Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. RESULTS: The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. CONCLUSION: The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA

Developmental regulation of CB1-mediated spike-time dependent depression at immature mossy fiber-CA3 synapses

Early in postnatal life, mossy fibres (MF), the axons of granule cells in the dentate gyrus, release GABA which is depolarizing and excitatory. Synaptic currents undergo spike-time dependent long-term depression (STD-LTD) regardless of the temporal order of stimulation (pre versus post and viceversa). Here we show that at P3 but not at P21, STD-LTD, induced by negative pairing, is mediated by endocannabinoids mobilized from the postsynaptic cell during spiking-induced membrane depolarization. By diffusing backward, endocannabinoids activate cannabinoid type-1 (CB1) receptors probably expressed on MF. Thus, STD-LTD was prevented by CB1 receptor antagonists and was absent in CB1-KO mice. Consistent with these data, in situ hybridization experiments revealed detectable level of CB1 mRNA in the granule cell layer at P3 but not at P21. These results indicate that CB1 receptors are transiently expressed on immature MF terminals where they counteract the enhanced neuronal excitability induced by the excitatory action of GABA

A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens

Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents

Self-reported Clinical Outcomes and Quality of Life in Agammaglobulinemia: the Importance of an Early Diagnosis

\ua9 The Author(s) 2025.Purpose: Patients with (X-linked) agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications such as sepsis, meningoencephalitis and chronic lung disease. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for early detection of XLA via newborn screening (NBS). Our international multicenter survey study aimed to evaluate self-reported outcomes and parental perspectives in XLA patients to determine whether an early diagnosis is associated with better quality of life (QoL). Methods: QoL-questionnaires included the PedsQL for children and SF-36, CVID_QOL, PADQOL-16 for adults. A new questionnaire was specifically developed for parents about an early diagnosis of XLA. Results: In total, 88 adult and 65 pediatric XLA patients, and 69 parents from 14 countries completed the survey. Patients with an early diagnosis reported less severe, recurrent infections and less hospitalization (p < 0.05). QoL was significantly lower in multiple health domains for pediatric and adult patients with a late diagnosis compared to the general population. Patients with an early diagnosis reported similar QoL outcomes compared to the general population. Parents showed immense support for NBS for XLA stating that an early diagnosis prevents emotional insecurity, health damage, unnecessary diagnostics and allows early access to medical care and informed family planning. Conclusion: Our study has shown supportive evidence to pursue an early diagnosis of XLA from both a self-reported clinical, health related QoL and parental perspective. The main plea from patients and parents is to achieve an early diagnosis for XLA and severe B-lymphocyte deficiencies with NBS

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

PMD23 Identifying The Optimal Use Of Ctcs In The Early Staging Phase Of Breast Cancer

Objectives: Circulating tumour cells (CTCs) in the blood can give important information about the prognosis and treatment options for cancer patients. Methods like cell-search are not sensitive enough because the blood samples are small (7,5 mL). Currently a technique is developed which can separate CTCs from the whole blood and is called the CTC Trap. This study addresses the potential impact of implementing the CTC Trap in addition to currently used imaging techniques in early staging of primary stage I-III breast cancer in women. Methods: The early staging process has been identified using the Dutch breast cancer guideline. This process is displayed in a decision tree. Three points in this process have been identified as possible implementation options for the CTC Trap. A simulation model has been built in Excel to simulate the cost-effectiveness of implementing the CTC Trap at these three different points. Results: Potentially relevant points for the CTC trap are: 1) following negative sentinel lymph node procedure to test for micro metastases, 2) following negative result of initial MRI to test for (micro-) metastases, 3) following negative results of further imaging. Usual care resulted in an average survival of 2,42 years, a 3-year survival of 93,71%, 1,51 QALYs and a cost of € 992,56. When implemented at all 3 implementation points simultaneously CTC Trap resulted in an average survival of 2,84 years, a 3-year survival of 97,46 %, 1,84 QALYS and a total cost of € 6.035,45. Conclusions: CTCs clearly have the potential to improve overall survival. Use of CTCs can potentially improve survival with 0,42 years and improve QALYs with 0,34. Costs do increase at all options but from a health economic perspective it is most valuable to implement CTC Trap in option 1) following negative sentinel lymph node procedure to test for (micro-) metastases

Strong light–matter coupling and exciton-polariton condensation in lattices of plasmonic nanoparticles

\u3cp\u3eArrays of metallic nanoparticles support collective plasmonic resonances known as surface lattice resonances (SLRs). The strong and delocalized electromagnetic fields associated with SLRs provide an excellent platform for experiments within the realm of light–matter interaction. The planar architecture of these arrays also provides a feasible system for coupling to different materials. One of the areas where SLRs have demonstrated their potential is strong light–matter coupling, with possible applications in nonlinear optics, coherent light generation, photochemistry, and optoelectronics. In this perspective, we describe how SLRs are formed in arrays of plasmonic nanoparticles, introduce different materials used for strong coupling with SLRs, discuss some experiments that demonstrate the nonlinear emission of strongly coupled organic molecules with SLRs, and give our vision on future research directions of strongly coupled SLRs with organic molecules.\u3c/p\u3