Oncolytic adenovirus ORCA-010 increases the type 1 T cell stimulatory capacity of melanoma-conditioned dendritic cells.

Immune checkpoint blockade has resulted in durable responses in patients with metastatic melanoma, but only in a fraction of treated patients. For immune checkpoint inhibitors (ICI) to be effective, sufficient infiltration with tumor-reactive T cells is essential. Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and so induce an immunogenic form of cell death, providing at once a source of tumor-associated (neo)antigens and of danger signals that together induce effective T cell immunity and tumor infiltration. Melanoma-associated suppression of dendritic cell (DC) differentiation effectively hampers OV- or immune checkpoint inhibitor (ICI)-induced anti-tumor immunity, due to a consequent inability to prime and attract anti-tumor effector T cells. Here, we set out to study the effect of ORCA-010, a clinical stage oncolytic adenovirus, on DC differentiation and functionality in the context of human melanoma. In melanoma and monocyte co-cultures, employing a panel of five melanoma cell lines with varying origins and oncogenic mutation status, we observed clear suppression of DC development with apparent skewing of monocyte differentiation to a more M2-macrophage-like state. We established the ability of ORCA-010 to productively infect and lyse the melanoma cells. Moreover, although ORCA-010 was unable to restore DC differentiation, it induced activation and an increased co-stimulatory capacity of monocyte-derived antigen-presenting cells. Their subsequent ability to prime effector T cells with a type I cytokine profile was significantly increased in an allogeneic mixed leukocyte reaction. Our findings suggest that ORCA-010 is a valuable immunotherapeutic agent for melanoma.

[Substance use and criminality: a review]. / Middelengebruik en criminaliteit: een overzicht.

BACKGROUND: Substance use regularly co-occurs with many types of criminality, including violent behaviour. AIM: To review the relationships between substance abuse and criminality, which can involve violent behaviour. METHOD: We searched the literature for meta-analyses, reviews and empirical articles about relationships between the problematic use of and addiction to psychoactive substances on the one hand and antisocial and aggressive behaviour and recidivism on the other hand. RESULTS: In the case of both men and women there are significant relationships between substance abuse and criminal behavior. The majority of substance users, however, are not criminals and most of the offences they commit can be termed 'acquisitive offences'. The relationship between alcohol and violence is stronger than the relationship between substance abuse and violence. Furthermore, it is only in cocaine users that we find indications that psychopharmacological effects stimulate violent behaviour. A number of factors, particularly interactions, determine whether substance abusers are criminal and are violent. Violent behaviour can result from interactions between the severity of illness caused by substance abuse, individual psychological, social and neurobiological characteristics, situational factors and expectancies regarding the psychopharmacological effects of a particular substance. CONCLUSION: Substance abuse, particularly the combination of alcohol and drugs, is a predictor of criminality and criminal recidivism.

Diffusivity interfaces in lattice Monte Carlo simulations: Modeling inhomogeneous delivery and release systems.

Lattice Monte Carlo (LMC) simulations are widely used to investigate diffusion-controlled problems such as drug-release systems. The presence of an inhomogeneous diffusivity environment raises subtle questions about the interpretation of stochastic dynamics in the overdamped limit, an issue sometimes referred to as the "Ito-Stratonovich-isothermal dilemma." We propose a LMC formalism that includes the different stochastic interpretations in order to model the diffusion of particles in a space-dependent diffusivity landscape. Using as an example a simple inhomogeneous one-dimensional system with a diffusivity interface and different boundary conditions, we demonstrate that we can properly reproduce the steady state and dynamic properties of these systems and that these properties do depend on the choice of calculus. In particular, we argue that the version of the LMC algorithm that uses Ito calculus, which is commonly used to model drug delivery systems, should be replaced by the isothermal version for most applications. Our LMC methodology provides an efficient alternative to Langevin simulations for a wide class of space-dependent diffusion problems.

Genetic determinants of activity and antigen levels of contact system factors.

Essentials Genetic variation may provide valuable insight into the role of the contact system in thrombosis. Explored associations of genetic variants with activity, antigen, and disease in RATIO study. Two novel loci were identified: KLKB1 rs4253243 for prekallikrein; KNG1 rs5029980 for HMWK levels. Contact system variants and haplotypes were not associated with myocardial infarction or stroke. SUMMARY: Background The complex, interdependent contact activation system has been implicated in thrombotic disease, although few genetic determinants of levels of proteins from this system are known. Objectives Our primary aim was to study the influence of common F11, F12, KLKB1, and KNG1 variants on factor (F) XI activity and FXI, FXII, prekallikrein (PK) and high-molecular-weight kininogen (HMWK) antigen levels, as well as the risk of myocardial infarction and ischemic stroke. Patients/methods We analyzed samples from all 630 healthy participants, 182 ischemic stroke patients and 216 myocardial infarction patients in the RATIO case-control study of women aged < 50 years. Forty-three tagging single nucleotide variants (SNVs) were genotyped to represent common genetic variation in the contact system genes. Antigen and activity levels were measured with sandwich-ELISA-based and one-stage clotting assays. We performed single variant, age-adjusted, linear regression analyses per trait and disease phenotype, assuming additive inheritance and determined conditionally independent associations. Haplotypes based on the lead SNV and all conditionally independent SNVs were tested for association with traits and disease. Results We identified two novel associations of KLKB1 SNV rs4253243 with PK antigen (ßconditional = -12.38; 95% CI, -20.07 to -4.69) and KNG1 SNV rs5029980 with HMWK antigen (ßconditional = 5.86; 95% CI, 2.40-9.32) and replicated previously reported associations in a single study. Further analyses probed whether the observed associations were indicative of linkage, pleiotropic effects or mediation. No individual SNVs or haplotypes were associated with the disease outcomes. Conclusion This study adds to current knowledge of how genetic variation influences contact system protein levels and clarifies interdependencies.

[Endometrial and ovarian tumours and their association with obesity]. / Tumoren van endometrium en ovarium en de samenhang met obesitas.

A 53-year-old woman was wheelchair-dependent and unable to work due to an extreme increase in abdominal circumference. Closer investigation revealed an ovarian tumour. A mucinous cystadenoma of the ovary weighing more than 20 kg was removed with laparotomy. A 63-year-old woman presented with postmenopausal haemorrhage. Morbid obesity and agoraphobia had prevented her from visiting a doctor earlier. She was eventually diagnosed with stage 1C grade III endometrial carcinoma, which was treated with surgery and vaginal brachytherapy. The incidence of gynaecological tumours is increased in patients with a high BMI. This association is stronger for endometrial carcinoma than for ovarian carcinoma. Obesity has a favourable influence on the histological grade of endometrial carcinoma, and is associated with lower-stage ovarian cancer. Surgery-related complications are more common in obese patients. Determining the optimal dose of adjuvant therapy is also problematic in obese patients.

Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.

Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.

Male-specific risk of first and recurrent venous thrombosis: a phylogenetic analysis of the Y chromosome.

Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E-carriers may have an increased risk of recurrent VT, but a larger study is needed. SUMMARY: Background The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case-control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3-86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6-46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk.

Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep.

OBJECTIVE: To assess the clinical utility of overshoot fetal heart rate (FHR) decelerations by examining their occurrence after umbilical cord occlusions of varying frequency and length in near-term fetal sheep. METHODS: Fetuses were allocated to the following three groups: 1-minute umbilical cord occlusion repeated every 5 minutes (1:5 group, n = 8) or every 2.5 minutes (1:2.5 group, n = 8) or 2-minute occlusions repeated every 5 minutes (2:5 group, n = 4). Occlusions were continued for 4 hours or until fetal mean arterial pressure decreased below 20 mmHg during two successive occlusions. RESULTS: In the 1:5 group, fetuses tolerated 4 hours of occlusion without hypotension or clinically significant acidosis and overshoot never occurred. In the 2:5 group, fetuses rapidly became hypotensive and acidotic, and occlusions were terminated at 116.3 +/- 22.9 min (mean +/- standard deviation). Overshoot was seen after every occlusion, starting with the first occlusion. In the 1:2.5 group, fetuses became progressively acidotic and hypotensive and occlusions were stopped at 183.1 +/- 42.8 min. Overshoot occurred after 91.6 +/- 42.5 minutes, at a pH of 7.17 +/- 0.06, base deficit 9.3 +/- 4.5 mmol/L. After the appearance of overshoot there was a more rapid decrease in fetal mean arterial pressure (0.25 [0.21, 0.35, 25-75th percentile] mmHg/minute versus 0.11 [0.03, 0.15] mmHg/minute before overshoot appeared, P <.01). CONCLUSION: These data suggest that overshoot is related to longer (2-minute) occlusions or to developing fetal acidosis and hypotension during 1-minute occlusions. This pattern could have clinical utility, as 1-minute contractions are typical of active labor.

Cue reactivity and effects of cue exposure in abstinent posttreatment drug users.

After 12 months of inpatient treatment, 16 opiate-addicted patients were exposed to drug-related stimuli. The results of this study indicate that cue reactivity in opiate-addicted subjects is still present after 12 months of intensive inpatient treatment. After exposing subjects to drug-related stimuli, there is an increase in craving, feelings of depression, and anger. Because posttreatment subjects are likely to be confronted with these stimuli following discharge, a reduction of this reactivity is desirable. In the present study, cue reactivity (feelings of depression, anger, tension, craving, and physical symptoms) reduced after protocolized cue exposure treatment. This effect maintained for at least 6 weeks after the last cue exposure session.

Neuronal death after perinatal asphyxia.

During perinatal asphyxia several mechanisms aim to limit cerebral damage. However, when the degree of asphyxia passes beyond a certain threshold, brain damage is inevitable. This review focuses on the various factors determining the final cerebral outcome. Metabolic and biochemical events, such as the intracellular level of calcium, the formation of oxygen derived free radicals, the release of excitotoxic neurotransmitters and the interrelationship of these parameters are discussed. Furthermore, steps possibly useful to pharmacologic intervention aiming to reduce cerebral damage are presented.

Determination of cadmium, zinc, copper, chromium and arsenic in crude oil cargoes.

One of the sources of trace heavy metal elements in air is emission by the oil industry, either directly through stack emissions from refineries or indirectly from emissions of combustion of hydrocarbons. Emission estimates are based mainly on the trace metal content of the crude oil processed. From a literature study carried out at the beginning of the 1990s it became clear that data on the trace metal content of crudes were scarce and showed a very large scatter. For this reason a measurement programme to assess the occurrence and concentrations of a number of trace metals, i.e. Cadmium (Cd), Zinc (Zn), Copper (Cu), Chromium (Cr), and arsenic (As), in crudes which are regularly processed in the Netherlands, was set up. By drafting strict sampling protocols and by constructing a special sampling device, as many as possible of the additional contamination sources were avoided. The study suggests that sample contamination may explain a significant amount of the scatter and some of the high concentrations reported in the literature for certain metals. The measured variation in the concentrations of Cd, Zn, and Cu is thought to be due to associated water and/or sediment particles from the producing wells or that picked up during transport. The greater consistency in our measurements for Cr and As suggests that these metals are predominantly associated with the hydrocarbon matrix. Based on the results of this work, it can be concluded that emissions of Cd, Zn, Cu, Cr, and As by the oil industry in the Netherlands are most probably significantly lower than hitherto assumed.

[Diagnostic image (165). A woman with an inguinal mass. Lymphangitis carcinomatosis spread to the skin by metastases of an ovarian carcinoma]. / Diagnose in beeld (165). Een vrouw met een inguïnale zwelling. Lymphangitis carcinomatosa met doorgroei in de huid door metastasering van een ovariumcarcinoom.

In a 57-year-old woman ovarian cancer spread lymphogenically to the groin and suprapubic skin.

[Unavoidable surgical intervention in two women with severe actinomycosis during IUD use]. / Onvermijdelijke chirurgische interventie bij twee IUD-draagsters met ernstige actinomycose.

Extensive abdominal infections with Actinomyces were diagnosed in two women aged 35 and 33 years respectively, who suffered from the nonspecific symptoms fever and abdominal pain. These infections occur more often in women with an intrauterine device. Development of an abdominal mass with ureter or bowel obstruction may cause hydronephrosis and mechanical ileus. The patients underwent a laparotomy and a double-J catheter was inserted, which could be removed later on (temporary stoma). Treatment included high-dose penicillin i.v. followed by oral amoxicillin. Both patients recovered. It may be difficult to establish this diagnosis: the first patient was diagnosed by histopathological examination, in the second Actinomyces had been found in a routine cervical smear a few years earlier.

[Relatively low HIV prevalence among drug users in The Hague in spite of risky injection behavior]. / Relatief lage HIV-prevalentie onder druggebruikers in Den Haag ondanks riskant spuitgedrag.

Between September 1987 and January 1989 101 drug users in The Hague were studied for HIV seroprevalence and risky injecting behaviour. A comparison was made between this group and a group of 241 drug users who were studied in the same period in Amsterdam. All HIV-infected drug users, except for one homosexual man in Amsterdam, had a history of intravenous drug use. The HIV seroprevalence for 56 intravenous drug users in The Hague was 1.8% (95% CI: 0-5.3), and for 194 intravenous drug users in Amsterdam 26.8% (95% CI: 20.6-33.0). With regard to risky injecting behaviour no differences in frequency of borrowing or lending used needles and syringes were found between the two groups. Concluded is that further spread of HIV among intravenous drug users in The Hague (and Amsterdam) will be likely unless risk reduction in injecting behaviour will occur.