Formalizing, Verifying and Applying ISA Security Guarantees as Universal Contracts

Progress has recently been made on specifying instruction set architectures (ISAs) in executable formalisms rather than through prose. However, to date, those formal specifications are limited to the functional aspects of the ISA and do not cover its security guarantees. We present a novel, general method for formally specifying an ISAs security guarantees to (1) balance the needs of ISA implementations (hardware) and clients (software), (2) can be semi-automatically verified to hold for the ISA operational semantics, producing a high-assurance mechanically-verifiable proof, and (3) support informal and formal reasoning about security-critical software in the presence of adversarial code. Our method leverages universal contracts: software contracts that express bounds on the authority of arbitrary untrusted code. Universal contracts can be kept agnostic of software abstractions, and strike the right balance between requiring sufficient detail for reasoning about software and preserving implementation freedom of ISA designers and CPU implementers. We semi-automatically verify universal contracts against Sail implementations of ISA semantics using our Katamaran tool; a semi-automatic separation logic verifier for Sail which produces machine-checked proofs for successfully verified contracts. We demonstrate the generality of our method by applying it to two ISAs that offer very different security primitives: (1) MinimalCaps: a custom-built capability machine ISA and (2) a (somewhat simplified) version of RISC-V with PMP. We verify a femtokernel using the security guarantee we have formalized for RISC-V with PMP

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.</p

Development and external validation of a prediction model for tube feeding dependency for at least four weeks during chemoradiotherapy for head and neck cancer

Background & aims: Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF ≥ 4 weeks and would benefit from prophylactic gastrostomy insertion. Methods: A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency ≥4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose–volume parameters were calculated. Results: The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency ≥4 weeks were 81.8% and 42.3% respectively. Conclusions: We developed and externally validated a prediction model to estimate TF-dependency ≥4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice

Influence of air/hydrogen momentum ratio, equivalence ratio and dilution hole geometry on the performance of a micromix combustor for a 100 kWe mGT

Against the background of a growing deployment of renewable electricity production, like wind and solar, the demand for energy storage will only increase. One of the most promising ways to cover the medium to long-term storage is to use the excess electricity to produce hydrogen via electrolysis. In a modern energy grid, filled with intermittent power sources and everincreasing problems to construct large power plants in densely populated areas, a network of Decentralised Energy Systems (DES) seems more logical. Consequently, building a previous work, there is a need for the design and optimisation of a hydrogen fuelled micro Gas Turbine (mGT). This paper focusses on our continued development and optimisation of the low-NOx hydrogen combustion chamber, using steady-state RANS CFD simulations. To further optimise the primary zone of the combustor, this work concentrates on the specific impact of the air/fuel momentum ratio, the primary zone equivalence ratio and dilution zone geometry on the combustor performance. First, the air mass flow rate and the hydrogen inlet pressure are varied within a specified control range. This results in a range for the momentum ratio and the equivalence ratio for which we can analyse the resultant NOx concentration at the combustor outlet. This allows the momentum ratio and the equivalence ratio to be optimally chosen for a new primary zone combustor geometry with lower NOx formation. In a second step, this primary zone design is completed with an initial and separately optimised design of the secondary air zone or dilution zone. An analysis was made on the variation of several key dilution zone design parameters such as; the diameter of a dilution hole, the number of dilution holes in a single row, the variation in size between the holes in the same row and the distance from the centre of the single row of dilution holes to the combustor head. This parameter variation study affected the secondary air mass flow rate, the average outlet temperature, the outlet temperature homogeneity and the NOx emissions at the combustor outlet, on the basis of which a first simple, single dilution hole row is proposed and optimised. Both the final optimisation of the primary zone and the optimisation of the secondary zone will come together a new micromix combustor geometry that will be part of the future work and will be included in the presentation at GT2023.<br/

Prediction model for tube feeding dependency during chemoradiotherapy for at least four weeks in head and neck cancer patients: A tool for prophylactic gastrostomy decision making

Background & aims: Chemoradiation and bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often comes with high toxicity rates, interfering with oral intake and leading to temporary tube feeding (TF) dependency. High-quality scientific evidence for indicators of prophylactic gastrostomy insertion is not available. The aim of this retrospective cohort study was to develop a prediction model to identify patients who need prophylactic gastrostomy insertion, defined as the expected use of TF for at least four weeks. Methods: Four-hundred-fifty LAHNSCC patients receiving CRT/BRT with curative intent between 2013 and 2016 were included in the study. Primary outcome was TF-dependency for four weeks or longer. Patient, tumor, and treatment characteristics were extracted from the medical records and their effects on the use of TF were analyzed using univariable and multivariable analysis. The prediction model was internally validated using bootstrapping techniques. Results: Sixty-five percent (294/450 patients) required TF for four weeks or longer. Variables included in the model were: body mass index and adjusted diet at start of CRT/BRT, percentage weight change at baseline, World Health Organization performance status, tumor subsite, TNM-classification, CRT/BRT, mean radiation dose on the contralateral submandibular and parotid gland. The corrected Area Under the Curve after internal validation was 72.3%, indicating good discriminative properties of the prediction model. Conclusions: We developed and internally validated a prediction model that is intended to estimate TF-dependency for at least four weeks in LAHNSCC patients treated with CRT/BRT. This model can be used as a tool to support personalized decision making on prophylactic gastrostomy insertion

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study

H2020 UNITED : is scour protection suitable for flat oyster restoration in Belgium?

Once a key habitat in the North Sea, European flat oyster (Ostrea edulis) reefs have completely disappeared in the Belgium part of the North Sea (BPNS) due to a combination of factors, including overexploitation, destruction by bottom trawling and diseases such as bonamiosis. Across Europe, a number of projects and initiatives are being deployed to bring back this iconic species and the associated ecosystem, but Belgium is trailing behind this wave of renewed interest in flat oyster restoration. However, with the UNITED project, a first and important initiative has started to restore flat oyster reefs in the BPNS. UNITED (2020-2023) is a research project co-funded by the European Union’s Horizon 2020 programme. The acronym UNITED stands for Multi-Use offshore platforms demoNstrators for boostIng cost-effecTive and Eco-friendly proDuction in sustainable marine activities. By installing specific test pilots at five different marine sites in five European countries, UNITED aims to assess the feasibility and added value of marine multi-use. The Belgian pilot focuses on a combination of flat oyster restoration and aquaculture, and sugar kelp (Saccharina latissima) aquaculture in an offshore wind farm. Belgian offshore wind farms might offer a unique environment for both flat oyster aquaculture and restoration. Bottom-disturbing activities such as trawling are forbidden here, while the scour protection around the wind turbine foundations might serve as a suitable substrate for oyster settlement. Recruitment from the aquaculture individuals can initiate and sustain natural oyster reef development on this scour protection, and as such restore a lost ecosystem in the BPNS. An overview of the oyster restoration activities within UNITED will be presented, including the latest, promising results of the nearshore experiments and the successful offshore (within an offshore wind farm) installation of oyster restoration structures, which house broodstock animals. Before moving offshore, the nearshore experiments have tested and optimised the restoration structures and investigated the settlement of flat oyster spat on different materials as well as the survival, growth and reproduction of flat oysters in aquaculture systems