APPLICATION OF ADVANCED COMBUSTION MODELS IN INTERNAL COMBUSTION ENGINES BASED ON 3-D CFD LES APPROACH

This paper deals with the application of advanced simulation techniques for combustion modeling in the case of an internal combustion engine. The main focus is put on models with a high predictive ability hence 3-D CFD was selected while using LES (turbulence model) and detailed chemistry (both SI and CI ICE) or turbulent flame propagation (SI ICE). Both engine types are considered – spark ignited ICE and a compression ignited engine. Examples are shown and comparison with available experimental data is presented. The main conclusion is that such models are capable of high quality predictions while very little tuning is needed. This is desired as such models could be applied in the early phases of ICE development. On the other hand, such calculations are very demanding in terms of computational power

Simulation of flame lift-off on a diesel jet using a generalized flame surface density modeling approach

A generalized flame surface density modelling approach is presented to simulate the transient ignition and flame stabilization of a diesel jet flame, for which experimental data are available. The approach consists of four submodels: a mixing model, a generalized flame surface density model, a generalized progress variable model, and a chemistry model. A database containing the laminar model reaction rates per unit generalized flame surface density is generated by solving the unsteady flamelet equations. The RANS-CFD code solves for the mean flame surface density and mean progress variable. The coupling of the models is done via the progress variable and the scalar dissipation rate. The proposed approach is found to be adapted to simulate such a lifted flame and yields good trend agreement for ignition delay and flame lift-off vs. liquid penetration. These first promising results are encouraging to further explore and to apply this method to a more industrial configuration such as a diesel engin

A generalized flame surface density modelling approach for the auto-ignition of a turbulent non-premixed system

Auto-ignition of turbulent non-premixed systems is encountered in practical devices such as diesel internal combustion engines. It remains a challenge for modellers, as it exhibits specific features such as unsteadiness, flame propagation and combustion far from stoichiometric conditions. In this paper, a two-dimensionalDNSdatabase of an ignitingH2/O2/N2 mixing layer, including detailed chemistry and transport, is extensively post-processed in order to gain physical insight into the flame structure and dynamics during auto-ignition. The results are used as a framework for the development of a generalized flame surface density modelling approach by integrating the equations over all possible mixture fraction values. The mean reaction rate is split into two contributions: a generalized flame surface density and a mean reaction rate per unit generalized flame surface density. The unsteadiness of the ignition phenomenon is accounted for via a generalized progress variable. Closures for the generalized surface average of the reaction rate and for the generalized progress variable are proposed, and the modelling approach is tested a priori versus the DNS data. The use of a laminar database for the chemistry coupled to the mean turbulent field via the generalized progress variable shows very promising results, capturing the correct ignition delay and the premixed peak in the turbulent mean heat release rate evolution. This allows confidence in future inclusion and validation of this approach in a RANS-CFD code

Detection and Control of Fungal Outbreaks.

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The High-Quality Complete Genome Sequence of the Opportunistic Fungal Pathogen Candida vulturna CBS 14366T

Candida vulturna is a new member of the Candida haemulonii species complex that recently received much attention as it includes the emerging multidrug-resistant pathogen Candida auris. Here, we describe the high-quality genome sequence of C. vulturna type strain CBS 14366T to cover all genomes of pathogenic C. haemulonii species complex members

Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST)

826 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Overall population safety (30-600 mg starting doses) and efficacy in the response-evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 [56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with mDOR of 10.2 months (95% CI: 7.2–NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3–NE). Most AEs were grade 1–2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3–4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows impressive activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Blueprint Medicines