Arabidopsis thaliana response to extracellular dna: Self versus nonself exposure

The inhibitory effect of extracellular DNA (exDNA) on the growth of conspecific individuals was demonstrated in different kingdoms. In plants, the inhibition has been observed on root growth and seed germination, demonstrating its role in plant\u2013soil negative feedback. Several hypotheses have been proposed to explain the early response to exDNA and the inhibitory effect of conspecific exDNA. We here contribute with a whole-plant transcriptome profiling in the model species Arabidopsis thaliana exposed to extracellular self-(conspecific) and nonself-(heterologous) DNA. The results highlight that cells distinguish self-from nonself-DNA. Moreover, confocal microscopy analyses reveal that nonself-DNA enters root tissues and cells, while self-DNA remains outside. Specifically, exposure to self-DNA limits cell permeability, affecting chloroplast functioning and reactive oxygen species (ROS) production, eventually causing cell cycle arrest, consistently with macroscopic observations of root apex necrosis, increased root hair density and leaf chlorosis. In contrast, nonself-DNA enters the cells triggering the activation of a hypersensitive response and evolving into systemic acquired resistance. Complex and different cascades of events emerge from exposure to extracellular selfor nonself-DNA and are discussed in the context of Damage-and Pathogen-Associated Molecular Patterns (DAMP and PAMP, respectively) responses

Energy, forest, and indoor air pollution models for Sagarmatha National Park and Buffer Zone, Nepal

This paper presents the results of management-oriented research on energy, forest, and human health issues in a remote mountain area, the Sagarmatha National Park and Buffer Zone (SNPBZ), Nepal. The research was based on a broader, integrated participatory framework ultimately intended for use in adaptive management. The present study focused on the application of a participatory modeling framework to address problems related to energy demand and consumption, forest condition, and indoor air pollution, which were defined by the stakeholders as important issues to be addressed. The models were developed using a generalizing design that allows for user-friendly adaptation to other contexts (free download at http://hkkhpartnership.org). Moreover, we simulated management scenarios in collaboration with all modeling actors with the aim of building consensus on the understanding of the system as well as supporting decision-makers' capacity not only to respond to changes, but also to anticipate them. Importantly, the system dynamics assessment found that the SNPBZ forests are affected by an increasing demand for fuelwood (occurring due to tourism growth), as one of the main sources of energy. Selected forests show an average reduction of 38 in forest biomass from 1992 to 2008. This shows that the business-as-usual scenario is unlikely to result in the preservation of the current forest status; in fact, such preservation would require 75 of fuelwood to be replaced with alternative energy sources. At the same time, a 75 reduction of fuelwood use (and an 80 reduction of dung use) would reduce indoor carbon monoxide (CO) concentrations to the standard limits for CO exposure set by the World Health Organization

53pimmune related adverse events correlate with clinical outcomes in non small cell lung cancer nsclc patients treated with nivolumab in the italian expanded access programme

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The changes of lipid metabolism in advanced renal cell carcinoma patients treated with everolimus: A new pharmacodynamic marker?

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. Methods: 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. Results: Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C, T and C +T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p =0.030), C (8 vs 5, p =0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. Conclusion: C+T raise is an early predictor for everolimus efficacy for patients with mRCC

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: A Phase III study

BACKGROUND. The noninferiority of a 6-week dosing schedule of lanreotide Auto-gel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). METHODS. Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase 111, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase < 25% in tumor marker, tumor size, or symptom frequency. RESULTS. Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. CONCLUSIONS. Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

A distribution regional freight demand model

The complexity of freight mobility is characterized by a large number of journeys connecting several activities in different locations, i.e., journeys consisting of sequences of trips influencing each other. This paper presents a tour-based freight model for the simulation of regional distribution. This kind of model allows to simulate the dependences existing between successive trips of the same distribution channel. That means that each destination will be chosen considering the preceding and successive destinations by considering the number of transfers as a whole, and so on. In order to implement such a model it is essential to understand the constraints linking all decision-maker’s choices and to identify the type of relations linking one decision-maker to the other

A distribution regional freight demand model

The complexity of freight mobility is characterized by a large number of journeys connecting several activities in different locations, i.e., journeys consisting of sequences of trips influencing each other. This paper presents a tour-based freight model for the simulation of regional distribution. This kind of model allows to simulate the dependences existing between successive trips of the same distribution channel. That means that each destination will be chosen considering the preceding and successive destinations by considering the number of transfers as a whole, and so on. In order to implement such a model it is essential to understand the constraints linking all decision-maker’s choices and to identify the type of relations linking one decision-maker to the other

System Dynamics modeling of tumor growth: a possible tool for optimization of pharmacological treatment?

Process-based modeling has been widely used to simulate the behavior of all kinds of biological systems. Recent modeling studies on plants, proposed a new concept of autotoxicity as a main driver, along environmental gradients, of plant systems development (Mazzoleni et al., 2010). The release of autotoxic compounds was showed to be responsible for the generation of ring-like spatial patterns of individual plants, presenting an increase of dead biomass in their central growth zone (Cartenì et al., 2012). This has been recently associated to the levels of washing out of turnover products, showing that the occurrence of spatial patterns is dependent on the balance between positive and negative feedbacks by nutrients and toxic products respectively (Marasco et al., 2013). In oncology, simulation modeling was used to understand and predict tumor growth and also to anticipate the effects of different therapies (Anderson and Quaranta, 2008). In this work we discuss the possible application of the autotoxicity hypothesis on modeling the growth of solid tumors. In particular, simulations are implemented showing the development and the spatial arrangement, in relation to different levels of vascularization, of 3 different layers: (i) proliferating, (ii) quiescent and (iii) necrotic cell