CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

Age of the magma chamber and its physicochemical state under Elbrus Greater Caucasus, Russia using zircon petrochronology and modeling insights.

Mount Elbrus, Europe's tallest and largely glaciated volcano, is made of silicic lavas and is known for Holocene eruptions, but the size and state of its magma chamber remain poorly constrained. We report high spatial resolution U-Th-Pb zircon ages, co-registered with oxygen and hafnium isotopic values, span ~ 0.6 Ma in each lava, documenting magmatic initiation that forms the current edifice. The best-fit thermochemical modeling constrains magmatic fluxes at 1.2 km3/1000 year by hot (900 °C), initially zircon-undersaturated dacite into a vertically extensive magma body since ~ 0.6 Ma, whereas a volcanic episode with eruptible magma only extends over the past 0.2 Ma, matching the age of oldest lavas. Simulations explain the total magma volume of ~ 180 km3, temporally oscillating δ18O and εHf values, and a wide range of zircon age distributions in each sample. These data provide insights into the current state (~ 200 km3 of melt in a vertically extensive system) and the potential for future activity of Elbrus calling for much-needed seismic imaging. Similar zircon records worldwide require continuous intrusive activity by magmatic accretion of silicic magmas generated at depths, and that zircon ages do not reflect eruption ages but predate them by ~ 103 to 105 years reflecting protracted dissolution-crystallization histories.

Understanding morphological evolution and sediment dynamics at multi-time scales helps balance human activities and protect coastal ecosystems: An example with the Gironde and Pertuis Marine Park.

Finding a balance between the preservation of habitat, species and the sustainable development of human activities in Marine Protected Areas (MPAs) is made even more challenging in coastal areas where sediment dynamics entails naturally changing habitats. To achieve this goal, a solid knowledge base is needed, and reviews are essential. Starting from an extensive review of sediment dynamics and coastal evolution at three-time scales (from millenaries to events), in the Gironde and Pertuis Marine Park (GPMP, French Atlantic coast), we investigated the interactions between human activities, sediment dynamics and morphological evolution in the GPMP. Five activities were identified as having a maximum interaction with coastal dynamics: Land reclamation, shellfish farming, coastal defences, dredging and sand mining. In sheltered areas, where natural sediment fill occurs, land reclamation and shellfish farming increase sedimentation through a positive feedback mechanism, leading to instability. Natural coastal erosion and sediment fill in harbours and tidal channels are fought by coastal defences and dredging, respectively, creating negative feedback and stability. However, these activities also generate negative side effects such as upper beach erosion, pollution, and increased turbidity. Sand mining, mainly developed in submarine incised valleys, results in a deepening of the sea floor, which is naturally filled by sediments from surrounding areas, tending towards shoreface profile restoration. However, sand extraction exceeds natural renewal rates, and may impact the stability of coastal ecosystems in the long term. These activities are at the heart of environmental management and preservation issues. This review and a discussion of the interactions between human activities and coastal behaviour enabled us to make recommendations that could counteract instabilities and negative side effects. They mainly include depolderization, strategic retreat, optimization and sufficiency. Given the diversity of the coastal environments and human activities found in the GPMP, this work is transferable to many MPAs and coastal areas whose objective is to foster sustainable human activities compatible with habitat preservation.

Systemic relapses of primary CNS lymphomas (PCNSL): a LOC network study.

Primary central nervous system lymphomas (PCNSLs) classically remain confined within the CNS throughout their evolution for unknown reasons. Our objective was to analyse the rare extracerebral relapses of PCNSL in a nationwide population-based study. We retrospectively selected PCNSL patients who experienced extracerebral relapse during their follow-up from the French LOC database. Of the 1968 PCNSL included in the database from 2011, 30 (1.5%, median age 71 years, median KPS 70) presented an extracerebral relapse, either pure (n = 20) or mixed (both extracerebral and in the CNS) (n = 10), with a histological confirmation in 20 cases. The median delay between initial diagnosis and systemic relapse was 15.5 months [2-121 months]. We found visceral (n = 23, 77%), including testis in 5 (28%) men and breast in 3 (27%) women, lymph node (n = 12, 40%), and peripheral nervous system (PNS) (n = 7, 23%) involvement. Twenty-seven patients were treated with chemotherapy, either with only systemic targets (n = 7) or mixed systemic and CNS targets (n = 20), 4 were consolidated by HCT-ASCT. After systemic relapse, the median progression-free survival and overall survival (OS) were 7 and 12 months, respectively. KPS > 70 and pure systemic relapses were significantly associated with higher OS. Extracerebral PCNSL relapses are rare, mainly extranodal, and frequently involve the testis, breast, and PNS. The prognosis was worse in mixed relapses. Early relapses raise the question of misdiagnosed occult extracerebral lymphoma at diagnostic workup that should systematically include a PET-CT. Paired tumour analysis at diagnosis/relapse would provide a better understanding of the underlying molecular mechanisms.

Molecular and clinical diversity in primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

Expanding self-consciousness of health status for diabetes chronic complications among adults: a systematic review.

OBJECTIVE: Self-consciousness is defined as a subject (I) then becomes the object (Me) associated with a present moment of self-experience in which one is aware of their experience without any reflexive judgment attached, a state commonly investigated in mindfulness studies. On the other hand, self-consciousness is viewed as a reflexive experience and, thus, as a synonym for self-reflection. Self-consciousness is an important determinant of behaviors. Expanding self-consciousness is important among adults with diabetes to optimize health prevention and compliance with diabetes self-management in the long term. The chronic complications of diabetes comprise heart disease, stroke, nephropathy, retinopathy, and neuropathy. This review aims to explain the relationship between self-consciousness and chronic diabetes complications. MATERIALS AND METHODS: An electronic literature search was conducted in the English language in several databases. The Joanna-Briggs Institute was referenced for the quality assessment of case studies, cohort and cross-sectional studies, and qualitative studies, while systematic reviews were evaluated through PRISMA-S. Results were reported according to the PRISMA guidelines. RESULTS: A total of 89 studies related to self-consciousness of diabetes chronic complications were not found. However, many findings related to chronic complications are based on a lack of knowledge of diabetes and long-term self-management. People with less education, multiple comorbidities, and cognitive dysfunction need lifestyle changes to prevent diabetes and chronic complications. CONCLUSIONS: Future research should be oriented toward assessing the risk of chronic diabetes complications. Our findings suggest that research should expand self-consciousness and caring partnerships to improve self-consciousness and patients' obedience.

Predictors and outcomes in primary depression care (POKAL) - a research training group develops an innovative approach to collaborative care.

BACKGROUND: The interdisciplinary research training group (POKAL) aims to improve care for patients with depression and multimorbidity in primary care. POKAL includes nine projects within the framework of the Chronic Care Model (CCM). In addition, POKAL will train young (mental) health professionals in research competences within primary care settings. POKAL will address specific challenges in diagnosis (reliability of diagnosis, ignoring suicidal risks), in treatment (insufficient patient involvement, highly fragmented care and inappropriate long-time anti-depressive medication) and in implementation of innovations (insufficient guideline adherence, use of irrelevant patient outcomes, ignoring relevant context factors) in primary depression care. METHODS: In 2021 POKAL started with a first group of 16 trainees in general practice (GPs), pharmacy, psychology, public health, informatics, etc. The program is scheduled for at least 6 years, so a second group of trainees starting in 2024 will also have three years of research-time. Experienced principal investigators (PIs) supervise all trainees in their specific projects. All projects refer to the CCM and focus on the diagnostic, therapeutic, and implementation challenges. RESULTS: The first cohort of the POKAL research training group will develop and test new depression-specific diagnostics (hermeneutical strategies, predicting models, screening for suicidal ideation), treatment (primary-care based psycho-education, modulating factors in depression monitoring, strategies of de-prescribing) and implementation in primary care (guideline implementation, use of patient-assessed data, identification of relevant context factors). Based on those results the second cohort of trainees and their PIs will run two major trials to proof innovations in primary care-based a) diagnostics and b) treatment for depression. CONCLUSION: The research and training programme POKAL aims to provide appropriate approaches for depression diagnosis and treatment in primary care.

AFSOS-SFRO-SFH-SFNEP-SFCE-GFRP guidelines on radio-induced nausea and vomiting.

INTRODUCTION: The prevalence of radiation-induced nausea and vomiting varies between 40% and 80%. They have many consequences on treatment and comorbidities. This work thus aimed to define clinical practice guidelines for the management of radiation-induced nausea and vomiting. METHODS: XXXXX, XXXX, XXX, XXXXX, XXXX and XXXX compiled a working group who draft these recommendations. RESULTS: The assessment of the emetogenic risk found two main predictive factors: 1) the irradiated anatomical location, 2) an associated concomitant chemotherapy. In the case of exclusive radiotherapy, primary antiemetic prophylaxis depends on the emetogenic risk (the irradiated anatomical location). In the case of concomitant chemotherapy, the emetogenic risk is generally higher and the primary antiemetic prophylaxis corresponds to that of chemotherapy-induced nausea and vomiting. In cases where symptoms persist, remedial treatments are poorly codified. CONCLUSION: Radiation-induced nausea and vomiting remains underdiagnosed and undertreated, its rapid detection and treatment are essential to reinstate good clinical practice.

Standardized evaluation of the quality and persuasiveness of mobile health applications for diabetes management.

This study evaluates diabetes self-management mobile health applications available from European app stores with respect to quality, concordance with recommended self-management tasks and implementation of persuasive system design principles. The European Play Store and Apple App Store were systematically searched and relevant apps were tested. Two raters independently assessed app quality using the Mobile Application Rating Scale and conducted a content analysis of provided persuasive system design principles and self-management tasks. A total of 2,269 mobile health applications were identified and 120 could be included in the evaluation. The overall quality was rated as moderate M = 3.20 (SD = 0.39, min = 2.31, max = 4.62), with shortcomings in the subcategories of engagement (M = 2.80, SD = 0.67) and information quality (M = 2.26, SD = 0.48). Scientific evidence is available for 8% of the apps. The reviewed apps implemented a median of three persuasive system design principles (range 0-15) and targeted a median of 4.5 (range 1-8) self-management tasks, however, with a lack of information about psychosocial coping strategies. Most available diabetes self-management apps lack a scientific evidence base. Persuasive system design features are underrepresented and may form a promising tool to improve app quality. Furthermore, the interaction of physical and behavioral health should be improved in existing diabetes self-management mobile health applications.

Nitrous oxide for pain management of first-trimester instrumental termination of pregnancy under local anaesthesia and/or minimal sedation: A systematic review and meta-analysis.

BACKGROUND: Inhalation of nitrous oxide and oxygen (N2O/O2) is used to reduce pain that is spontaneous or induced by procedures. N2O/O2 could be useful in the treatment of the pain in first-trimester termination of pregnancy performed under local anaesthesia and/or minimal sedation (FTOPL). OBJECTIVE: To evaluate the usefulness of N2O/O2 to reduce pain in FTOPL. SEARCH STRATEGY: Electronic databases including PubMed, Embase, and MEDLINE were searched using keywords. STUDY SELECTION: All studies comparing the use of N2O/O2 versus a placebo in the management of pain during FTOPL during the first trimester were included. Of the 199 studies identified, four were deemed eligible for this meta-analysis. DATA COLLECTION: The extracted results were perioperative pain, immediate and delayed postoperative pain, anxiety scores, and the secondary effects (nausea, vomiting). The data were analysed using Comprehensive Meta-Analysis software version 2.2.064. MAIN RESULTS: There was a significant difference in favour of N2O/O2 for perioperative pain (p = 0.006; SMD = - 0.31; 95 % CI, -0.54 - -0.09). No difference was found, however, in postoperative pain, nor was there a difference in the secondary effects (nausea, vomiting) (p = 0.61). A significant decrease in postoperative anxiety scores was seen in the pooled placebo group (p = 0.049; SMD = 0.41; and 95 % CI, 0.001-0.83). CONCLUSIONS: N2O/O2 reduces the pain of FTOPL. N2O/O2 could be recommended in FTOPL.

[Contribution of electronic cigarettes in smoking patients with psychotic disorders. A literature review]. / Cigarette électronique chez les patients fumeurs présentant une pathologie psychotique. Revue de la littérature.

OBJECTIVES: This systematic literature review focused on patients suffering from schizophrenia (SZ), psychotic disorders or mental illness (MI) including SZ. It was interested in data on prevalence of electronic cigarette (EC) use, patient perceptions and expectations, as well as caregivers' attitudes towards the EC and its benefit in helping to stop or reduce smoking. METHOD: The research was carried out on Medline for the period 2000-2020. Cross-sectional, case-control, prospective, randomized controlled studies and preliminary studies were included in this review. RESULTS: EC is widely used by MI patients with current and lifetime use from 7.4% to 28.6%. More specifically, patients with SZ and schizoaffective disorders observe current and lifetime use from 7% to 36%, respectively. Many reasons are given by patients for its use including the possibility of using it in places where smoking is prohibited, its lower toxicity compared to cigarettes for oneself and those around, its lower cost, and the help provided to reduce consumption. CONCLUSION: EC is used by smokers with MI; several studies confirm the possibility for these smokers to reduce tobacco consumption through EC and without disturbing their mental state. However, its value in helping to quit smoking remains uncertain.

Is there a Role for Frozen Section Evaluation of Parotid Masses After Preoperative Cytology or Biopsy Diagnosis?

Fine-needle aspiration (FNA) biopsy reliably diagnoses parotid gland lesions preoperatively, whereas intraoperative frozen section (FS) has the additional benefit of assessing surgical margins and refining diagnoses; however, the role of FS in the setting of prior FNA diagnosis is not well established. Our aim was to determine whether FS should still be performed after a prior FNA/ CNB diagnosis. Parotid gland resections from January 2009 to January 2020 were identified; however, only patients who had both FNA and FS constituted our study population. For the purpose of statistical analysis, FNA diagnoses were classified into non-diagnostic (ND), non-neoplastic (NN), benign neoplasm (BN), indeterminate, and malignant. FS diagnoses were classified into benign, indeterminate, or malignant. Resections were dichotomized into benign and malignant and regarded as the gold standard to subsequently calculate diagnostic accuracy of FNA and FS. A total of 167 parotid gland resections were identified, but only 76 patients (45.5%) had both FNA and FS. In 35 cases deemed as benign preoperatively, three (8.6%) were reclassified as malignant on FS. Out of 18 lesions reported as malignant on FNA, four (22.2%) were interpreted as benign on FS, with three of these benign lesions confirmed on permanent slides. In addition, in patients with both FNA and FS, compared to FNA, FS was able to provide a definitive diagnosis in all five ND cases and in 61.1% (11/18) of indeterminate tumors. Intraoperative assessment provided a relative increase of 33.3% in specificity and 38.5% in positive predictive value when compared to preoperative FNA. The addition of FS to FNA was helpful to further refine the diagnoses of parotid gland lesions, which may provide better guidance for surgical intervention.

Potential predictors of depressive symptoms during the initial stage of the COVID-19 outbreak among Brazilian adults.

BACKGROUND: In early 2020, Sars-Cov-2 was identified in China as a new coronavirus. Due to its transmission, Sars-Cov-2 has spread rapidly across the world. In the early stage of the disease outbreak, psychiatric symptoms have been reported, including depressive symptoms. In this study, we assessed the prevalence of depressive symptoms in quarantine and its association with sociodemographic variables and known protective factors for depression, such as spirituality, social support, resilience, and quality of life. METHODS: A cross-sectional web-based questionnaire was distributed via social media. The instruments consisted of the 8-item EUROHIS-QOL, PHQ-9, Social Support Questionnaire, WHOQoL-SRPB, and CD-RISC. RESULTS: A total of 3,274 participants were included in this study. 23.67% of the participants met the criteria for a depressive episode. Higher age, spirituality, social support, resiliency, and quality of life were associated with less depressive symptoms. Quarantine length; mental health treatment; chronic disease; age; sex; lower levels of spirituality, social support, resilience, quality of life, physical exercise, and education; and unpaid occupation were found to be predictors of depressive symptoms during COVID-19 quarantine. LIMITATIONS: The data are limited to the pandemic initial period, the sample isn't random and the use of self-reported questionnaires are some limitations of our study. CONCLUSIONS: During the initial phase of the COVID-19 outbreak in Brazil, quarantine time, treatment for mental health, chronic illness, lower levels of education, and unpaid occupation were positively associated with depressive symptoms. Age, sex, spirituality, social support, resilience, quality of life, and physical exercise showed a negative relationship with depressive symptoms.

A zone melting device for the in situ observation of directional solidification using high-energy synchrotron x rays.

Directional solidification (DS) is an established manufacturing process to produce high-performance components from metallic materials with optimized properties. Materials for demanding high-temperature applications, for instance in the energy generation and aircraft engine technology, can only be successfully produced using methods such as directional solidification. It has been applied on an industrial scale for a considerable amount of time, but advancing this method beyond the current applications is still challenging and almost exclusively limited to post-process characterization of the developed microstructures. For a knowledge-based advancement and a contribution to material innovation, in situ studies of the DS process are crucial using realistic sample sizes to ensure scalability of the results to industrial sizes. Therefore, a specially designed Flexible Directional Solidification (FlexiDS) device was developed for use at the P07 High Energy Materials Science beamline at PETRA III (Deutsches Elektronen-Synchrotron, Hamburg, Germany). In general, the process conditions of the crucible-free, inductively heated FlexiDS device can be varied from 6 mm/h to 12 000 mm/h (vertical withdrawal rate) and from 0 rpm to 35 rpm (axial sample rotation). Moreover, different atmospheres such as Ar, N2, and vacuum can be used during operation. The device is designed for maximum operation temperatures of 2200 °C. This unique device allows in situ examination of the directional solidification process and subsequent solid-state reactions by x-ray diffraction in the transmission mode. Within this project, different structural intermetallic alloys with liquidus temperatures up to 2000 °C were studied in terms of liquid-solid regions, transformations, and decompositions, with varying process conditions.

Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4.

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/-) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/- mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.

Direct drive with the argon fluoride laser as a path to high fusion gain with sub-megajoule laser energy.

Argon fluoride (ArF) is currently the shortest wavelength laser that can credibly scale to the energy and power required for high gain inertial fusion. ArF's deep ultraviolet light and capability to provide much wider bandwidth than other contemporary inertial confinement fusion (ICF) laser drivers would drastically improve the laser target coupling efficiency and enable substantially higher pressures to drive an implosion. Our radiation hydrodynamics simulations indicate gains greater than 100 are feasible with a sub-megajoule ArF driver. Our laser kinetics simulations indicate that the electron beam-pumped ArF laser can have intrinsic efficiencies of more than 16%, versus about 12% for the next most efficient krypton fluoride excimer laser. We expect at least 10% 'wall plug' efficiency for delivering ArF light to target should be achievable using solid-state pulsed power and efficient electron beam transport to the laser gas that was demonstrated with the U.S. Naval Research Laboratory's Electra facility. These advantages could enable the development of modest size and lower cost fusion power plant modules. This would drastically change the present view on inertial fusion energy as being too expensive and the power plant size too large. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 1)'.

Passage of uranium through human cerebral microvascular endothelial cells: influence of time exposure in mono- and co-culture in vitro models.

PURPOSE: Depleted uranium (DU) has several civilian and military applications. The effects of this emerging environmental pollutant on human health raise some concerns. Previous experimental studies have shown that uranium (U) exposure can disturb the central nervous system. A small quantity of U reaches the brain via the blood, but the effects on the blood-brain barrier (BBB) remain unclear. MATERIALS AND METHODS: In the present work, two cell culture models were exposed to DU for different times to study its cytotoxicity, paracellular permeability and extracellular concentration of U. The well-known immortalized human cerebral microvascular endothelial cells, hCMEC/D3, were cultured on the filter in the first model. In the second model, human primary cells of pericytes were cultured under the filter to understand the influence of cell environment after U exposure. RESULTS: The results show that U is not cytotoxic to hCMEC/D3 cells or pericytes until 500 µM (1.6 Bq.L-1). In addition, acute or chronic low-dose exposure of U did not disturb permeability and was conserved in both cell culture models. However, U is able to reach the brain compartment. During the first hours of exposure, the passage of U to the abluminal compartment was significantly reduced in the presence of pericytes. Electronic microscopy studies evidenced the formation of needlelike structures, like urchin-shaped precipitates, from 1 h of exposure. Analytical microscopy confirmed the U composition of these precipitates. Interestingly, precipitated U was detected only in endothelial cells and not in pericytes. U was localized in multilamellar or multivesicular bodies along the endo-lysosomal pathway, suggesting the involvement of these traffic vesicles in U sequestration and/or elimination. CONCLUSIONS: We show for the first time the in vitro passage of U across a human cerebral microvascular endothelial cells, and the intracellular localization of U precipitates without any cytotoxicity or modification of paracellular permeability. The difference between the results obtained with monolayers and co-culture models with pericytes illustrates the need to use complex in vitro models in order to mimic the neurovascular unit. Further in vivo studies should be performed to better understand the passage of U across the blood-brain barrier potentially involved in behavioral consequences.