Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the ...aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.
Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant ...protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible. To address this problem we introduce and experimentally validate a new algorithm, virtual inference of protein activity by enriched regulon analysis (VIPER), for accurate assessment of protein activity from gene expression data. We used VIPER to evaluate the functional relevance of genetic alterations in regulatory proteins across all samples in The Cancer Genome Atlas (TCGA). In addition to accurately infer aberrant protein activity induced by established mutations, we also identified a fraction of tumors with aberrant activity of druggable oncoproteins despite a lack of mutations, and vice versa. In vitro assays confirmed that VIPER-inferred protein activity outperformed mutational analysis in predicting sensitivity to targeted inhibitors.
To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human ...tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer.
•Assembly of cross-species regulatory networks supports genome-wide interrogation•Cross-species interrogation identifies conserved master regulators of malignancy•FOXM1 and CENPF interact synergistically to drive malignant prostate cancer•Co-expression of FOXM1 and CENPF is prognostic for prostate cancer outcome
Aytes et al. assembled human and mouse prostate cancer gene regulatory networks and applied cross-species computational analyses to find master regulators. They identified FOXM1 and CENPF, which cooperate to coordinate an expression program that promotes prostate cancer malignancy, illustrating the strategy’s utility.
When claiming territories, States use all kinds of legal, geographical, and historical arguments, as well aseffectivités. In recent maritime cases, States have begun using underwater archaeology and ...submerged heritage as a basis for their claims. This book takes a critical look at that policy.
We evaluated the MYD88 L265P mutation in Waldenström's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity ∼10(-3)). No mutation ...was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P=0.022), more lymphocytosis (24 vs 5%, P=0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P=0.002), atypical immunophenotype (CD23-CD27+ +FMC7+ +), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P=0.012) and less IGHV3-23 gene selection (9 vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival.
Advances in surfactants for agrochemicals Castro, Mariano J. L; Ojeda, Carlos; Cirelli, Alicia Fernández
Environmental chemistry letters,
03/2014, Letnik:
12, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pesticide efficacy is improved by surfactants. Increase in the foliar uptake is particularly useful for herbicides, growth regulators and defoliants, because less active compounds are needed, thus ...decreasing cost and pollution. Therefore, the choice of the adjuvant in an agrochemical formulation is crucial. The surfactants commonly used as adjuvants include anionic, non-ionic, amphoteric and cationic surfactants. This review analyses the role and properties of the new adjuvants for agriculture and the improvement of the ecotoxicity profile of the pesticide formulations in glyphosate formulation.
Citizen science (CS) currently refers to the participation of non-scientist volunteers in any discipline of conventional scientific research. Over the last two decades, nature-based CS has flourished ...due to innovative technology, novel devices, and widespread digital platforms used to collect and classify species occurrence data. For scientists, CS offers a low-cost approach of collecting species occurrence information at large spatial scales that otherwise would be prohibitively expensive. We examined the trends and gaps linked to the use of CS as a source of data for species distribution models (SDMs), in order to propose guidelines and highlight solutions. We conducted a quantitative literature review of 207 peer-reviewed articles to measure how the representation of different taxa, regions, and data types have changed in SDM publications since the 2010s. Our review shows that the number of papers using CS for SDMs has increased at approximately double the rate of the overall number of SDM papers. However, disparities in taxonomic and geographic coverage remain in studies using CS. Western Europe and North America were the regions with the most coverage (73%). Papers on birds (49%) and mammals (19.3%) outnumbered other taxa. Among invertebrates, flying insects including Lepidoptera, Odonata and Hymenoptera received the most attention. Discrepancies between research interest and availability of data were as especially important for amphibians, reptiles and fishes. Compared to studies on animal taxa, papers on plants using CS data remain rare. Although the aims and scope of papers are diverse, species conservation remained the central theme of SDM using CS data. We present examples of the use of CS and highlight recommendations to motivate further research, such as combining multiple data sources and promoting local and traditional knowledge. We hope our findings will strengthen citizen-researchers partnerships to better inform SDMs, especially for less-studied taxa and regions. Researchers stand to benefit from the large quantity of data available from CS sources to improve global predictions of species distributions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Marine Protected Area (MPA) Namuncurá−Burdwood Bank was created in 2013 to protect the benthic community. After five years of multidisciplinary research, it was reorganized, and a second, ...contiguous MPA Namuncurá−Burdwood Bank II was created. The objectives of this study were to evaluate the decapod assemblages in both the previous and current management zones and to compare them with the neighboring areas of southern South America. The decapod fauna was studied integratively by comparing captured species onboard scientific expeditions with online records. Our study showed that the original design of the MPAN−BB had the lowest decapod species richness. However, the constitution of a larger protected area, including the slope, increased the species richness, with unique records of Campylonotus arntzianus and Lithodes couesi. The MPA could be considered ecologically representative as it shares various species with the nearby areas (the Beagle Channel and the Atlantic). Furthermore, we theorize it could act as a “hub” for decapod species as marine currents provide the Burdwood Bank with new individuals from the west and disperse them northward to the Patagonian Shelf and eastward to the Scotia Arc. This result shows the great value of protecting this area, ensuring the conservation of the decapod fauna of southern South America.
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state ...heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.
Eradicating triple-negative breast cancer (TNBC) resistant to neoadjuvant chemotherapy (NACT) is a critical unmet clinical need. In this study, patient-derived xenograft (PDX) models of ...treatment-naïve TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after treatment with standard frontline chemotherapies, doxorubicin (Adriamycin) combined with cyclophosphamide (AC), maintained the subclonal architecture of untreated tumors, yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to AC-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as an AC resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes and maintenance of stable subclonal architecture, demonstrating that AC-treated PDXs capture molecular features characteristic of human TNBC chemoresistance. Last, pharmacologic inhibition of oxidative phosphorylation using an inhibitor currently in phase 1 clinical development delayed residual tumor regrowth. Thus, AC resistance in treatment-naïve TNBC can be mediated by nonselective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.
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