Enhancing neutrophil cytotoxicity of a panel of clinical EGFR antibodies by Fc engineering to IgA3.0.

The epidermal growth factor receptor (EGFR) plays an essential role in cellular signaling pathways that regulate cell growth, proliferation and survival, and is often found dysregulated in cancer. Several monoclonal IgG antibodies have been clinically tested over the years which exert their function via blocking the ligand binding domain (thereby inhibiting downstream signaling) and induction of Fc-related effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, these IgG antibodies do not optimally recruit neutrophils, by far the most abundant white blood cell population in humans. Therefore, we reformatted six therapeutic EGFR antibodies (cetuximab, panitumumab, nimotuzumab, necitumumab, zalutumumab, and matuzumab) into the IgA3.0 format, which is an IgA2 isotype that has been adapted for clinical application. Reformatting these antibodies preserved Fab-mediated functions such as EGFR binding, growth inhibition and ligand blockade. Additionally, whole leukocyte ADCC was significantly increased when using this panel of IgA3.0 antibodies compared to their respective IgG counterparts, with no major differences between IgA3.0 antibodies. In vivo, IgA3.0 matuzumab outperformed the other antibodies, resulting in the strongest suppression of tumor outgrowth in a long intraperitoneal model. We show that neutrophils are important for the suppression of tumor outgrowth. IgA3.0 matuzumab exhibited reduced receptor internalization compared to the other antibodies, possibly accounting for its superior in vivo Fc-mediated tumor cell killing efficacy. In conclusion, reformatting EGFR antibodies into an IgA3.0 format increased Fc-mediated killing while retaining Fab-mediated functions and could therefore be a good alternative for the currently available antibody therapies.

A novel method to estimate the response of habitat types to nitrogen deposition.

Increasing nitrogen depositions adversely affect European landscapes, including habitats within the Natura2000 network. Critical loads for nitrogen deposition have been established to quantify the loss of habitat quality. When the nitrogen deposition rises above a habitat-specific critical load, the quality of the focal habitat is expected to be negatively influenced. Here, we investigate how the quality of habitat types is affected beyond the critical load. We calculated response curves for 60 terrestrial habitat types in the Netherlands to the estimated nitrogen deposition (EMEP-data). The curves for habitat types are based on the occurrence of their characteristic plant species in North-Western Europe (plot data from the European Vegetation Archive). The estimated response curves were corrected for soil type, mean annual temperature and annual precipitation. Evaluation was carried out by expert judgement, and by comparison with gradient deposition field studies. For 39 habitats the response to nitrogen deposition was judged to be reliable by five experts, while out of the 41 habitat types for which field studies were available, 25 showed a good agreement. Some of the curves showed a steep decline in quality and some a more gradual decline with increasing nitrogen deposition. We compared the response curves with both the empirical and modelled critical loads. For 41 curves, we found a decline already starting below the critical load.

Self-reported health related quality of life in children and adolescents with an eating disorder.

BACKGROUND: Eating disorders in children and adolescents can have serious medical and psychological consequences. The objective of this retrospective quantitative study is to gain insight in self-reported Health Related Quality of Life (HRQoL) of children and adolescents with a DSM-5 diagnosis of an eating disorder. METHOD: Collect and analyse data of patients aged 8-18 years, receiving treatment for an eating disorder. At the start and end of treatment patients completed the KIDSCREEN-52, a questionnaire measuring HRQoL. RESULTS: Data of 140 patients were analysed. Children diagnosed with Anorexia Nervosa, Bulimia Nervosa, and Other Specified Feeding or Eating Disorder all had lower HRQoL on multiple dimensions at the start of treatment, there is no statistically significant difference between these groups. In contrast, patients with Avoidant Restrictive Food Intake Disorder only had lower HRQoL for the dimension Physical Well-Being. HRQoL showed a significant improvement in many dimensions between start and end of treatment, but did not normalize compared to normative reference values of Dutch children. CONCLUSION: The current study showed that self-reported HRQoL is low in children with eating disorders, both at the beginning but also at the end of treatment. This confirms the importance of continuing to invest in the various HRQoL domains.

Reading Difficulties in Individuals with Homonymous Visual Field Defects: A Systematic Review of Reported Interventions.

Reading difficulties are amongst the most commonly reported problems in individuals with homonymous visual field defects (HVFDs). To be able to provide guidance for healthcare professionals considering offering reading training, researchers in this field and interested individuals with HVFDs, this systematic review aims to (1) provide an overview of the contextual and intervention characteristics of all published HVFD interventions and (2) generate insights into the different reading outcome measures that these studies adopted. A search on PsycINFO, MEDLINE and Web of Science was conducted up to February 2, 2023. All intervention studies for HVFD in which reading was measured were included. Data was collected about the intervention type, session duration, number of sessions, the intensity, duration, circumstance of the interventions, country in which the intervention was studied and reading measures. Sixty records are included, describing 70 interventions in total of which 21 are specifically reading interventions. Overall, adjusted saccadic behaviour interventions occur most in the literature. A wide range within all intervention characteristics was observed. Forty-nine records reported task-performance reading measures, and 33 records reported self-reported reading measures. The majority of task-performance measures are based on self-developed paragraph reading tasks with a time-based outcome measure (e.g. words per minute). Future research could benefit from making use of validated reading tests, approaching the measurement of reading mixed-methods and providing participants the possibility to supply outcomes relevant to them.

East-to-west human dispersal into Europe 1.4 million years ago.

Stone tools stratified in alluvium and loess at Korolevo, western Ukraine, have been studied by several research groups1-3 since the discovery of the site in the 1970s. Although Korolevo's importance to the European Palaeolithic is widely acknowledged, age constraints on the lowermost lithic artefacts have yet to be determined conclusively. Here, using two methods of burial dating with cosmogenic nuclides4,5, we report ages of 1.42 ± 0.10 million years and 1.42 ± 0.28 million years for the sedimentary unit that contains Mode-1-type lithic artefacts. Korolevo represents, to our knowledge, the earliest securely dated hominin presence in Europe, and bridges the spatial and temporal gap between the Caucasus (around 1.85-1.78 million years ago)6 and southwestern Europe (around 1.2-1.1 million years ago)7,8. Our findings advance the hypothesis that Europe was colonized from the east, and our analysis of habitat suitability9 suggests that early hominins exploited warm interglacial periods to disperse into higher latitudes and relatively continental sites-such as Korolevo-well before the Middle Pleistocene Transition.

Voice outcome in medialisation thyroplasty with and without arytenoid adduction: a prospective comparison using intraoperative voice measurements.

PURPOSE: Arytenoid adduction as an addition to medialisation thyroplasty is highly advocated by some surgeons in selected cases but deemed less necessary by others in patients with unilateral vocal fold paralysis. This study aims to evaluate the additional benefits on voice outcome of arytenoid adduction in patients with unilateral vocal fold paralysis undergoing medialisation thyroplasty using intra-operative voice measurements. DESIGN/METHODS: A prospective study was conducted. Voice audio recordings were obtained at 4 moments; 1. direct prior to the start of surgery, 2. during surgery after medialisation thyroplasty, 3. during surgery after medialisation and arytenoid adduction, 3 months postoperative. At these same timepoints patients rated their own voice on a numeric rating scale between 0 and 10. The blinded recordings were rated by consensus in a team of experienced listeners, using the Grade of the GRBAS scale. Furthermore, the Voice Handicap Index was administered before and at 3 months after surgery. RESULTS: Ten patients who underwent medialisation and arytenoid adduction at our tertiary referral hospital between 2021 and 2022, were included. One patient was excluded after surgery. The intraoperative measurements showed a Grade score of 1.4 preoperatively, improving to 1.2 after medialisation, 1.2 after medialisation and arytenoid adduction, and further improving to 0.4 at 3 months postoperative, which was a not statistically significant improvement (p = 0.2). The intraoperative subjective numeric rating scale showed a statistically significant improvement from 3.9 preoperatively, to 6.1 after medialisation, 7.1 after medialisation and arytenoid adduction and a 7.6 at 3 months postoperative (p = 0.001). The Voice Handicap Index total score showed a statistically significant improvement from 71 points before surgery to 13 at 3 months after surgery (p = 0.008). CONCLUSIONS: Our study using intraoperative voice measurements indicate that the addition of arytenoid adduction to medialisation thyroplasty is a benefit in selected patients although more studies are needed due to the many limitations inherent to this field of investigation.

Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Financial dissatisfaction in people with psychotic disorders - A short report on its prevalence and correlates in a large naturalistic psychosis cohort.

Psychotic disorders have a strong negative impact on multiple aspects of daily life, including people's financial situation. This exploratory study examines the level of financial dissatisfaction and its correlates in a large cohort of people with psychotic disorders. Data from the first assessments of people with psychotic disorders (n = 5271) who were included in the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS; 2006-2020), which is conducted in the northern Netherlands, were used. The Manchester Short Assessment of Quality of Life (MANSA) was used to measure financial dissatisfaction. In addition, sociodemographic and psychiatric characteristics, substance use and global and social functioning were assessed. One-fifth to one-third of people with psychotic disorders report financial dissatisfaction, fluctuating over the year in which they were assessed. These proportions are considerably higher than in the general population. Cannabis and other substance use were associated with higher levels of financial dissatisfaction (small to medium effect). The other significant associations showed (very) small effect sizes. Therefore, we conclude that financial dissatisfaction in people with psychotic disorders appears to be relatively independent of other demographic and psychiatric characteristics, and global and social functioning. These findings are an important first step for increasing knowledge on financial dissatisfaction among people with psychotic disorders. The findings can also contribute to raising awareness about the topic for healthcare professionals working in this field.

Leukocyte-associated immunoglobulin-like receptor-1 blockade in combination with programmed death-ligand 1 targeting therapy mediates increased tumour control in mice.

Collagen expression and structure in the tumour microenvironment are associated with tumour development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor. LAIR-2 is a soluble homologue of LAIR-1 that competes for collagen binding. Multiple studies in mice implicate blockade of LAIR-1:collagen interaction in cancer as a promising therapeutic strategy. Here, we investigated the role of LAIR-1 in anti-tumour responses. We show that although LAIR-1 inhibits activation, proliferation, and cytokine production of mouse T cells in vitro, tumour outgrowth in LAIR-1-deficient mice did not differ from wild type mice in several in vivo tumour models. Furthermore, treatment with NC410, a LAIR-2-Fc fusion protein, did not result in increased tumour clearance in tested immunocompetent mice, which contrasts with previous data in humanized mouse models. This discrepancy may be explained by our finding that NC410 blocks human LAIR-1:collagen interaction more effectively than mouse LAIR-1:collagen interaction. Despite the lack of therapeutic impact of NC410 monotherapy, mice treated with a combination of NC410 and anti-programmed death-ligand 1 did show reduced tumour burden and increased survival. Using LAIR-1-deficient mice, we showed that this effect seemed to be dependent on the presence of LAIR-1. Taken together, our data demonstrate that the absence of LAIR-1 signalling alone is not sufficient to control tumour growth in multiple immunocompetent mouse models. However, combined targeting of LAIR-1 and PD-L1 results in increased tumour control. Thus, additional targeting of the LAIR-1:collagen pathway with NC410 is a promising approach to treating tumours where conventional immunotherapy is ineffective.

Advancements in kidney organoids and tubuloids to study (dys)function.

The rising prevalence of kidney diseases urges the need for novel therapies. Kidney organoids and tubuloids are advanced in vitro models and have recently been described as promising tools to study kidney (patho)physiology. Recent developments have shown their application in disease modeling, drug screening, and nephrotoxicity. These applications rely on their ability to mimic (dys)function in vitro including endocrine activity and drug, electrolyte, and water transport. This review provides an overview of these emerging kidney models and focuses on the most recent developments that utilize their functional capabilities. In addition, we cover current limitations and provide future perspectives for this rapidly evolving field, including what these functional properties mean for translational and personalized medicine now and in the future.

Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Sialic Acids on Tumor Cells Modulate IgA Therapy by Neutrophils via Inhibitory Receptors Siglec-7 and Siglec-9.

Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, contributing to treatment resistance. While CD47/SIRPα-axis inhibitors in combination with IgA therapy have shown promise, complete tumor eradication remains a challenge, indicating the presence of other checkpoints. We investigated hypersialylation on the tumor cell surface as a potential myeloid checkpoint and found that hypersialylated cancer cells inhibit neutrophil-mediated tumor killing through interactions with sialic acid-binding immunoglobulin-like lectins (Siglecs). To enhance antibody-dependent cellular cytotoxicity (ADCC) using IgA as therapeutic, we explored strategies to disrupt the interaction between tumor cell sialoglycans and Siglecs expressed on neutrophils. We identified Siglec-9 as the primary inhibitory receptor, with Siglec-7 also playing a role to a lesser extent. Blocking Siglec-9 enhanced IgA-mediated ADCC by neutrophils. Concurrent expression of multiple checkpoint ligands necessitated a multi-checkpoint-blocking approach. In certain cancer cell lines, combining CD47 blockade with desialylation improved IgA-mediated ADCC, effectively overcoming resistance that remained when blocking only one checkpoint interaction. Our findings suggest that a combination of CD47 blockade and desialylation may be necessary to optimize cancer immunotherapy, considering the upregulation of checkpoint molecules by tumor cells to evade immune surveillance.

Good manufacturing practice production of CD34+ progenitor-derived NK cells for adoptive immunotherapy in acute myeloid leukemia.

Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34+ hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27).

Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells.

Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy.

Characterization of human Fc alpha receptor transgenic mice: comparison of CD89 expression and antibody-dependent tumor killing between mouse strains.

Since mice do not express a homologue of the human Fc alpha receptor (FcαRI or CD89), a transgenic mouse model was generated in four different backgrounds (C57BL/6, BALB/c, SCID and NXG) expressing the FcαRI under the endogenous human promoter. In this study, we describe previously unknown characteristics of this model, such as the integration site of the FCAR gene, the CD89 expression pattern in healthy male and female mice and in tumor-bearing mice, expression of myeloid activation markers and FcγRs and IgA/CD89-mediated tumor killing capacity. In all mouse strains, CD89 expression is highest in neutrophils, intermediate on other myeloid cells such as eosinophils and DC subsets and inducible on, among others, monocytes, macrophages and Kupffer cells. CD89 expression levels are highest in BALB/c and SCID, lower in C57BL/6 and lowest in NXG mice. Additionally, CD89 expression on myeloid cells is increased in tumor-bearing mice across all mouse strains. Using Targeted Locus Amplification, we determined that the hCD89 transgene has integrated in chromosome 4. Furthermore, we established that wildtype and hCD89 transgenic mice have a similar composition and phenotype of immune cells. Finally, IgA-mediated killing of tumor cells is most potent with neutrophils from BALB/c and C57BL/6 and less with neutrophils from SCID and NXG mice. However, when effector cells from whole blood are used, SCID and BALB/c are most efficient, since these strains have a much higher number of neutrophils. Overall, hCD89 transgenic mice provide a very powerful model to test the efficacy of IgA immunotherapy against infectious diseases and cancer.

Ex vivo intervertebral disc cultures: degeneration-induction methods and their implications for clinical translation.

Because low back pain is frequently a result of intervertebral disc degeneration (IVDD), strategies to regenerate or repair the IVD are currently being investigated. Often, ex vivo disc cultures of non-human IVD organs or tissue explants are used that usually do not exhibit natural IVDD. Therefore, degenerative changes mimicking those reported in human IVDD need to be induced. To support researchers in selecting ex vivo disc cultures, a systematic search was performed for them and their potential use for studying human IVDD reviewed. Five degeneration induction categories (proinflammatory cytokines, injury/damage, degenerative loading, enzyme, and other) were identified in 129 studies across 7 species. Methods to induce degeneration are diverse and can induce mild to severe degenerative changes that progress over time, as described for human IVDD. The induced degenerative changes are model-specific and there is no "one-fits-all" IVDD induction method. Nevertheless, specific aspects of human IVDD can be well mimicked. Currently, spontaneously degenerated disc cultures from large animals capture human IVDD in most aspects. Combinatorial approaches of several induction methods using discs derived from large animals are promising to recapitulate pathological changes on several levels, such as cellular behaviour, extracellular matrix composition, and biomechanical function, and therefore better mimic human IVDD. Future disc culture setups might increase in complexity, and mimic human IVDD even better. As ex vivo disc cultures have the potential to reduce and even replace animal trials, especially during preclinical development, advancement of such models is highly relevant for more efficient and cost-effective clinical translation from bench-to-bedside.

Differentiated mouse kidney tubuloids as a novel in vitro model to study collecting duct physiology.

Kidney tubuloids are cell models that are derived from human or mouse renal epithelial cells and show high similarities with their in vivo counterparts. Tubuloids grow polarized in 3D, allow for long-term expansion, and represent multiple segments of the nephron, as shown by their gene expression pattern. In addition, human tubuloids form tight, functional barriers and have been succesfully used for drug testing. Our knowledge of mouse tubuloids, on the other hand, is only minimal. In this study, we further characterized mouse tubuloids and differentiated them towards the collecting duct, which led to a significant upregulation of collecting duct-specific mRNAs of genes and protein expression, including the water channel AQP2 and the sodium channel ENaC. Differentiation resulted in polarized expression of collecting duct water channels AQP2 and AQP3. Also, a physiological response to desmopressin and forskolin stimulation by translocation of AQP2 to the apical membrane was demonstrated. Furthermore, amiloride-sensitive ENaC-mediated sodium uptake was shown in differentiated tubuloids using radioactive tracer sodium. This study demonstrates that mouse tubuloids can be differentiated towards the collecting duct and exhibit collecting duct-specific function. This illustrates the potential use of mouse kidney tubuloids as novel in vitro models to study (patho)physiology of kidney diseases.

Cerebral volume is unaffected after pre-eclampsia.

OBJECTIVES: Pre-eclampsia has been associated with cardiovascular, cerebrovascular and/or psychological complaints. Signs of altered brain morphology and more white-matter hyperintensities (WMHs) during and shortly after pre-eclampsia have been observed in some, but not all, studies. We compared volumes of cerebral structures and the number of WMHs between formerly pre-eclamptic women and those with normotensive gestational history and assessed the effect of age on brain volumes. METHODS: Structural 7-Tesla magnetic resonance imaging of the brain was performed in 59 formerly pre-eclamptic women (aged 37 ± 6 years, 0.5-16 years postpartum) and 20 women with a history of normotensive pregnancy (aged 39 ± 5 years, 1-18 years postpartum). Fazekas scores were obtained to assess WMH load. Volumes of the whole brain, gray and white matter, brain lobes, and ventricular and pericortical cerebrospinal fluid (CSF) spaces were calculated after semiautomatic segmentation. Group differences were analyzed using ANCOVA and Bayes factors. Results were adjusted for age, educational attainment, presence of current hypertension and total intracranial volume. The effect of age on cerebral volumes was analyzed using linear regression analysis. RESULTS: No changes in global and local brain volumes were observed between formerly pre-eclamptic and control women. Also, no difference in WMH load was observed. Independent of pre-eclamptic history, gray-matter volume significantly decreased with age, while ventricular and pericortical CSF space volumes significantly increased with age. CONCLUSIONS: Volumetric changes of the cerebrum are age-related but are independent of pre-eclamptic history in the first two decades after childbirth. No evidence of greater WMH load after pre-eclampsia was found. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Effective, Long-Term, Neutrophil Depletion Using a Murinized Anti-Ly-6G 1A8 Antibody.

Neutrophils are crucial innate immune cells but also play key roles in various diseases, such as cancer, where they can perform both pro- and anti-tumorigenic functions. To study the function of neutrophils in vivo, these cells are often depleted using Ly-6G or Gr-1 depleting antibodies or genetic "knockout" models. However, these methods have several limitations, being only partially effective, effective for a short term, and lacking specificity or the ability to conditionally deplete neutrophils. Here, we describe the use of a novel murinized Ly-6G (1A8) antibody. The murinized Ly-6G antibody is of the mouse IgG2a isotype, which is the only isotype that can bind all murine Fcγ receptors and C1q and is, therefore, able to activate antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) pathways. We show that this mouse-Ly-6G antibody shows efficient, long-term, and near-complete (>90%) neutrophil depletion in the peripheral blood of C57Bl6/J, Balb/c, NXG and SCID mice for up to at least four weeks, using a standardized neutrophil depletion strategy. In addition, we show that neutrophils are efficiently depleted in the blood and tumor tissue of IMR32 tumor-bearing SCID mice, analyzed six weeks after the start of the treatment.

ON THE PLACEMENT OF APRON DOSEMETERS AND DOSE ASSESSMENT IN INTERVENTIONAL CARDIOLOGY PROCEDURES: PRELIMINARY RESULTS.

Personnel involved in interventional practices are likely to be exposed to higher radiation doses than other workers in the medical field. Personnel monitoring and radiation protection measures play a crucial role in keeping these doses below the limits. EURADOS (European Radiation Dosimetry Group) Working Group 12 performed a series of investigations showing how the complexity of the scattered field reaching the operators can influence the doses to the operators. The present work was aimed at determining the possible effects on the registered doses of the scattered field and the actual position of a dosemeter on apron. This study has been performed through Monte Carlo simulations and it was validated through measurements. It does not claim to identify the 'best' position for the dosemeter, but to assess the variability of its response, showing how a variability of the order of +/- 30% to 40 should be taken into account.