VOF Simulation of The Cavitating Flow in High Pressure GDI Injectors

The paper describes the development in the OpenFOAM ® technology of a dynamic multiphase Volume-of-Fluid (VoF) solver, supporting mesh handling with topological changes, that has been used for the study of the physics of the primary jet breakup and of the flow disturbance induced by the nozzle geometry during the injector opening event in high-pressure Gasoline Direct Injection (GDI) engines. Turbulence modeling based on a scale-resolving approach has been applied, while phase change of fuel is accounted by means of a cavitation model that has been coupled with the VOF solver. Simulations have been carried out on a 6-hole prototype injector, especially developed for investigations in the framework of the collaborative project FUI MAGIE and provided by Continental Automotive SAS. Special attention has been paid to the domain decomposition strategy and to the code development of the solver, to ensure good load balancing and to minimize inter-processor communication, to achieve good performance and also high scalability on large computing clusters

Ultrastructural changes in enterocytes in subjects with Hashimoto's thyroiditis

We have recently described1 mucosal ultrastructural impairments, such as height and thickness of microvilli, space between microvilli, and thickness of tight junctions, in non-coeliac type 1 diabetic patients after a preliminary report of an alteration in intestinal mucosal permeability (IP) evaluated by the lactulose/mannitol (LA/MA) test.2,3 Therefore, in the “aetiological” classification of autoimmunity based on initiating factors,4 the category of diet induced diseases could be expanded to include type 1 diabetes and, perhaps, other endocrine autoimmune diseases. Thyroiditis is the most frequently associated autoimmune endocrine disease with type 1 diabetes. Moreover, type 1 diabetes and Hashimoto thyroiditis present similar pathogenetic mechanisms of cellular damage, a cell mediated autoimmunity induced by Th1 cytokines. However, mucosal intestinal morphology and function have not yet been studied in autoimmune thyroiditis patients. Hence we investigated intestinal mucosal ultrastructural morphology and IP in a group of patients with autoimmune thyroiditis. The study was approved by the local ethics committee. Fourteen patients (12 females and 2 males; mean age 33.2 (SD 10.2) years) and 23 controls (12 females and 11 males; mean age 27.9 (SD 8.01) years) were enrolled into the study after giving written informed consent. The diagnosis of autoimmune thyroiditis was based on the following criteria: plasma autoantibody TPO positive at high titre and a typical thyroiditis ultrasound pattern. All patients were in euthyroidism (normal FT3, FT4, and TSH plasma levels without hormonal therapy). Mean duration of known disease was 5.2 (2.5) years. All patients were negative for the presence of antigliadin antibodies IgA and IgG, antiendomysium antibodies IgA, as well as antihuman transglutaminase IgA following a gluten rich Mediterranean diet. Type 1 diabetes mellitus was excluded according to the 1997 American Diabetes Association criteria, and none of the participants had a family history of diabetes mellitus. Other intestinal and endocrine diseases were excluded through clinical and, when indicated, laboratory evaluation. Food or other allergies were excluded. None of the subjects reported gastrointestinal signs or symptoms, or was a habitual smoker, abuser of alcohol, or regularly took non-steroidal anti-inflammatory drugs

Preliminary efficacy and safety data of nivolumab in never smoker patients with advanced squamous NSCLC: Experience from Italian sites participating in the Expanded Access Programme (EAP)

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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

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

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

Survivin promoter -31G/C polymorphism in oral cancer cell lines.

Survivin (SVV) is a protein that belongs to the inhibitor of apoptosis proteins (IAP) family and is involved in the G2/M phase progression of the cell cycle as a spindle-associated molecule. The biological features of this protein are well documented and its activity appears to be involved in mitochondria-dependent and -independent antiapoptotic pathways. Overexpression of SVV at the transcriptional and translational level has been associated with cancer, a multifactorial disorder in which the occurrence of a -31G to C polymorphism in the promoter region may significantly contribute to the development of this pathology. To verify this hypothesis, the occurrence of a single nucleotide polymorphism (SNP) in cis-acting cell cycle-dependent elements (CDEs) and in cell cycle homology regions (CHRs) of the survivin TATA-less promoter was investigated. A total of 23 oral squamous cell carcinoma (OSCC) cell lines and normal epithelium-derived normal human epidermal keratinocyte (NHEK) cell lines were analyzed by RFLP and direct DNA sequencing of their promoter region. Furthermore, survivin expression at the transcriptional and translational levels was evaluated in these cells by RT-PCR and Western blotting, respectively. The findings indicate that the presence of a G or C allele is not directly correlated to survivin expression, at the mRNA or at the protein level, at least in the OSCC lines analyzed in this study

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

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