MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer

Prostaglandin E₂ (PGE₂) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE₂, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1^−/− PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1^−/− macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.     

Treatment of epilepsy in daily clinical practice: have outcomes improved over the past 10 years?

In the past decade, many new antiepileptic drugs have become available, but their influence on patient outcomes in daily practice is not well known. In a community-based study, we assessed changes in epilepsy treatment and outcomes over a 10-year period. We compared two cross-sectional community-based samples that were obtained from the same Dutch suburban region in 2000 and 2010 using pharmacy records for recruitment, including 344 and 248 epilepsy patients, respectively. The main outcome was self-reported quality of life (QoL, using the QOLIE-31). Potential predictors of QoL (adverse effects, seizure control, seizure acceptability, demographic, epilepsy- or treatment-related determinants) were assessed by multivariable linear regression. New antiepileptic drugs were used by 9 % of patients in 2000 and 34 % in 2010, P < 0.001. More than 80 % in both samples reported to be treated by a neurologist. We found no significant differences in QOLIE-31 scores (72.57 vs. 72.44), or in the proportion of patients with complete seizure control (51 vs. 54 %), between the two study samples. Seizure control and adverse effects were important independent predictors of quality of life, explaining 58 % of the variance. We found no evidence that in this community the QoL of epilepsy patients has improved in the last decade, despite unrestricted availability of healthcare resources, including accessibility to new AEDs. The relatively low proportion with complete seizure control and the high rate of adverse effects in these community-based samples suggest that the effectiveness of epilepsy treatment is still far from optimal.     

Visual attention in a multiple‐choice task: Influences of image characteristics with and without presentation of a verbal stimulus

Background: Use of multiple‐choice items is common in the assessment of language comprehension. Stimulus‐driven aspects of multiple‐choice images may interfere with valid assessment. Understanding the influences of stimulus‐driven factors is crucial because individuals with neurological disorders have increased susceptibility to them.

Aims: The first goal of this study was to explore the influence of objectively measurable image characteristics in multiple‐choice image sets that are otherwise well controlled in terms of physical stimulus features on individuals' visual attention. The second goal was to explore viewers' visual attention under the influence of a verbal stimulus.

Methods & Procedures: The effects of controlled manipulation of physical image characteristics on visual attention in 40 healthy adults were assessed. Eye movements were recorded while participants viewed 40 image sets with and without a verbal stimulus. Within each set, two images shared the same image characteristics (colour, orientation, size, and luminance) and one image differed in terms of one of those characteristics.

Outcomes & Results: All characteristics had a significant influence on visual attention in verbal and nonverbal conditions. The influence of verbal stimuli on visual attention did not override the tendency for physical stimulus characteristics to distract attention from target images.

Conclusions: Research and clinical relevance is highlighted in terms of the potential for assessment confounds to be greater in individuals with neurological impairments.     

The spatial relationship between neurons and astrocytes in HIV-associated dementia

Specific neuronal spatial distributional patterns have previously been correlated with increasing severity of HIV-associated dementia (HAD). As astrocytes are also a putative site of neurotoxicity, we investigated the spatial relationships of astrocytes with pyramidal and interneurons in the superior frontal gyrus from 29 patients who died from acquired immunodeficiency syndrome. Frontal cortical brain tissue was taken from diseased HIV patients who had been assessed for the presence and severity of HAD using the Memorial Sloan-Kettering Scale. No correlation was found between neuronal density and severity of dementia. However, the pattern of astrocytes became more clustered as dementia progressed. Bivariate spatial pattern analysis of neuronal populations with astrocytes revealed that, with increasing dementia severity, astrocytes and large pyramidal neurons increasingly “repelled” each other, while astrocytes and interneurons evidenced increasing “attraction.” This implies that astrocytes may be more likely to be situated in the vicinity of surviving interneurons but less likely to be situated near surviving large pyramidal neurons in the setting of progressing HAD.     

Adherence to the Dutch Breast Cancer Guidelines for Surveillance in Breast Cancer Survivors: Real-World Data from a Pooled Multicenter Analysis

BackgroundRegular follow-up after treatment for breast cancer is crucial to detect potential recurrences and second contralateral breast cancer in an early stage. However, information about follow-up patterns in the Netherlands is scarce.Patients and MethodsDetails concerning diagnostic procedures and policlinic visits in the first 5 years following a breast cancer diagnosis were gathered between 2009 and 2019 for 9916 patients from 4 large Dutch hospitals. This information was used to analyze the adherence of breast cancer surveillance to guidelines in the Netherlands. Multivariable logistic regression was used to relate the average number of a patient’s imaging procedures to their demographics, tumor–treatment characteristics, and individual locoregional recurrence risk (LRR), estimated by a risk-prediction tool, called INFLUENCE.ResultsThe average number of policlinic contacts per patient decreased from 4.4 in the first to 2.0 in the fifth follow-up year. In each of the 5 follow-up years, the share of patients without imaging procedures was relatively high, ranging between 31.4% and 33.6%. Observed guidelines deviations were highly significant (P < .001). A higher age, lower UICC stage, and having undergone radio- or chemotherapy were significantly associated with a higher chance of receiving an imaging procedure. The estimated average LRR-risk was 3.5% in patients without any follow-up imaging compared with 2.3% in patients with the recommended number of 5 imagings.ConclusionCompared to guidelines, more policlinic visits were made, although at inadequate intervals, and fewer imaging procedures were performed. The frequency of imaging procedures did not correlate with the patients’ individual risk profiles for LRR.