A multifactorial \u2018Consensus Signature\u2019 by in silico analysis to predict response to neoadjuvant anthracycline-based chemotherapy in triple-negative breast cancer

BACKGROUND: Owing to the complex processes required for anthracycline-induced cytotoxicity, a prospectively defined multifactorial Consensus Signature (ConSig) might improve prediction of anthracycline response in triple-negative breast cancer (TNBC) patients, whose only standard systemic treatment option is chemotherapy. AIMS: We aimed to construct and evaluate a multifactorial signature, comprising measures of each function required for anthracycline sensitivity in TNBC. METHODS: ConSigs were constructed based on five steps required for anthracycline function: drug penetration, nuclear topoisomerase II\u3b1 (topoII\u3b1) protein location, increased topoII\u3b1 messenger RNA (mRNA) expression, apoptosis induction, and immune activation measured by, respectively, HIF1\u3b1 or SHARP1 signature, LAPTM4B mRNA, topoII\u3b1 mRNA, Minimal Gene signature or YWHAZ mRNA, and STAT1 signature. TNBC patients treated with neoadjuvant anthracycline-based chemotherapy without taxane were identified from publicly available gene expression data derived with Affymetrix HG-U133 arrays (training set). In silico analyses of correlation between gene expression data and pathological complete response (pCR) were performed using receiver-operating characteristic curves. To determine anthracycline specificity, ConSigs were assessed in patients treated with anthracycline plus taxane. Specificity, sensitivity, positive and negative predictive value, and odds ratio (OR) were calculated for ConSigs. Analyses were repeated in two validation gene expression data sets derived using different microarray platforms. RESULTS: In the training set, 29 of 147 patients had pCR after anthracycline-based chemotherapy. Various combinations of components were evaluated, with the most powerful anthracycline response predictors being ConSig1: (STAT1+topoII\u3b1 mRNA +LAPTM4B) and ConSig2: (STAT1+topoII\u3b1 mRNA+HIF1\u3b1). ConSig1 demonstrated high negative predictive value (85%) and high OR for no pCR (3.18) and outperformed ConSig2 in validation sets for anthracycline specificity. CONCLUSIONS: With further validation, ConSig1 may help refine selection of TNBC patients for anthracycline chemotherapy

Morphological and Chemical Traits of Cladonia Respond to Multiple Environmental Factors in Acidic Dry Grasslands

Terricolous lichen communities in lowlands occur especially in open dry habitats. Such communities are often dominated by species of the genus Cladonia, which are very variable in morphology, reproduction strategies, and secondary metabolites. In this work, we investigated traits-environment relationships considering vegetation dynamics, substrate pH, disturbance, and climate. A total of 122 plots were surveyed in 41 acidic dry grasslands in the western Po Plain (Northern Italy). Relationships between Cladonia traits and environmental variables were investigated by means of a model-based Fourth Corner Analysis. Thallus morphology and metabolites responded to vegetation dynamics, substrate pH, disturbance, and climate, whereas reproduction strategies responded only to vegetation dynamics. Traits\u2019 correlations with vegetation dynamics elucidate their colonization patterns in open dry habitats or suggest biotic interactions with bryo-phytes and vascular plants. In addition, correlations between metabolites and environmental factors support interpretations of their ecological roles. Our results also stress the importance of studying traits\u2019 relationships with climatic factors as an alert towards lichen reactions to climate change

Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect

AbstractClinical and experimental biomedical studies have shown Type 2 diabetes mellitus (T2DM) to be a risk factor for the development of Alzheimer's disease (AD). This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models. Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD. Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect. Comparable results were obtained using peripheral blood mononuclear cells. Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression

Life-stage dependent response of the epiphytic lichen Lobaria pulmonaria to climate

Lichens are poikilohydric organisms, whose internal water content tends to reflect external humidity conditions. After drying, they can reactivate their metabolic activity through water vapor uptake or liquid water input. Thus, lichen water-related functional traits are important as they are involved in the duration of the hydrated period. Models predicting the effect of environmental conditions on lichens are based mainly on the presence or absence of adult thalli. Nevertheless, ecological conditions required by lichens might vary during their life cycle, for example during propagule establishment or in the first stages of thallus development. Little is known about the different ecological requirements at the different development stages in lichens. In this work, we measured water holding capacity (WHC) and specific thallus mass (STM) of adult and juvenile thalli of the model species Lobaria pulmonaria along a climatic gradient to constrain the processbased model LiBry. The LiBry model allows accounting for the productivity of lichens with different physiological strategies under various environmental conditions. We simulated the activity and performance of adult and juvenile thalli in 9 regions of Italy and Corsica. The model was used to test if adult thalli of L. pulmonaria have a higher survival probability due to their higher aerodynamic resistance. In the current climatic condition, the LiBry model predicts a higher survival probability of adults with decreasing absolute survival rates of both life stages with increasing temperature. Adult thalli also result in having higher active time, STM, and relative growth rate (RGR). We discuss the main implications of our simulation outputs, provide future perspectives and possible implementations of the LiBry mode

Lobaria pulmonaria (L.) Hoffm.: The Multifaceted Suitability of the Lung Lichen to Monitor Forest Ecosystems

Lobaria pulmonaria (L.) Hoffm. is a tripartite, broad-lobed foliose lichen usually found on bark and on epiphytic and epilithic mosses in humid forests. Currently, the species is threatened in most European countries because of its sensitivity to environmental alterations. In this paper, a total of 107 previous studies across more than 50 years were analysed to gain insight into the multiple roles that L. pulmonaria plays in forest habitats, specifically relating to ecosystem services and as environmental bioindicator. Content analysis was employed to systematically characterise and classify the existing papers on the functions performed by L. pulmonaria into several groups mostly based on research topic and scope. Two main types of ecosystem services (N2 fixation and feeding) offered by L. pulmonaria have been identified, with varying research aims and types of parameters measured in the studies. Two aspects of current biomonitoring applications using L. pulmonaria in forest habitats (concerning atmospheric pollution and forest management) were analysed, and it was found that the number of related studies increased significantly in recent years. Finally, the current practices of monitoring using L. pulmonaria as a biological indicator are discussed, and recommendations are provided

The Key Role of Memory in Next-Generation Embedded Systems for Military Applications

With the increasing use of multi-core platforms in safety-related domains, aircraft system integrators and authorities exhibit a concern about the impact of concurrent access to shared-resources in the Worst-Case Execution Time (WCET). This paper highlights the need for accurate memory-centric scheduling mechanisms for guaranteeing prioritized memory accesses to Real-Time safety-related components of the system. We implemented a software technique called cache coloring that demonstrates that isolation at timing and spatial level can be achieved by managing the lines that can be evicted in the cache. In order to show the effectiveness of this technique, the timing properties of a real application are considered as a use case, this application is made of parallel tasks that show different trade-offs between computation and memory loads

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post‐Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin‐binding protein cyclase‐associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post‐mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non‐psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson’s and Alzheimer’s disease. Interestingly, also in Parkinson’s disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies