Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.

Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

Validation of an LC-MS/MS method for the quantification IOA-289 in human plasma and its application in a first-in-human clinical trial.

IOA-289 is a novel small molecule inhibitor of autotaxin developed as a first-in-class therapy of fibrotic pathologies including cancer. A method for quantitation of IOA-289 in human plasma was developed using a stable isotope labeled compound ([13C4]IOA-289) as internal standard. The analytes were extracted from human plasma by protein precipitation and the analysis was performed by liquid chromatography coupled with tandem mass spectrometric detection (LCMS/MS). The chromatographic separation was performed with a gradient elution from a BEH C18 column and under these conditions the retention time and the run time were 1 and 2 min, respectively. The assay was fully validated over the range 3-3000 ng/mL, proved to be accurate, precise and selective and was successfully applied to quantitate IOA-289 in plasma samples from subjects in a first-in-humanclinical trial.

[Cereal related complaints in children]. / Granengerelateerde klachten bij kinderen.

There's a lot of attention for gluten-free diets on social media. Doctors get many questions about gluten sensitivity or possible wheat allergy. With some basic knowledge, it's easier to give answers to these questions and to prevent unnecessary and sometimes harmful diets. This article gives basic information about cereals, gluten, grasses and their crossreactivity. We give an overview about the differences between celiac disease, gluten sensitivity and IgE-mediated wheat allergy. We also describe diagnostics, treatment and natural history of coeliakie, gluten sensitivity and wheat or cereal allergy.

Uncertainty quantification patterns for multiscale models.

Uncertainty quantification (UQ) is a key component when using computational models that involve uncertainties, e.g. in decision-making scenarios. In this work, we present uncertainty quantification patterns (UQPs) that are designed to support the analysis of uncertainty in coupled multi-scale and multi-domain applications. UQPs provide the basic building blocks to create tailored UQ for multiscale models. The UQPs are implemented as generic templates, which can then be customized and aggregated to create a dedicated UQ procedure for multiscale applications. We present the implementation of the UQPs with multiscale coupling toolkit Multiscale Coupling Library and Environment 3. Potential speed-up for UQPs has been derived as well. As a proof of concept, two examples of multiscale applications using UQPs are presented. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

VECMAtk: a scalable verification, validation and uncertainty quantification toolkit for scientific simulations.

We present the VECMA toolkit (VECMAtk), a flexible software environment for single and multiscale simulations that introduces directly applicable and reusable procedures for verification, validation (V&V), sensitivity analysis (SA) and uncertainty quantication (UQ). It enables users to verify key aspects of their applications, systematically compare and validate the simulation outputs against observational or benchmark data, and run simulations conveniently on any platform from the desktop to current multi-petascale computers. In this sequel to our paper on VECMAtk which we presented last year [1] we focus on a range of functional and performance improvements that we have introduced, cover newly introduced components, and applications examples from seven different domains such as conflict modelling and environmental sciences. We also present several implemented patterns for UQ/SA and V&V, and guide the reader through one example concerning COVID-19 modelling in detail. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

Impact of early-life feeding on local intestinal microbiota and digestive system development in piglets.

Early-life gut microbial colonisation is known to influence host physiology and development, shaping its phenotype. The developing gastro-intestinal tract of neonatal piglets provides a "window of opportunity" for programming their intestinal microbiota composition and corresponding intestinal development. Here, we investigated the impact of early feeding on jejunum and colon microbiota composition, and intestinal maturation in suckling piglets. From two days of age, early-fed (EF; n = 6 litters) piglets had access to solid feed containing a mixture of fibres till weaning (day29) in addition to sow's milk, whereas the control (CON; n = 6 litters) piglets exclusively fed on sow's milk. Early feeding elicited a significant impact on the colon microbiota, whereas no such effect was seen in the jejunal and ileal microbiota. Quantified eating behavioural scores could significantly explain the variation in microbiota composition of EF piglets and support their classification into good, moderate, and bad eaters. Members of the Lachnospiraceae family, and the genera Eubacterium, Prevotella, and Ruminococcus were quantitatively associated with eating scores. EF piglets were found to have a decreased pH in caecum and colon, which coincided with increased short-chain fatty acid (SCFA) concentrations. Moreover, they also had increased weights and lengths of several intestinal tract segments, as well as a decreased villus-crypt ratio in jejunal mucosa and an increased abundance of proliferative cells in colon mucosa. The approaches in this study indicate that early feeding of a mixed-fibre (pre-weaning) diet changes the microbiota composition, pH, and fermentation products in the distal gut of piglets, while it also alters both macroscopic and microscopic intestinal measurements. These results exemplify the potential of early feeding to modulate intestinal development in young piglets.

Semi-intrusive multiscale metamodelling uncertainty quantification with application to a model of in-stent restenosis.

We explore the efficiency of a semi-intrusive uncertainty quantification (UQ) method for multiscale models as proposed by us in an earlier publication. We applied the multiscale metamodelling UQ method to a two-dimensional multiscale model for the wound healing response in a coronary artery after stenting (in-stent restenosis). The results obtained by the semi-intrusive method show a good match to those obtained by a black-box quasi-Monte Carlo method. Moreover, we significantly reduce the computational cost of the UQ. We conclude that the semi-intrusive metamodelling method is reliable and efficient, and can be applied to such complex models as the in-stent restenosis ISR2D model. This article is part of the theme issue 'Multiscale modelling, simulation and computing: from the desktop to the exascale'.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, ß values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.

[Respiratory insufficiency caused by acute disseminated encephalomyelitis in a child]. / Respiratoire insufficiëntie bij een kind door acute disseminerende encefalomyelitis.

A 1.5-year-old boy presented with progressive ataxia and meningeal irritation after a period of general malaise and fever. He was eventually admitted to a paediatric intensive care unit for respiratory insufficiency. A diagnosis of acute disseminated encephalomyelitis (ADEM) with pontine involvement was made. The patient was mechanically ventilated and treated with immunoglobulins and corticosteroids, after which he recovered almost completely. ADEM is characterised by rapidly progressive demyelination of the central nervous system. The exact incidence and aetiology are unknown. The disorder is considered to be an autoimmune reaction, and current treatment is aimed at the suppression of this reaction. Despite the dramatic clinical and radiological presentation of ADEM, the prognosis is favourable in most cases.

[A girl with breath-holding spells and anaemia, treated with iron supplementation]. / Een meisje met 'breath-holding spells' en anemie, behandeld door ijzersuppletie.

A girl aged 1.5 years was presented because of frequent breath-holding spells. Anaemia was also diagnosed. Iron supplementation reduced the frequency and severity of the spells until they fully disappeared. The pathophysiological relationship between breath-holding spells and anaemia has not been clarified, but iron supplementation appears to be effective in many patients.

[Conservative treatment of open incomplete radial fracture in an adult horse]. / Conservatieve behandeling van een open onvolledige radiusfractuur bij een volwassen paard.

A non-displaced radialfracture of a horse was,diagnosed. The horse had an open fracture resulting from external trauma. A diagnosis was made on radiographs taken 48h after trauma. The horse was treated conservatively by box rest and Robert-Jones bandages. After 7 days the wound was opened to let the wound drainage necrotic material and small sequesters and was washed every other day. After 7 weeks, radiographs showed complete consolidation. Four months after the injury the horse was back to work at his former level and is still working two years after the incident.

[Acute generalised exanthematous pustolosis in a 2-year-old girl following treatment with amoxicillin]. / Acute gegeneraliseerde exanthemateuze pustulosis bij een 2-jarig meisje na amoxicillinegebruik.

A two-year-old girl had had fever for one week, and since the previous day general malaise, cutaneous pustolosis with swollen hands and feet. The skin condition had developed three days after the start of amoxicillin therapy. Laboratory tests at the time of admission indicated an infection. The diagnosis was 'acute generalised exanthematous pustulosis' (AGEP). During treatment with a soothing lotion, lasting one week, the patient improved and the skin condition disappeared. AGEP is characterised by acute onset of a pustular eruption in association with fever. It is usually seen after the use of drugs. This is an uncommon disease in children.

[Toxic shock syndrome in 3 children]. / Toxischeshocksyndroom bij 3 kinderen.

A 16-year-old and a 10-year-old girl were admitted with general signs of illness, and respectively a green vaginal discharge and a panaritium. They recovered following antibiotic treatment and surgical relief of the panaritium. A 2-year-old boy became ill the morning after eating tainted cold meat; he died in the course of the following night. In all 3 patients Staphylococcus aureus was incubated with the toxic-shock-toxin-1-gene and/or the enterotoxin-A-gene. These 3 cases occurred within one year in a general hospital. TSS probably occurs more frequently than is generally assumed. Given that it is a life-threatening disease, rapid diagnosis is of major importance.

Studies of the transmission routes of Ornithobacterium rhinotracheale and immunoprophylaxis to prevent infection in young meat turkeys.

The importance and prevention of the horizontal as well as the vertical transmission of Ornithobacterium rhinotracheale were investigated. In our first experiment we observed that specific-pathogen-free broiler chickens that were placed in hatching incubators at a commercial turkey hatchery during hatch showed respiratory tract lesions at postmortem examination that were positive for O. rhinotracheale by bacteriology and immunohistology. It appeared that vertical transmission occurred and that horizontal transmission of O. rhinotracheale is possible. In a second experiment, the turkeys derived from vaccinated parents showed significantly fewer respiratory tract lesions at postmortem examination at 16 days of age than the birds derived from nonvaccinated parents. In a third experiment, all vaccinated young birds, regardless of the vaccination state of their parents, showed significantly fewer respiratory tract lesions at 6 wk of age. We concluded that vaccination of the breeders reduces vertical transmission and that vaccination of the progeny is needed to resist challenge at 6 wk of age.

[Bladder infection with Capillaria plica in a male dog]. / Blaasinfectie met Capillaria plica bij een sheltie reu.

In a male dog with symptoms of haematuria an infection with C. plica was established. During the first urine examination large numbers of erythrocytes and leucocytes were seen. The dog was treated with antibiotics. After 10 days a second urine examination revealed several eggs of C. plica, accompanied by leucocytes and erythrocytes. The infection was eliminated with fenbendazole treatment (50 mg/kg/day, for 10 days).

Three cases of hyperperfusion syndrome identified by daily transcranial Doppler investigation after carotid surgery.

BACKGROUND: cerebral hyperperfusion syndrome (HS), occurs in 0.5-1% of patients undergoing carotid endarterectomy (CEA), and may result in intracerebral haemorrhage and death. AIM: to diagnose HS by means of postoperative Transcranial Doppler (TCD). METHODS: between 1998 and 2001 nearly all 112 patients who underwent CEA were monitored for four days postoperatively by Transcranial Doppler. RESULTS: there were 3 patients with HS. All three showed TCD abnormalities hours before developing symptoms. One patient developed a full blown HS. Presumably, symptoms in the other two patients could be prevented by timely starting or restoring anti-hypertensive treatment. CONCLUSION: daily TCD investigation in all patients undergoing CEA seems an effective strategy for the presymptomatic detection of HS.