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Birds, bats and ants are recognised as significant arthropod predators. However, empirical studies reveal inconsistent trends in their relative roles in top‐down control across strata. Here, we describe the differences between forest strata in the separate effects of birds, bats and ants on arthropod densities and their cascading effects on plant damage.We implemented a factorial design to exclude vertebrates and ants in both the canopy and understorey. Additionally, we separately excluded birds and bats from the understorey using diurnal and nocturnal exclosures. At the end of the experiments, we collected all arthropods and assessed herbivory damage.Arthropods responded similarly to predator exclusion across forest strata, with a density increase of 81% on trees without vertebrates and 53% without both vertebrates and ants. Additionally, bird exclusion alone led to an 89% increase in arthropod density, while bat exclusion resulted in a 63% increase. Herbivory increased by 42% when vertebrates were excluded and by 35% when both vertebrates and ants were excluded. Bird exclusion alone increased herbivory damage by 28%, while the exclusion of bats showed a detectable but non‐significant increase (by 22%). In contrast, ant exclusion had no significant effect on arthropod density or herbivory damage across strata.Our results reveal that the effects of birds and bats on arthropod density and herbivory damage are similar between the forest canopy and understorey in this temperate forest. In addition, ants were not found to be significant predators in our system. Furthermore, birds, bats and ants appeared to exhibit antagonistic relationships in influencing arthropod density. These findings highlight, unprecedentedly, the equal importance of birds and bats in maintaining ecological balance across different strata of a temperate forest. [ABSTRACT FROM AUTHOR]

Tropical rainforest trees host a diverse arthropod fauna that can be characterised by their functional diversity (FD) and phylogenetic diversity (PD). Human disturbance degrades tropical forests, often coinciding with species invasion and altered assembly that leads to a decrease in FD and PD. Tree canopies are thought to be particularly vulnerable, but rarely investigated.Here, we studied the effects of forest disturbance on an ecologically important invertebrate group, the ants, in a lowland rainforest in New Guinea. We compared an early successional disturbed plot (secondary forest) to an old‐growth plot (primary forest) by exhaustively sampling their ant communities in a total of 852 trees.We expected that for each tree community (1) disturbance would decrease FD and PD in tree‐dwelling ants, mediated through species invasion. (2) Disturbance would decrease ant trait variation due to a more homogeneous environment. (3) The main drivers behind these changes would be different contributions of true tree‐nesting species and visiting species. We calculated FD and PD based on a species‐level phylogeny and 10 ecomorphological traits. Furthermore, we assessed by data exclusion the influence of species, which were not nesting in individual trees (visitors) or only nesting species (nesters), and of non‐native species on FD and PD.Primary forests had higher ant species richness and PD than secondary forest. However, we consistently found increased FD in secondary forest. This pattern was robust even if we decoupled functional and phylogenetic signals, or if non‐native ant species were excluded from the data. Visitors did not contribute strongly to FD, but they increased PD and their community weighted trait means often varied from nesters. Moreover, all community‐weighted trait means changed after forest disturbance.Our finding of contradictory FD and PD patterns highlights the importance of integrative measures of diversity. Our results indicate that the tree community trait diversity is not negatively affected, but possibly even enhanced by disturbance. Therefore, the functional diversity of arboreal ants is relatively robust when compared between old‐growth and young trees. However, further study with higher plot‐replication is necessary to solidify and generalise our findings. [ABSTRACT FROM AUTHOR]

Polyphagous insect herbivores feed on multiple host‐plant species and face a highly variable chemical landscape. Comparative studies of polyphagous herbivore metabolism across a range of plants is an ideal approach for exploring how intra‐ and interspecific chemical variation shapes species interactions. We used polyphagous caterpillars of Lymantria mathura (Erebidae, Lepidoptera) to explore mechanisms that may contribute to its ability to feed on various hosts. We focused on intraspecific variation in polyphenol metabolism, the fates of individual polyphenols, and the role of previous feeding experience on polyphenol metabolism and leaf consumption. We collected the caterpillars from Acer amoenum (Sapindaceae), Carpinus cordata (Betulaceae), and Quercus crispula (Fagaceae). We first fed the larvae with the leaves of their original host and characterized the polyphenol profiles in leaves and frass. We then transferred a subset of larvae to a different host species and quantified how host shifting affected their leaf consumption and polyphenol metabolism. There was high intraspecific variation in frass composition, even among caterpillars fed with one host. While polyphenols had various fates when ingested by the caterpillars, most of them were passively excreted. When we transferred the caterpillars to a new host, their previous experience influenced how they metabolized polyphenols. The one‐host larvae metabolized a larger quantity of ingested polyphenols than two‐host caterpillars. Some of these metabolites could have been sequestered, others were probably activated in the gut. One‐host caterpillars retained more of the ingested leaf biomass than transferred caterpillars. The pronounced intraspecific variation in polyphenol metabolism, an ability to excrete ingested metabolites and potential dietary habituation are factors that may contribute to the ability of L. mathura to feed across multiple hosts. Further comparative studies can help identify if these mechanisms are related to differential host‐choice and response to host‐plant traits in specialist and generalist insect herbivores. [ABSTRACT FROM AUTHOR]

Forkhead box protein P3 (FOXP3) is known to orchestrate the development and maintenance of T regulatory cells, a cell population specialized in immune suppression and peripheral immune tolerance. FOXP3 activity is fine‐tuned through its interaction with several protein‐binding partners. By using IntAct database, we retrieved three physical binary interactors: E3 ubiquitin‐protein ligase CHIP, Zfp‐90, and nuclear receptor ROR‐α. Coevolution clusters between FOXP3 and its interactors were identified with the use of iBIS2 algorithm, the iterative version of BIS/BIS2. Most of the coevolving pairs came from some species of monotremes and marsupials, as well as from a group of bats, thus suggesting that protein interactions of FOXP3 with its partners may be changed and/or modulated during mammalian speciation. Furthermore, our analysis would suggest the occurrence of a determinant role of FOXP3 in suppressing pregnancy alloreactions in placental mammals. Similarly, FOXP3, through its interaction with different protein interaction mechanisms, would explain the unique control of inflammatory response to infections in bats. By identifying several inter‐protein clusters between the different protein pairs, our findings may provide a guide for new therapeutic approaches to modulate T regulatory suppression and/or enhance immune tolerance. [ABSTRACT FROM AUTHOR]

Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%–10% of cases evolves into a B cell Non‐Hodgkin's Lymphoma (NHL). B‐cell activating factor (BAFF) is a key regulator in B‐cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF‐receptor (BAFF‐R) polymorphisms in order to determine if they predispose to HCV‐related CV and NHL. The analysis was performed on 416 HCV‐chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV‐CV) and 114 HCV with NHL (HCV‐NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF‐R and rs12428930 on the BAFF gene were evaluated by Real‐Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV‐CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV‐CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV‐NHL versus HCV. T minor allele was more frequent in HCV‐NHL and HCV‐CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV‐CV and HCV‐NHL than in HCV. Genotyping of rs61756766 on BAFF‐R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV‐NHL versus 3% in HCV. The T minor allele frequency was higher in HCV‐NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF‐R genetic pattern has a role in the pathogenesis of HCV‐related lymphoproliferations. BAFF/BAFF‐R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF‐R genetic profile assessment could potentially contribute to tailoring anti‐BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial. [ABSTRACT FROM AUTHOR]

The community composition of insect herbivores is largely shaped by host–plant phylogeny and functional traits. These effects differ between herbivores due at least in part to varying levels of diet specialisation. Distinguishing between herbivores with differing specialisation is therefore necessary to understand the roles of host phylogeny and traits in shaping complex insect communities.We surveyed the complete plant–caterpillar food web in a 0.2 ha plot of a lowland cool‐temperate deciduous forest. We measured leaf nutrients, physical traits and polyphenols of the hostplants and analysed the effects of leaf traits and phylogeny on Lepidoptera caterpillars with differing levels of host specialisation.We sampled 190 species from 16 433 individual caterpillars on 20 host plant species. These included 102 species of specialists using confamilial hostplant species, 17 species of conservative generalists using allofamilial but phylogenetically close hostplant species and 71 species of non‐conservative generalists using phylogenetically distant hostplant species.The species composition of non‐conservative generalists associated with the polyphenol protein precipitation capacity and overall leaf trait dissimilarity; conservative generalists were weakly associated with polyphenol oxidative activity. In contrast, the composition of specialist assemblages showed no correlation with leaf traits.Our results demonstrate that host phylogeny and traits play variable roles in structuring communities of herbivores, based on the phylogenetic specialisation of herbivores. Understanding the factors that shape the community structures of various herbivores traditionally classified as 'generalists' is important as they account for a large proportion of herbivore species while showing differential responses to traits of hosts. [ABSTRACT FROM AUTHOR]

Assemblages of insect herbivores are structured by plant traits such as nutrient content, secondary metabolites, physical traits, and phenology. Many of these traits are phylogenetically conserved, implying a decrease in trait similarity with increasing phylogenetic distance of the host plant taxa. Thus, a metric of phylogenetic distances and relationships can be considered a proxy for phylogenetically conserved plant traits and used to predict variation in herbivorous insect assemblages among co‐occurring plant species.Using a Holarctic dataset of exposed‐feeding and shelter‐building caterpillars, we aimed at showing how phylogenetic relationships among host plants explain compositional changes and characteristics of herbivore assemblages.Our plant–caterpillar network data derived from plot‐based samplings at three different continents included >28,000 individual caterpillar–plant interactions. We tested whether increasing phylogenetic distance of the host plants leads to a decrease in caterpillar assemblage overlap. We further investigated to what degree phylogenetic isolation of a host tree species within the local community explains abundance, density, richness, and mean specialization of its associated caterpillar assemblage.The overlap of caterpillar assemblages decreased with increasing phylogenetic distance among the host tree species. Phylogenetic isolation of a host plant within the local plant community was correlated with lower richness and mean specialization of the associated caterpillar assemblages. Phylogenetic isolation had no effect on caterpillar abundance or density. The effects of plant phylogeny were consistent across exposed‐feeding and shelter‐building caterpillars.Our study reveals that distance metrics obtained from host plant phylogeny are useful predictors to explain compositional turnover among hosts and host‐specific variations in richness and mean specialization of associated insect herbivore assemblages in temperate broadleaf forests. As phylogenetic information of plant communities is becoming increasingly available, further large‐scale studies are needed to investigate to what degree plant phylogeny structures herbivore assemblages in other biomes and ecosystems. [ABSTRACT FROM AUTHOR]

In arthropod community ecology, species richness studies tend to be prioritised over those investigating patterns of abundance. Consequently, the biotic and abiotic drivers of arboreal arthropod abundance are still relatively poorly known. In this cross‐continental study, we employ a theoretical framework in order to examine patterns of covariance among herbivorous and predatory arthropod guilds. Leaf‐chewing and leaf‐mining herbivores, and predatory ants and spiders, were censused on > 1000 trees in nine 0.1 ha forest plots. After controlling for tree size and season, we found no negative pairwise correlations between guild abundances per plot, suggestive of weak signals of both inter‐guild competition and top‐down regulation of herbivores by predators. Inter‐guild interaction strengths did not vary with mean annual temperature, thus opposing the hypothesis that biotic interactions intensify towards the equator. We find evidence for the bottom‐up limitation of arthropod abundances via resources and abiotic factors, rather than for competition and predation. [ABSTRACT FROM AUTHOR]

Invertebrate predators and parasitoids are among the most important natural enemies of insect herbivores. Yet, the strength of natural enemy pressure along an altitudinal gradient and interactions between the groups of natural enemies (such as predation on parasitized prey) are not well known. Various methods are used to reveal the mortality factors of herbivores. Predation pressure is usually assessed through exposure of artificial prey. However, this method cannot provide information about the attacks of parasitoids, or their eventual interactions with predators. Furthermore, artificial or dead prey might not attract predators because they do not show expected host behavior, and this method mostly cannot distinguish between predation and scavenging. For the first time in a tropical rainforest, we quantified elevational contrast in mortality factors using exposure of live caterpillars. We exposed a total of 800 live caterpillars of Talanga excelsalis moresbyensis Strand (Lepidoptera: Crambidae) on saplings of Ficus copiosa Steud. (Moraceae) at two elevations in primary tropical rain forest in Papua New Guinea (200 and 1 200 m a.s.l.). We exposed the caterpillars in two treatments: exposed to and protected from invertebrate predators and parasitoids. Disappearance of caterpillars was significantly higher in the exposed treatment. Furthermore, caterpillar disappearance was significantly higher in lowlands than in highlands (43 vs. 12%). We consider the vast majority of the disappearance to be due to predation, as migration of the caterpillars from the focal trees was not observed (except one caterpillar). This estimate of invertebrate predation rate corresponds with studies which used artificial caterpillar models. No significant difference in parasitism rate between the two elevations was observed (12 vs. 13%). The combination of the disappearance and parasitism rate patterns means that larval parasitoids face stronger pressure from invertebrate predators through higher predation of their hosts in the lowlands than in the highlands. [ABSTRACT FROM AUTHOR]

Abstract: Unsymmetrical dialkylamino‐substituted zinc azaphthalocyanine (AzaPc) exhibits unique spectral and photophysical properties for dark quenchers of fluorescence in DNA hybridization probes. The panchromatic light absorption of AzaPc from 300 nm up to at least 700 nm and its lack of fluorescence make it an ideal candidate for a universal dark quencher. To prove this experimentally, oligodeoxyribonucleotide probes were labeled at the 3′‐end by this AzaPc and at the 5′‐end by a fluorophore used in the polymerase chain reaction (PCR)—that is, fluorescein, CAL Fluor Red 610, and Cy5. AzaPc showed a significantly higher quenching efficiency compared to the commercially available dark quenchers (BHQ‐1, BHQ‐2, BBQ‐650) in a developed model of TaqMan PCR assay. The AzaPc‐labeled probe proved to also be useful in a practical PCR assay for the quantification of the SLCO2B1 transporter gene expression. The constructed calibration curves indicated linearity in the range from 102 to 107 of target copies. [ABSTRACT FROM AUTHOR]

Plant litter decomposition is one of the most important processes in terrestrial ecosystems, as it is a key factor in nutrient cycling. Decomposition rates depend on environmental factors, but also plant traits, as these determine the character of detritus. We measured litter decomposition rate for 57 common tree species displaying a variety of functional traits within four sites in primary and four sites in secondary tropical forest in Madang Province, Papua New Guinea. The phylogenetic relationships between these trees were also estimated using molecular data. The leaves collected from different tree species were dried for two days, placed into detritus bags and exposed to ambient conditions for two months. Nitrogen, carbon and ash content were assessed as quantitative traits and used together with a phylogenetic variance- covariance matrix as predictors of decomposition rate. The analysis of the tree species composition from 96 quadrats located along a successional gradient of swidden agriculture enabled us to determine successional preferences for individual species. Nitrogen content was the only functional trait measured to be significantly positively correlated with decomposition rate. Controlling for plant phylogeny did not influence our conclusions, but including phylogeny demonstrated that the mainly early successional family Euphorbiaceae is characterized by a particularly high decomposition rate. The acquisitive traits (high nitrogen content and low wood density) correlated with rapid decomposition were characteristic for early successional species. Decomposition rate thus decreased from early successional to primary forest species. However, the decomposition of leaves from the same species was significantly faster in primary than in secondary forest stands, very probably because the high humidity of primary forest environments keeps the decomposing material wetter. [ABSTRACT FROM AUTHOR]

Insects tend to feed on related hosts. The phylogenetic composition of host plant communities thus plays a prominent role in determining insect specialization, food web structure, and diversity. Previous studies showed a high preference of insect herbivores for congeneric and confamilial hosts suggesting that some levels of host plant relationships may play more prominent role that others., We aim to quantify the effects of host phylogeny on the structure of quantitative plant-herbivore food webs. Further, we identify specific patterns in three insect guilds with different life histories and discuss the role of host plant phylogeny in maintaining their diversity., We studied herbivore assemblages in three temperate forests in Japan and the Czech Republic. Sampling from a canopy crane, a cherry picker and felled trees allowed a complete census of plant-herbivore interactions within three 0·1 ha plots for leaf chewing larvae, miners, and gallers. We analyzed the effects of host phylogeny by comparing the observed food webs with randomized models of host selection., Larval leaf chewers exhibited high generality at all three sites, whereas gallers and miners were almost exclusively monophagous. Leaf chewer generality dropped rapidly when older host lineages (5-80 myr) were collated into a single lineage but only decreased slightly when the most closely related congeneric hosts were collated. This shows that leaf chewer generality has been maintained by feeding on confamilial hosts while only a few herbivores were shared between more distant plant lineages and, surprisingly, between some congeneric hosts. In contrast, miner and galler generality was maintained mainly by the terminal nodes of the host phylogeny and dropped immediately after collating congeneric hosts into single lineages., We show that not all levels of host plant phylogeny are equal in their effect on structuring plant-herbivore food webs. In the case of generalist guilds, it is the phylogeny of deeper plant lineages that drives the food web structure whereas the terminal relationships play minor roles. In contrast, the specialization and abundance of monophagous guilds are affected mainly by the terminal parts of the plant phylogeny and do not generally reflect deeper host phylogeny. [ABSTRACT FROM AUTHOR]

Hyperglycemia and hyperinsulinemia may play a role in breast carcinogenesis and prediabetes and diabetes have been associated with increased breast cancer (BC) risk. However, whether BC molecular subtypes may modify these associations is less clear. We therefore investigated these associations in all cases and by BC molecular subtypes among women living in Southern Italy. Cases were 557 patients with non-metastatic incident BC and controls were 592 outpatients enrolled during the same period as cases and in the same hospital for skin-related non-malignant conditions. Adjusted multivariate logistic regression models were built to assess the risks of developing BC in the presence of prediabetes or diabetes. The analyses were repeated by strata of BC molecular subtypes: Luminal A, Luminal B, HER2+, and Triple Negative (TN). Prediabetes and diabetes were significantly associated with higher BC incidence after controlling for known risk factors (OR = 1.94, 95% CI 1.32-2.87 and OR = 2.46, 95% CI 1.38-4.37, respectively). Similar results were seen in Luminal A and B while in the TN subtype only prediabetes was associated with BC (OR = 2.43, 95% CI 1.11-5.32). Among HER2+ patients, only diabetes was significantly associated with BC risk (OR = 3.04, 95% CI 1.24-7.47). Furthermore, when postmenopausal HER2+ was split into hormone receptor positive versus negative, the association with diabetes remained significant only in the former (OR = 5.13, 95% CI 1.53-17.22). These results suggest that prediabetes and diabetes are strongly associated with BC incidence and that these metabolic conditions may be more relevant in the presence of breast cancer molecular subtypes with positive hormone receptors. J. Cell. Physiol. 232: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Rapamycin and modified rapamycins (rapalogs) have been used to prevent allograft rejection after organ transplant for over 15 years. The mechanistic target of rapamycin (mTOR) has been determined to be a key component of the mTORC1 complex which consists of the serine/threonine kinase TOR and at least five other proteins which are involved in regulating its activity. Some of the best characterized substrates of mTORC1 are proteins which are key kinases involved in the regulation of cell growth (e.g., p70S6K) and protein translation (e.g., 4E-BP1). These proteins may in some cases serve as indicators to sensitivity to rapamycin-related therapies. Dysregulation of mTORC1 activity frequently occurs due to mutations at, or amplifications of, upstream growth factor receptors (e.g., human epidermal growth factor receptor-2, HER2) as well as kinases (e.g., PI3K) and phosphatases (e.g., PTEN) critical in the regulation of cell growth. More recently, it has been shown that certain rapalogs may enhance the effectiveness of hormonal-based therapies for breast cancer patients who have become resistant to endocrine therapy. The combined treatment of certain rapalogs (e.g., everolimus) and aromatase inhibitors (e.g., exemestane) has been approved by the United States Food and Drug Administration (US FDA) and other drug regulatory agencies to treat estrogen receptor positive (ER+) breast cancer patients who have become resistant to hormonal-based therapies and have progressed. This review will summarize recent basic and clinical research in the area and evaluate potential novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA-PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53MUT-dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells. [ABSTRACT FROM AUTHOR]

Rapamycin is a macrocyclic lactone currently used for the treatment of cancer and for the prevention of transplant rejection. The primary pharmacological mode of action of rapamycin occurs through the inhibition (blocking) of the mammalian target of rapamycin ( mTOR). By doing so, rapamycin interferes with the phosphoinositide 3-kinase ( PI3 K)- Akt- mTOR axis that controls several cellular functions involving cell growth, proliferation and angiogenesis. The frequent activation of the phosphoinositide 3-kinase ( PI3 K)/ AKT pathway in advanced prostate cancer has provided a rationale for the use of mTOR inhibitors in this setting. We carried out a comparative study on the effects of rapamycin and temsirolimus on the in vitro and in vivo growth of the prostate cancer cell lines, Ln Cap and PC3. Our results demonstrate that rapamycin and temsirolimus exert similar in vitro and in vivo anti-proliferative effects against prostate cancer cells. [ABSTRACT FROM AUTHOR]

Most high-risk neuroblastomas develop resistance to cytostatics and therefore there is a need to develop new drugs. In previous studies, we found that ellipticine induces apoptosis in human neuroblastoma cells. We also investigated whether ellipticine was able to induce resistance in the UKF-NB-4 neuroblastoma line and concluded that it may be possible after long-term treatment with increasing concentrations of ellipticine. The aim of the present study was to investigate the mechanisms responsible for ellipticine resistance. To elucidate the mechanisms involved, we used the ellipticine-resistant subline UKF-NB-4ELLI and performed comparative genomic hybridization, multicolor and interphase FISH, expression microarray, real-time RT-PCR, flow cytometry and western blotting analysis of proteins. On the basis of our results, it appears that ellipticine resistance in neuroblastoma is caused by a combination of overexpression of Bcl-2, efflux or degradation of the drug and downregulation of topoisomerases. Other mechanisms, such as upregulation of enzymes involved in oxidative phosphorylation, cellular respiration, V-ATPases, aerobic respiration or spermine synthetase, as well as reduced growth rate, may also be involved. Some changes are expressed at the DNA level, including gains, amplifications or deletions. The present study demonstrates that resistance to ellipticine is caused by a combination of mechanisms. ( Cancer Sci 2012; 103: 334-341) [ABSTRACT FROM AUTHOR]

Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health. J. Cell. Physiol. 226: 2762-2781, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

1. The novel nuclear factor (NF)-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-α-induced activation of NF-κB by suppressing nuclear translocation of NF-κB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-γ- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-γ and 10−4 mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 μg/mL) or hydrocortisone (10−5 mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 μg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-γ- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect. [ABSTRACT FROM AUTHOR]

This investigation was focused on the contribution of individual human leukocyte antigen (HLA)-DR and -DQ alleles to the human hepatitis C virus (HCV)+ non-Hodgkin's lymphoma (NHL), with and without mixed cryoglobulinemia (MC), to study whether individual HLA class II alleles are expressed preferentially or equally in human HCV-specific NHL. For this purpose, peripheral blood mononuclear cells were obtained from two groups of patients with HCV+ NHL and with or without MC (70 and 71 cases, respectively), and from 4575 blood donors. Eighty-three subjects with HCV infection only, and 118 patients with MC, only without lymphoma, were added as additional control groups. Individual HLA-DR and -DQ alleles were determined using high-resolution sequence-based typing and then data were collected by considering the HLA-DRB1 and DQB1 supertypes on the basis of common structural and functional features, proposed by in silico Bioinformatic studies. From the data, it is evidenced that the DR5-DQ3 HLA combination was strongly associated with the HCV + MC + NHL group of patients compared with bone marrow donor population ( P≤ 0.001, RR = 2.498), while the contribution of DR1-DQ1 was higher in HCV + NHL without MC ( P≤ 0.001, RR = 2.519). Thus, cryoglobulinemia clinical manifestation was found to be correlated with the preferential use of HLA DR-DQ combination in HCV-associated NHL. These data provide new insight into HCV-associated lymphoproliferative pathogenesis. [ABSTRACT FROM AUTHOR]

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, charateristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs. [ABSTRACT FROM AUTHOR]

1. Breast cancer resistance protein (BCRP, ABCG2) is a drug efflux transporter that is believed to affect the drug disposition of several drugs and xenobiotics. In the present study, we evaluated the localization and functional expression of BCRP in the human choriocarcinoma cell line BeWo, an in vitro model of the human trophoblast, and compared it with the expression of P-glycoprotein (MDR1, ABCB1) as the most widely studied placental transporter. In addition, the expression of BCRP at the mRNA level was compared with that of MDR1 in the human term placenta. 2. Western blotting analysis revealed high endogenous expression of BCRP protein in BeWo cells. Using indirect immunofluorescence microscopy, we found that the BCRP transporter appears to be localized predominantly at the apical plasma membrane. Functional studies showed a significant effect of the BCRP inhibitors GF120918 (5 mmol/L) and Ko143 (1 mmol/L) on mitoxantrone accumulation and, thus, confirmed efflux activity of BCRP in BeWo cells. 3. Using absolute mRNA quantification with real-time reverse transcription–polymerase chain reaction, we found high expression of BCRP in BeWo cells, whereas no transcript of MDR1 (P-glycoprotein), the most extensively studied drug transporter, was detected. 4. In the human placenta, BCRP was localized predominantly in the syncytiotrophoblast layer; however, immunopositivity for the BXP-21 antibody was also observed in fetal vessels of the chorionic villi. The number of BCRP transcripts in the human term placenta was found to be more than 10-fold higher compared with the expression of MDR1. 5. In conclusion, we suggest that BeWo cells could serve as a suitable in vitro model to study trans-trophoblast transport of BCRP substrates and that placental BCRP can play an important role in preventing the accumulation of potentially toxic xenobiotics in the trophoblast cells. [ABSTRACT FROM AUTHOR]

The aeration systems of two full-scale, activated-sludge basins were compared during a period of three years, under the same operating conditions, using dynamic offgas testing. Only the material of the diffuser was different (membrane versus ceramic-tube diffusers). The investigation has shown that, although the membrane diffusers have higher initial standard-oxygen-transfer efficiency (αSOTE) and standard-aeration efficiency (αSAE), these decreased over time, while the αSAE of the ceramic diffusers started lower, but increased slightly over the whole period. A cost comparison makes clear how important it is to evaluate the aeration system under process conditions. The operating costs were the dominant factor (∼10x higher than capital costs), and operating costs were approximately 20% higher for membrane versus ceramic diffusers. The poor performance of the membrane-tube diffusers under process conditions could be explained on the basis of the actual αAE values in the basin, not the standardized values. [ABSTRACT FROM AUTHOR]

Reconsiders the comparison of historical and contemporary nitrate concentrations in the Des Moines River. Average annual nitrate concentrations in the river; Correlation of nitrate concentration with stream discharge; Installation of artificial subsurface drainage systems in many rivers.

Presents a study that determined if streamflow characteristics have changed in Iowa's streams since the early to mid-20th century. Methodology; Relation of streamflow to watershed characteristics; Trends in streamflow characteristics over time.

A variety of white-rot fungi can oxidize textile dyes under sterile conditions; however, an important consideration for their use in treating wastewater containing textile dyes is whether similar degrees of treatment can be achieved under non-sterile conditions. Four strategies were investigated for their potential in optimizing the use of the fungus Trametes versicolor in non-sterile culture for treating wastewater containing the diazo textile dye C.I. Reactive Black 5 (RB5). Three strategies with suspended culture were designed to increase the decolorization activity in suspended culture from a given amount of T. versicolor inoculum based on its tolerance of low pH (pH reduction in medium), production of extracellular enzymes (use of suspended enzymes alone), and its ability to produce enzymes independent of growth (nitrogen limitation in medium). The results showed that reduction of the medium pH to 3 did not suppress bacterial growth, while enzyme production by T. versicolor ceased. The use of the extracellular enzymes alone would allow the decoupling of the process of fungal growth from wastewater treatment; however, the enzyme activity of an enzyme suspension decreased rapidly under non-sterile conditions. The strategy of limiting nitrogen in the medium to suppress bacterial growth has potential together with the fourth strategy, the cultivation of fungi on organic solids to produce inocula for a decolorization process under non-sterile conditions. A high degree of decolorization of RB5 under non-sterile conditions was achieved with T. versicolor grown on grains as sole substrate. The rate of decolorization was dependent on the amount of fungal inoculum used. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 736–744, 2003. [ABSTRACT FROM AUTHOR]

Summary. Relapses in non-Hodgkin's lymphomas (NHL) could be due to the reappearance of the initial neoplasm or new primary tumours. Discrimination between the two events would allow a more targeted therapeutic approach. VDJ rearrangement was used as marker of clonality in metachronous biopsy specimens from 10 patients with relapsed B-NHL. Complimentarity determining region 3 was amplified and sequenced. D-JH was identical in eight matched primary/secondary tumours, confirming the diagnosis of recurrence. In contrast, primary and secondary tumours in two patients were of different clonal origin. Our data indicate that VDJ analysis is a fundamental tool for identificaton of relapses in NHL. [ABSTRACT FROM AUTHOR]

BSTRACT: Many studies of ground water pollution in general and nitrate contamination in particular have often relied on a one-time investigation, tracking of individual wells, or aggregate summaries. Studies of changes in spatial distribution of contaminants over time are lacking. This paper presents a method to compare spatial distributions for possible changes over time. The large-scale spatial distribution at a given time can be considered as a surface over the area (a trend surface). The changes in spatial distribution from period to period can be revealed by the differences in the shape and/or height of surfaces. If such a surface is described by a polynomial function, changes in surfaces can be detected by testing statistically for differences in their corresponding polynomial functions. This method was applied to nitrate concentration in a population of wells in an agricultural drainage basin in Iowa, sampled in three different years. For the period of 1981-1992, the large-scale spatial distribution of nitrate concentration did not show significant change in the shape of spatial surfaces; while the magnitude of nitrate concentration in the basin, or height of the computed surfaces showed significant fluctuations. The change in magnitude of nitrate concentration is closely related to climatic variations, especially in precipitation. The lack of change in the shape of spatial surfaces means that either the influence of land use/nitrogen management was overshadowed by climatic influence, or the changes in land use/management occurred in a random fashion. [ABSTRACT FROM AUTHOR]

Since 1982, the Iowa Groundwater Monitoring (IGWM) Program has been used to sample untreated groundwater from Iowa municipal wells for selected agricultural chemicals. This long-term database was used to determine if concentrations of select agricultural chemicals in groundwater have changed with time. Nitrate, alachlor [2-chloro-2'-6'- diethyl-N-(methoxymethyl)-acetanilide, atrazine (2-chloro-4- ethylamino-6-isopropylamino-s-triazine), cyanazine (2-[[4- chloro-6- (ethylamino)-1,3,5-triazin-2-yl]amino]-2-methylpro pionitrile)], and metolachlor [2-chloro-N-(2-ethyl-6- methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide] were selected for this temporal analysis of the data. Conclusive temporal changes in frequency of detection and median chemical concentrations were found only for atrazine (decrease) and metolachlor (increase). The greatest temporal chemical changes occurred in the shallowest wells and in alluvial aquifers both relating to groups of wells generally having the youngest groundwater age. The temporal patterns found for atrazine and metolachlor are consistent with their patterns of chemical use and/or application rates and are suggestive of acausal relation. Only continued data collection, however, will indicate if the trends in chemical concentrations described here representlong-term temporal patterns or only short-term changes in groundwater. No definitive answers could be made in regards to the question of overall improvements in groundwater quality with respect to agricultural chemical contamination and time, due to the inherent problems with the simplistic measurement of overall severity (summation of alachlor + atrazine + cyanazine + metolachlor concentrations) examined for this study. To adequately determine if there is an actual decreasing trend in the overall severity of contamination (improving groundwaterquality), the collection of additional water-chemistry date and the investigation of other measures of severity are needed. [ABSTRACT FROM AUTHOR]