combinations with bevacizumab, sunitinib or EMAP improved survival to similar extent (36 or 37 days). Combinations of gemcitabine with Bev+EMAP (43 days) or with Bev+Su+EMAP (46 days) led to the maximum survival benefit observed. Combination of antiangiogenic agents improves gemcitabine response, with sunitinib inducing the strongest effect. These findings demonstrate advantages of combining multi-targeting agents with standard gemcitabine therapy for PDAC

Low Resistance Polycrystalline Diamond Thin Films Deposited by Hot Filament Chemical Vapour Deposition

Polycrystalline diamond thin films with outgrowing diamond (OGD) grains were deposited onto silicon wafers using a hydrocarbon gas (CH4) highly diluted with H2 at low pressure in a hot filament chemical vapour deposition (HFCVD) reactor with a range of gas flow rates. X-ray diffraction (XRD) and SEM showed polycrystalline diamond structure with a random orientation. Polycrystalline diamond films with various textures were grown and (111) facets were dominant with sharp grain boundaries. Outgrowth was observed in flowerish character at high gas flow rates. Isolated single crystals with little openings appeared at various stages at low gas flow rates. Thus, changing gas flow rates had a beneficial influence on the grain size, growth rate and electrical resistivity. CVD diamond films gave an excellent performance for medium film thickness with relatively low electrical resistivity and making them potentially useful in many industrial applications

The effect of intervertebral cartilage on neutral posture and range of motion in the necks of sauropod dinosaurs

The necks of sauropod dinosaurs were a key factor in their evolution. The habitual posture and range of motion of these necks has been controversial, and computer-aided studies have argued for an obligatory sub-horizontal pose. However, such studies are compromised by their failure to take into account the important role of intervertebral cartilage. This cartilage takes very different forms in different animals. Mammals and crocodilians have intervertebral discs, while birds have synovial joints in their necks. The form and thickness of cartilage varies significantly even among closely related taxa. We cannot yet tell whether the neck joints of sauropods more closely resembled those of birds or mammals. Inspection of CT scans showed cartilage:bone ratios of 4.5% for Sauroposeidon and about 20% and 15% for two juvenile Apatosaurus individuals. In extant animals, this ratio varied from 2.59% for the rhea to 24% for a juvenile giraffe. It is not yet possible to disentangle ontogenetic and taxonomic signals, but mammal cartilage is generally three times as thick as that of birds. Our most detailed work, on a turkey, yielded a cartilage:bone ratio of 4.56%. Articular cartilage also added 11% to the length of the turkey's zygapophyseal facets. Simple image manipulation suggests that incorporating 4.56% of neck cartilage into an intervertebral joint of a turkey raises neutral posture by 15°. If this were also true of sauropods, the true neutral pose of the neck would be much higher than has been depicted. An additional 11% of zygapophyseal facet length translates to 11% more range of motion at each joint. More precise quantitative results must await detailed modelling. In summary, including cartilage in our models of sauropod necks shows that they were longer, more elevated and more flexible than previously recognised

Relationship between eating behaviors and physical activity of preschoolers and their peers: a systematic review

Abstract: Objectives: Children learn by observing and imitating others, meaning that their eating behaviors and physical activity may be influenced by their peers. This paper systematically reviews how preschoolers’ eating behaviors and physical activity relate to their peers’ behaviors, and discusses avenues for future research. Methods: Six databases were searched for quantitative, peer-reviewed studies published up to July 2015 reporting on the correlates, predictors or effectiveness of peers on eating behaviors and physical activity in preschoolers. Risk of bias was independently assessed by two evaluators using the Quality Assessment Tool for Quantitative Studies. Results: Thirteen articles were included: six measured physical activity, and seven assessed eating behaviors. Four of the six physical activity studies reported that children were more active when peers were present, while large peer group size was negatively associated with physical activity in two cross-sectional studies. All nutrition interventions reported that children’s eating behaviors may be influenced by their peers. Conclusions: Although supported by weak evidence, peers appear to influence children’s eating behaviors and physical activity. However, this influence may be moderated by the number of peers, gender, age and the perceived status of the role models. Future obesity prevention interventions should consider involving peers as agents for positive eating behaviors and physical activity in preschoolers

R^4 counterterm and E7(7) symmetry in maximal supergravity

The coefficient of a potential R^4 counterterm in N=8 supergravity has been shown previously to vanish in an explicit three-loop calculation. The R^4 term respects N=8 supersymmetry; hence this result poses the question of whether another symmetry could be responsible for the cancellation of the three-loop divergence. In this article we investigate possible restrictions from the coset symmetry E7(7)/SU(8), exploring the limits as a single scalar becomes soft, as well as a double-soft scalar limit relation derived recently by Arkani-Hamed et al. We implement these relations for the matrix elements of the R^4 term that occurs in the low-energy expansion of closed-string tree-level amplitudes. We find that the matrix elements of R^4 that we investigated all obey the double-soft scalar limit relation, including certain non-maximally-helicity-violating six-point amplitudes. However, the single-soft limit does not vanish for this latter set of amplitudes, which suggests that the E7(7) symmetry is broken by the R^4 term.Comment: 33 pages, typos corrected, published versio

Recent acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors

The porin and the permeating antibiotic: A selective diffusion barrier in gram-negative bacteria

Gram-negative bacteria are responsible for a large proportion of antibiotic resistant bacterial diseases. These bacteria have a complex cell envelope that comprises an outer membrane and an inner membrane that delimit the periplasm. The outer membrane contains various protein channels, called porins, which are involved in the influx of various compounds, including several classes of antibiotics. Bacterial adaptation to reduce influx through porins is an increasing problem worldwide that contributes, together with efflux systems, to the emergence and dissemination of antibiotic resistance. An exciting challenge is to decipher the genetic and molecular basis of membrane impermeability as a bacterial resistance mechanism. This Review outlines the bacterial response towards antibiotic stress on altered membrane permeability and discusses recent advances in molecular approaches that are improving our knowledge of the physico-chemical parameters that govern the translocation of antibiotics through porin channel

Strong Host-Feeding Preferences of the Vector Triatoma infestans Modified by Vector Density: Implications for the Epidemiology of Chagas Disease

Chagas disease is a complex zoonosis with more than 150 mammalian host species, nearly a dozen blood-sucking triatomine species as main vectors, and 9–11 million people infected with Trypanosoma cruzi (its causal agent) in the Americas. Triatoma infestans, a highly domesticated species and one of the main vectors, feeds more often on domestic animals than on humans in northern Argentina. The question of whether there are host-feeding preferences among dogs, cats, and chickens is crucial to estimating transmission risks and predicting the effects of control tactics targeting them. This article reports the first host choice experiments of triatomine bugs conducted in small huts under natural conditions. The results demonstrate that T. infestans consistently preferred dogs to chickens or cats, with host shifts occurring more frequently at higher vector densities. Combined with earlier findings showing that dogs have high infection rates, are highly infectious, and have high contact rates with humans and domestic bugs, our results reinforce the role of dogs as the key reservoirs of T. cruzi. The strong bug preference for dogs can be exploited to target dogs with topical lotions or insecticide-impregnated collars to turn them into baited lethal traps or use them as transmission or infestation sentinels