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Lung cancer remains the first cause of cancer-related deaths worldwide, of which Non-Small Cell Lung Cancer (NSCLC) represents more than 80% of patients with advanced disease at the time of diagnosis. NSCLC is a highly heterogenous disease, and the identification of its main actionable oncogenic drivers (i.e. EGFR, ALK, PI3K/AKT/mTOR, RET, MET, BRAF and NTRK/ROS1) and the development of specific inhibitors against these targets has transformed therapeutic care. In addition, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers, although biomarkers for predicting response to immune-checkpoint inhibition have remained elusive. Despite these new therapeutic options, NSCLC remains a lethal disease in the majority of patients due to tumor plasticity and selection leading to frequent resistance development and disease progression. Efforts are therefore needed to identify drugs and drug combinations that can prevent or overcome these resistance pathways. Patient-Derived Xenografts (PDX) models developed in immune-compromised mice recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic and genomic features. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies, facilitating the translation of preclinical results in the clinical setting. We describe a platform of over 35 NSCLC PDX models covering most of the molecular diversity of the disease, that have been fully characterized at the molecular level and for their response to a panel of cytotoxic chemotherapies and targeted therapies. These NSCLC PDX models have been established in immune-deficient mice from tumor biopsies collected in treatment-naïve patients or in patients having acquired resistance following an initial objective response to a variety of targeted inhibitors (EGFRi, ALKi, ROSi, BRAFi,⋯) in the MATCH-R clinical trial. In addition, 4 PDX models were established from circulating tumor cells (CTC) isolated from the blood of advanced NSCLC patients. Finally, some of these NSCLC PDX models were established in highly immunodeficient mice humanized with human PBMCs or CD34+ cells allowing testing of efficacy of bispecific T-Cell engager antibody or immune-checkpoint inhibitors. This panel of NSCLC PDX models provides a powerful preclinical platform to improve our knowledge on the mechanisms underlying resistance to treatment and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Laura Brulle-Soumare, Katell Mevel, Ludovic Bigot, Tala Tayoun, Benjamin Besse, Françoise Farace, Luc Friboulet, Didier Decaudin, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Deas. Characterization of a PDX panel covering molecular diversity of non-small cell lung cancer to accelerate the development of precision therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4678.

Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. It is a highly heterogenous and complex disease, presenting serious challenges to preclinical drug development and biomedical research. Prostate normal development, growth and function, as well as most of its pathological drifts, are associated to androgen receptor (AR) pathway regulation. Most patients subjected to androgen deprivation therapy (ADT) respond well to the treatment, however they usually progress into intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of castration resistance underlying PCa progression is key to develop future therapies. Patient-Derived Xenografts (PDX) are mouse models that recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results in the clinical setting. PCa PDXs are challenging to develop, and only few are available to the scientific community. This lack of relevant preclinical models is a major limitation in PCa research. In particular, the development of PCa PDX models from castration-resistant tumors to explore new treatments against CRPC is a requirement. To fill this gap, XenTech and Gustave Roussy Institute are collaborating to develop a panel of PCa PDX models. In the framework of the MATCH-R clinical trial (NCT02517892), in which patients with disease progression under treatment are enrolled and switched to new targeted therapy based on the genetic alterations identified in biopsies, 8 PCa PDXs have been developed from metastatic lesions biopsy. In addition, we developed a PCa PDX model from circulating tumor cells (CTCs) obtained by leukapheresis at diagnosis. These 9 models, plus 4 PCa PDXs previously developed at XenTech, increases our PCa PDX panel to 13 models. All models were characterized at molecular level by whole exome and RNA sequencing and pharmacologically for response to standards of care, physical castration and response to the androgen receptor inhibitor enzalutamide. This PDX collection is a valuable preclinical tool to identify pivotal mechanisms underlying acquired resistance to current therapies and develop novel treatment strategies against PCa and CRPC. Citation Format: Laura Brulle-Soumare, Ludovic Bigot, Katell Mevel, Enora Le Ven, Luc Friboulet, Benjamin Besse, Françoise Farace, Jean Gabriel Judde, Stefano Cairo, Yohann Loriot, Olivier Déas. Molecular and pharmacological profiling of a novel prostate cancer-derived xenograft panel to identify resistance mechanisms and new therapeutic options [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3113.

International audience; Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N = 148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area, and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture associated with autistic traits. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.

Visual scenes are processed in terms of spatial frequencies. Low spatial frequencies (LSF) carry coarse information, whereas high spatial frequencies (HSF) subsequently carry information about fine details. The present magnetic resonance imaging study investigated how cortical thickness covaried with LSF/HSF processing abilities in ten-year-old children and adults. Participants indicated whether natural scenes that were filtered in either LSF or HSF represented outdoor or indoor scenes, while reaction times (RTs) and accuracy measures were recorded. In adults, faster RTs for LSF and HSF images were consistently associated with a thicker cortex (parahippocampal cortex, middle frontal gyrus, and precentral and insula regions for LSF, parahippocampal cortex and fronto-marginal and supramarginal gyri for HSF). On the other hand, in children, faster RTs for HSF were associated with a thicker cortex (posterior cingulate, supramarginal and calcarine cortical regions), whereas faster RTs for LSF were associated with a thinner cortex (subcallosal and insula regions). Increased cortical thickness in adults and children could correspond to an expansion mechanism linked to visual scene processing efficiency. In contrast, lower cortical thickness associated with LSF efficiency in children could correspond to a pruning mechanism reflecting an ongoing maturational process, in agreement with the view that LSF efficiency continues to be refined during childhood. This differing pattern between children and adults appeared to be particularly significant in anterior regions of the brain, in line with the proposed existence of a postero-anterior gradient of brain development. Taken together, our results highlight the dynamic brain processes that allow children and adults to perceive a visual natural scene in a coherent way.

National audience; Some economic transactions require people to trust strangers, whose trustworthiness is unknown. In these circumstances, behavioral studies have shown that adults (but not young adolescents) seem to have some minimal ability to detect the trustworthiness of adult strangers based on their facial features. In this study, we explored the neural correlates of this facial trustworthiness detection. A group of adolescents and adults played a series of economic Trust Games with adult trustees of which we had previously recorded the strategy. Results showed that when adult investors were looking at the picture of a trust-abusing trustee, the left amygdala was relatively more activated than when they were looking at a trust-honoring player. Younger adolescents did not show this pattern and responded with a more pronounced deactivation when facing a trust-abusing trustee. An exploratory whole-brain analysis detected a similar age shift for mentalizing regions of the brain. Our results fit with an emerging model suggesting that the amygdala is implicated in an associative learning process that progressively refines a mapping of faces onto trustworthy behavior and may result in avoiding to be exploited by untrustworthy strangers.

Despite progress in understanding aberrations that contribute to the development and progression of cancer, resistance to classical chemotherapeutic agents or novel targeted drugs continues to be a major problem in cancer therapy. Hence, the identification of the mechanisms underlying drug resistance acquisition is the key to explore new and efficient therapeutic pathways for patients. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression under treatment. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models are being fully characterized at both molecular and pharmacological levels and used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Acquired Resistance) models is planned over 3 years. To favor successful xenograft establishment, the first passages are performed without drug treatment, then all the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy. When applying therapeutic pressure, we observed different types of response: resistance from the first passage under treatment, stabilization under treatment at the first passages and rapidly acquired resistance over passages, or sensitivity to treatment whereas the patient tumor showed progression under the same treatment. These different behaviors can be observed in PDX models developed from multiple metastases of a same patient and may reflect different mechanisms of resistance. Most interestingly, PDX models obtained from different metastatic lesions of a same patient can recapitulate the different behavior observed in this patient. This behavior is translated by either tumor progression in one PDX model and/or stabilization under treatment in another. These paired models greatly facilitate the identification of relevant mechanisms of drug resistance.We have now completed the development of a panel of 25 PDX models of various indications and exposed to a variety of last generation targeted therapies. We will discuss relevant examples of results that can be generated from this panel, with particular focus on the molecular features of models with acquired or intrinsic resistance to treatment and of paired models with different drug sensitivity. These data highlight the unique potential of the MATCH-R preclinical platform to identify resistance mechanisms and develop next generation therapeutic strategies. Citation Format: Olivier Deas, Emilie Dassé, Laura Brulle-Soumare, Katell Mevel, Ludovic Bigot, Yohann Loriot, Fabrice André, Jean-Charles Soria, Benjamin Besse, Enora Le Ven, Stefano Cairo, Luc Friboulet, Jean-Gabriel Judde. Identification of the mechanisms of resistance to targeted therapies in advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3016.

Autism spectrum disorder (ASD) has been found to be associated with alterations in resting state (RS) functional connectivity, including areas forming the default mode network (DMN) and salience network (SN). However, insufficient control for confounding genetic and environmental influences and other methodological issues limit the generalizability of previous findings. Moreover, it has been hypothesized that ASD might be marked by early hyper-connectivity followed by later hypo-connectivity. To date, only a few studies have explicitly tested age-related influences on RS connectivity alterations in ASD. Using a within-twin pair design (N=150 twins; 8-23 years), we examined altered RS connectivity between core regions of the DMN and SN in relation to autistic trait severity and age in a sample of monozygotic (MZ) and dizygotic (DZ) twins showing typical development, ASD or other neurodevelopmental conditions. Connectivity between core regions of the SN was stronger in twins with higher autistic traits compared to their co-twins. This effect was significant both in the total sample and in MZ twins alone, highlighting the effect of non-shared environmental factors on the link between SN-connectivity and autistic traits. While this link was strongest in children, we did not identify differences between age groups for the SN. In contrast, connectivity between core hubs of the DMN was negatively correlated with autistic traits in adolescents and showed a similar trend in adults but not in children. The results support hypotheses of age-dependent altered RS connectivity in ASD, making altered SN and DMN connectivity promising candidate biomarkers for ASD.

Since reasoning is often biased by intuitive heuristics, the development of sound reasoning has long been postulated to depend on successful bias monitoring and inhibition. The present fMRI study aimed to identify neural correlates of developmental changes in these processes. A group of adults and young adolescents were presented with ratio-bias problems in which an intuitively cued heuristic response could be incongruent (conflict item) or congruent (no-conflict item) with the correct response. Results showed that successfully avoiding biased responding on conflict items across both age groups was associated with increased activation in Anterior Cingulate Cortex (ACC) and the right Lateral Prefrontal Cortex (LPFC) regions of interest. Critically, the right LPFC activation decreased with age. Biased responding did not result in right LPFC or ACC modulation and failed to show any developmental activation changes. We discuss implications for ongoing debates on the nature of heuristic bias and its development.

Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

BackgroundFemales with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors.MethodsIn 75 twin pairs (n= 150, 62 females, 88 males) enriched for autism spectrum disorder (n= 32), and other neurodevelopmental disorders (n= 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks.ResultsCo-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum.LimitationsHowever, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution.ConclusionsOur findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.

Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. In 75 twin pairs (n=150, 62 females, 88 males) enriched for autism spectrum disorder (n=32), and other neurodevelopmental disorders (n =32), we explored the association of restricted and repetitive behaviors and interests – operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale), with cortical volume, surface area and thickness of neocortical, sub-cortical and cerebellar networks. Cotwin control analyses revealed within-pair associations between RRBI symptoms and the right intraparietal sulcus and right orbital gyrus in females only. These findings endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.

International audience; Inhibitory control (IC) is a core executive function that enables humans to resist habits, temptations, or distractions. IC efficiency in childhood is a strong predictor of academic and professional success later in life. Based on analysis of the sulcal pattern, a qualitative feature of cortex anatomy determined during fetal life and stable during development, we searched for evidence that interindividual differences in IC partly trace back to prenatal processes. Using anatomical magnetic resonance imaging (MRI), we analyzed the sulcal pattern of two key regions of the IC neural network, the dorsal anterior cingulate cortex (ACC) and the inferior frontal cortex (IFC), which limits the inferior frontal gyrus. We found that the sulcal pattern asymmetry of both the ACC and IFC contributes to IC (Stroop score) in children and adults: participants with asymmetrical ACC or IFC sulcal patterns had better IC efficiency than participants with symmetrical ACC or IFC sulcal patterns. Such additive effects of IFC and ACC sulcal patterns on IC efficiency suggest that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency. This view shares some analogies with the " common variant–small effect " model in genetics, which states that frequent genetic polymorphisms have small effects but collectively account for a large portion of the variance. Similarly, each sulcal polymorphism has a small but additive effect: IFC and ACC sulcal patterns, respectively, explained 3% and 14% of the variance of the Stroop interference scores. Significance Statement Inhibitory control (IC) is a cognitive function that plays a critical role in the pathophysiology of several psychiatric conditions and in academic and professional success. Using anatomical magnetic resonance imaging (MRI) of healthy children and adults, we found that IC efficiency is constrained by the morphology (sulcal pattern) of two key regions of the neural network underlying IC. Because the sulcal pattern is a morphologic feature of cortical anatomy that is determined during fetal life and stable during development, our findings provide evidence that interindividual differences in IC partly trace back to prenatal processes and that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency.

Human reasoning is often biased by heuristic thinking. A key question is whether people detect that their heuristic answer conflicts with logical considerations. Empirical studies suggest that the detection is typically successful but the generality of these findings has been questioned. The present study focuses on this issue. A response confidence measure was used to validate conflict sensitivity findings in the classical ratio bias task and identify individual differences in conflict detection efficiency. Participants were asked to indicate how confident they were after solving problems for which a cued heuristic response could be inconsistent or consistent with the correct response. Results confirmed that most reasoners showed a confidence decrease when they were biased, suggesting that they acknowledge that their intuitive answers are not fully warranted. However, there were also subgroups of reasoners who failed to show a confidence effect. Implications for the debate on conflict detection during th...

Current evidence suggests the phenotype of autism spectrum disorder to be driven by a complex interaction of genetic and environmental factors impacting onto brain maturation, synaptic function, and cortical networks. However, findings are heterogeneous, and the exact neurobiological pathways of autism spectrum disorder still remain poorly understood. The co-twin control or twin-difference design is a potentially powerful tool to disentangle causal genetic and environmental contributions on neurodevelopment in autism spectrum disorder. To this end, monozygotic twins discordant for this condition provide unique means for the maximum control of potentially confounding factors. Unfortunately, only few studies of a rather narrow scope, and limited sample size, have been conducted. In an attempt to highlight the great potential of combining the brain connectome approach with monozygotic twin design, we first give an overview of the existing neurobiological evidence for autism spectrum disorder and its cognitive correlates. Then, a special focus is made onto the brain imaging findings reported within populations of monozygotic twins phenotypically discordant for autism spectrum disorder. Finally, we introduce the brain connectome model and describe an ongoing project using this approach among the largest cohort of monozygotic twins discordant for autism spectrum disorder ever recruited.

Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. It is a highly heterogenous and complex disease, presenting serious challenges to preclinical drug development and biomedical research. The normal development, growth and function of the prostate and most of its malignancies are under androgen regulation. However, after initiation of androgen deprivation therapy (ADT), most patients progress to intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of resistance that cause PCa to progress to a castration-resistance stage is the key to developing future beneficial therapies. Patient Derived Xenografts (PDX) mouse models show greater fidelity to the disease than any other in vivo models in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results into the clinical setting. However, PCa PDXs have been challenging to develop and a major limitation in PCa research is the lack of relevant preclinical models. The development of PCa PDX models is a mandatory requirement to explore new treatments targeting castration-resistant tumor cells and to improve anti-androgen therapies. To overcome the limitations of the number of relevant available models, in the framework of the MATCH-R clinical trial, which enrolls patients with oncogene-driven cancer who had previously responded to targeted therapy and subsequently experienced disease progression, XenTech and Gustave Roussy Institute are collaborating to develop a panel of extensively characterized PCa PDX models. Using biopsy material from metastatic lesions implanted into the sub-renal capsule of NSG mice, we report the successful establishment of 8 advanced PCa PDX models. All PDX models are characterized at the molecular level by whole exome sequencing and RNA-sequencing. Their response to physical castration and to the androgen receptor inhibitor enzalutamide is compared to the response observed in patients. This collection of PCa PDX models will be a useful preclinical tool to identify pivotal mechanisms underlying acquired resistance to current targeted therapies and develop novel treatment strategies. Citation Format: Olivier Deas, Ludovic Bigot, Emilie Dassé, Fabrice André, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Luc Friboulet, Jean Gabriel Judde, Yohan Loriot. Establishment, molecular and pharmacological profiling of novel prostate cancer-derived xenografts from patients with advanced, treatment-refractory, disease to identify resistance mechanisms and new therapeutic options [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1929.

The last 20 years have witnessed the identification of an increasing number of actionable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be fully characterized at molecular and pharmacological level and used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Acquired Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. To favor successful xenograft establishment, the first two passages are performed without drug treatment, which is applied from the third passage on. When doing so, we observed 3 types of response: some models showed resistance from the first passage under treatment, some showed stabilization under treatment at the first passages and rapidly acquired resistance over passages, and others showed sensitivity to treatment, whereas the patient tumor showed progression under the same treatment. These different behaviors might be due to different mechanisms of resistance, irreversible for the former, reversible for the two latter, as well as to suboptimal correlation of the clinical dose with the one used in mice. An example of such discrepancies has been found in two models of NSCLC PDX obtained from two metastases from a patient treated by a ROS1 and ALK inhibitor. While LCx-MR135PD2-AR PDX does not respond to the treatment, the LCx-MR135PD1 model is highly sensitive. As both metastases were progressing under treatment in the patient, molecular and pharmacological comparative analysis of these two models will investigate these discrepancy and provide important insights into the mechanisms of resistance to such inhibitors. Overall, the MatchR PDX project will provide a unique preclinical platform to identify resistance mechanisms to current targeted therapies and to develop next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Emilie Dasse, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean-Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Generation of a fully characterized preclinical PDX panel to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2122.

Brain connectomics is a relatively new field of research that maps the brain's large-scale structural and functional networks at rest. The connectome of the human brain develops progressively from early infancy to late adolescence, and this review describes the theory behind the concept and its applicability to studying the development and dynamics of brain networks through graph theoretical metrics. We also describe how the brain connectome concept could further our understanding of autism spectrum disorders (ASD) CONCLUSION: Further research into the functional child brain connectome concept could enhance our understanding of atypical brain connectivity patterns presumed to be linked to ASD.

International audience; In the past decade, a "default mode network" (DMN) has been highlighted in neuroimaging studies as a set of brain regions showing increased activity in task-free state compared to cognitively demanding task, and synchronized activity at rest. Changes within this network have been described in healthy aging as well as in Alzheimer's disease (AD) and populations at risk for AD, that is, amnestic Mild Cognitive Impairment (aMCI) patients and APOE-ε4 carriers. This is of particular interest in the context of early diagnosis and more generally for our understanding of the physiopathological mechanisms of AD. This paper gives an overview of the anatomical and physiological characteristics of this network as well as its relationships with cognition, before focusing on changes in the DMN over normal aging and Alzheimer's disease. While perturbations of the DMN have been consistently reported, especially within the posterior cingulate, further studies are needed to understand their clinical implication.

INTRODUCTION: A "resting state" or "default mode network" has been highlighted in functional neuroimaging studies as a set of brain regions showing synchronized activity at rest or in task-independent cognitive state. STATE OF THE ART: A considerable and increasing number of studies have been conducted over the last few years so as to unravel the cognitive function(s) of this brain network. PERSPECTIVES: This review gives an overview of anatomical, physiological and phenomenological data regarding the default mode network. Different hypotheses have been proposed regarding the role of this network. Several studies have highlighted its involvement in autobiographical memory, prospection, self, attention, and theory of mind. The influence of the attention level and consciousness onto resting state brain network activity has also been discussed. Specific changes have been described in normal aging, Alzheimer's disease (AD) and multiple sclerosis (MS). CONCLUSIONS: These studies altogether contribute to a better definition of the default mode network, in terms of implicated brain structures, subtending mechanisms, and potential cognitive roles. For instance, similarities and relationships were found between self-related brain activity and resting-state activity in regions belonging to this network, namely posterior cingulate and prefrontal areas that may reflect introspective activity experienced, more or less consciously, when the brain is not specifically engaged in a cognitive task. As a whole, the default mode network appears as a non human-specific intrinsic functional network, active all over the life from birth until aging where it is progressively modified, and sensitive to different pathologies including AD and MS. On the other hand, many points remain to be clarified concerning this network, such as the exact part of its activity dedicated to self-related cognitive processes (introspection, imaginary mental scenario based on past autobiographical experiences) and that involved in a sentinel-like attentional process designated to react to possible environmental events. Indeed, it seems that this network is functional even in case of low level of consciousness, i.e., during light sleep. Conversely, a loss of self and environment perception as in coma, deep sleep or anesthesia might modulate its connectivity along the anteroposterior axis, i.e., frontal activity disappearance associated with a parietal reinforcement of connectivity. Since studies aiming at highlighting these points are still uncommon to date, exhaustive and objective explorations are needed to better understand all these resting state processes.

The last 20 years have witnessed the identification of an increasing number of druggable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Active Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. The following models have been established so far: • ENDx-MR-004-AR (endometrial): resistant to the combination of MEK and MDM2 inhibitors; • LCx-MR-007-AR: (NSCLC): resistant to third generation EGFR inhibitor (osimertinib); • UREx-MR-015A-AR (ureter) and VEx-MR-086A-AR (bladder): resistant to a FGFR inhibitor (erdafitinib); • PARx-MR-010-AR (parotid): resistant to a NOTCH Inhibitor; • TCx-MR-122-AR (colon): resistant to an ATR inhibitor. To favor successful xenograft establishment, the first two passages were performed without drug treatment, which was applied from the third passage on. When doing so, some models showed resistance from the first passage under treatment, whereas others showed stabilization under treatment at the first passages and rapidly acquired resistance over passages. These different behaviors might underlie different mechanisms of resistance, irreversible (monoclonal) for the former, reversible (polyclonal) for the latter. Parallel to the development of UREx-MR-015A-AR, we developed the UREx-MR-015B-SD (stable disease) model from a biopsy collected from a different metastasis in the same patient, but stabilized by the therapy. Comparative analysis of these two models will provide important insights into the mechanisms of resistance to FGFR inhibitors. The MATCH-R PDX project will provide a unique preclinical platform for identifying resistance mechanisms to current targeted therapies and developing next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Development of preclinical models to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2147.

Tumour heterogeneity is probably the reason for different sensitivity to the same treatment in patients. Therefore, we urgently need to develop tools to help assign the right treatment to the right patient. This is particularly challenging for paediatric cancers. Hepatoblastoma (HB) is the most frequent malignant embryonal tumor of the liver in childhood. About 25% of HB patients will develop metastatic disease which is associated with a poor prognosis. Because of the small number of patients eligible for enrollment, clinical trials in most of cases could not provide clinicians with statistically significant results. In oncology, preclinical data are generally poorly predictive of treatment efficacy in patients, probably due to oversimplification of tumor biology and underrepresentation of the genetic tumor heterogeneity observed in patients. To face this issue, we have launched a program to generate patient-derived xenografts, the gold standard in preclinical oncology, from surgical tissue from HB patients after chemotherapy, at relapse and from local and distant metastases. Therefore, the models developed are representative of relapsing, metastatic HB. So far, a panel of 24 HB PDXs models has been established. From these models 10 cell lines could be established so far to be used for large-scale in vitro screening of anticancer compound libraries. The aim of this project is to combine in vitro and in vivo drug screening to provide strong preclinical rationale to the development of novel therapeutic options for children with HB, and to identify candidate biomarkers predictive of tumor response. In vitro screening of a HB PDX-derived cells with a library of 60 compounds corresponding to treatments already available in the clinic lead us to identify 4 compounds with very strong cytotoxic activity on HB cells. One of them, Volasertib, a PLK1 inhibitor, was selected to be tested in the HB PDX the cells were derived from. The in vivo study compared the effect of volasertib as single agent or in combination with irinotecan to irinotecan alone or in combination with temozolomide. The results showed that high dose volasertib induce tumor regression with efficacy comparable to irinotecan/temozolomide combination. Following these encouraging results, Volasertib was tested in the complete panel of HB PDX-derived cells, and the majority of them showed strong sensitivity to the drug. This sensitivity was associated with specific molecular alterations that might be used as biomarkers to predict tumor sensitivity. Overall, these results suggest that volasertib could be an effective second line treatment for children with recurrent HB, and that this platform could be a very important preclinical tool to foster translational research in HB. Citation Format: Stefano Cairo, Bénédicte Noblet, Samuel Rasmussen, Matthew N. Svalina, Katell Mevel, Enora Le Ven, Delphine Nicolle, Olivier Déas, Charlotte Mussini, Sophie Branchereau, Jean-Gabriel Judde, Charles Keller. Tailoring personalized strategies for children with treatment-refractory liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4628.

International audience; With age, the brain undergoes both structural and functional alterations, probably resulting in reported cognitive declines. Relatively few investigations have sought to identify those areas that remain intact with aging, or undergo the least deterioration, which might underlie cognitive preservations. Our aim here was to establish a comprehensive profile of both structural and functional changes in the aging brain, using up-to-date voxel-based methodology (i.e. optimized voxel-based morphometry (VBM) procedure; resting-state (18)FDG-PET with correction for partial volume effects (PVE)) in 45 optimally healthy subjects aged 20-83 years. Negative and positive correlations between age and both gray matter (GM) volume and (18)FDG uptake were assessed. The frontal cortex manifested the greatest deterioration, both structurally and functionally, whereas the anterior hippocampus, the thalamus and (functionally) the posterior cingulate cortex were the least affected. Our results support the developmental theory which postulates that the first regions to emerge phylogenetically and ontogenetically are the most resistant to age effects, and the last ones the most vulnerable. Furthermore, the lesser affected anterior hippocampal region, together with the lesser functional alteration of the posterior cingulate cortex, appear to mark the parting of the ways between normal aging and Alzheimer's disease, which is characterized by early and prominent deterioration of both structures.

(1) Inserm-EPHE-Universite de Caen Basse Normandie, Unite E0218, Caen, France. La maladie d’Alzheimer (MA) est une maladie neurodegenerative qui touche les deux tiers des personnes âgees dementes. Avec le vieillissement de la population, ce chiffre risque d’augmenter dans les annees a venir. L’enjeu que constitue le depistage de cette maladie est donc tres important. A l’heure actuelle, le diagnostic n’est pose avec certitude que post-mortem , apres autopsie du cerveau. Les criteres cliniques (1, 45) ne fournissent qu’un diagnostic probabiliste de l’affection et ce a un stade deja evolue de la maladie. Le diagnostic de la MA a un stade precoce constitue donc une priorite du point de vue de la sante publique et devient un objectif pour la recherche. Aussi, les etudes visant a determiner des facteurs predictifs de la maladie se multiplient. Dans ce but, une population de patients s’avere etre une cible privilegiee : les patients MCI ( Mild Cognitive Impairment ou « deficit cognitif leger »). Ces patients presentent une perturbation des capacites cognitives superieure aux difficultes induites par le vieillissement normal mais en l’absence de syndrome dementiel. Plus particulierement, les MCI dits « amnestic » sont des individus presentant un deficit isole de la memoire episodique, systeme mnesique responsable de l’encodage, du stockage et de la recuperation des evenements et de leur contexte temporo-spatial d’acquisition (69), deficit qui pourrait constituer les premieres manifestations de la maladie. Chez ces patients, le risque de developper la MA est accru : le taux de conversion vers la MA est de 10 a 15 % par an (53, 56). En consequence, les MCI constituent une population d’etude ideale : parce qu’une partie importante d’entre eux developpera la MA dans les annees qui suivent, ils sont susceptibles de presenter entre autres des signes neurobiologiques precurseurs de la pathologie. ALTERATIONS NEUROBIOLOGIQUES ET NEUROIMAGERIE DANS LA MALADIE D’ALZHEIMER

Erectile dysfunction (ED) is another manifestation of vascular disease. We evaluated the natural history of ED in the spontaneously hypertensive rat (SHR) and the respective participation of associated pathophysiological modifications, i.e., endothelial dysfunction and tissue remodeling. SHR and their normotensive counterparts [Wistar-Kyoto rats (WKY)] of 6, 12, and 24 wk of age ( n = 12) were used to evaluate erectile function, erectile and aortic tissue reactivity, and remodeling. Erectile responses in SHR are reduced at all ages ( P < 0.001). In both aortic and erectile tissues of SHR and WKY, relaxations to ACh are altered progressively with age, although more markedly in SHR. They are decreased at 12 wk of age in erectile tissue of SHR compared with WKY (maximal relaxation: −19.2 ± 2.8% vs. −28.3 ± 3.9%, P < 0.001) but only at 24 wk of age in aortas (−47.9 ± 6.4% vs. −90.5 ± 2.9%, P < 0.001). Relaxations to sodium nitroprusside are unaltered in aortic rings of both strains but enhanced in erectile tissue of SHR at 12 wk of age. Major modifications in the distribution of collagen I, III, and V in SHR occur in both types of tissue and are detectable sooner in erectile tissue compared with aortic tissue. The onset of ED is detectable before the onset of hypertension in the SHR. Structural and functional alterations, while similar, occur earlier in erectile compared with vascular tissue. If confirmed in humans, ED could be an early warning sign for hypertension, and common therapeutic strategies targeting both ED and hypertension could be investigated.

Objectives: Sildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED. Methods: The effects of an 8-week long treatment with sildenafil (60mg/kg/d sc ) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv ). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36hours after the last injection of sildenafil. Results: Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil. Conclusions: This is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.

Hypertensive men have a higher prevalence of erectile dysfunction (ED) than the general population. Experimental evidence of ED in hypertensive animals is scarce. This study evaluates the erectile function of spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) in vivo by the increase in intracavernosal pressure after electrical stimulation of the cavernous nerve (CN) and by isometric tension studies on corporal strips. Frequency-dependent erectile responses to CN stimulations were reduced in SHR. Phenylephrine induced lower corporal contractions in SHR although pD2values were similar to WKY. Endothelium-dependent relaxations to ACh were impaired significantly in SHR, and indomethacin improved these relaxations in both WKY and SHR, the latter thus reaching values similar to WKY. Corporal relaxations to sodium nitroprusside were enhanced in SHR. Thus a dysfunctional α-adrenergic contraction of the corporal smooth muscle, an increased cyclooxygenase-dependent constrictor tone, and/or a defect in endothelium-dependent reactivity are associated with the altered erectile mechanisms in SHR. Drugs targeting endothelial dysfunction may delay the occurrence of ED as a complication of hypertension.

International audience; Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.

nonlinearly registered to MNI152 space. After registration to MRI, PET uptake ratios (UR) were calculated by dividing [18 F]AV45 and [18 F]FDG scans by the median counts of cerebellar GM and pons, respectively. PET imageswere subsequently registered toMNI152 space using non-linear transformations. Global [18 F]AV45 and [18 F]FDG estimates were conducted in native space grey matter regions. Voxel-based age-corrected regression analysis was calculated from images resampled in MNI152 after 6mm Gaussian convolution.Results:When the clinical subgroups were collapsed, an association between amyloidosis and BNT was found bilaterally/symmetrically in the base of the temporal lobe (TL). Additional areas were the left inferior parietal cortex (IPC), and left anterior/posterior cingulate. For FDG-UR, associations were found in the left IPC, left hippocampus (HIPP), left anterior temporal neocortex (TNeo) and the base of the left temporal cortex. At a subgroup level, amyloidosis was found to associate with BNT in the eMCI subgroup (right HIPP/entorhinal cortex), while FDG was found to associate with BNT in LMCI (left TNeo) and AD subgroups (left TNeo). Conclusions: Naming deficits are associated with amyloidosis and synaptic dysfunction in specific language areas. These effects are less evident at the subgroup level where amyloidosis was found to predominate in EMCI and synaptic dysfunction in LMCI and AD.

BACKGROUND AND PURPOSE To provide guidance regarding the most appropriate voxel-based morphometry (VBM)-derived method for assessing hippocampal atrophy in early Alzheimer's disease (AD). METHODS T1-MRI volume data were collected in 23 patients with amnestic mild cognitive impairment (aMCI) and 18 controls. Three types of data (unmodulated and 2 types of modulated MRI) and 2 extraction methods (with reference to the hippocampal peak of atrophy identified from a preliminary whole-brain analysis, or using a template region of interest–ROI–approach) were compared to the gold-standard individual ROI (ROI-i) method through 2 statistical approaches (ANOVA and Pearson's R). RESULTS First, whole-brain analyses performed on modulated data are as sensitive as the ROI-i approach in detecting aMCI patients’ hippocampal atrophy. Second, values extracted from the ROI-template applied to modulated data provide measures of hippocampal volume comparable to those obtained using the ROI-i approach. CONCLUSIONS This study provides guidance on how to extract accurate hippocampal measures from VBM-derived data in early AD, as a time-saving and easy alternative to the reference ROI-i method. J Neuroimaging 2011;21:310-316.

International audience; BACKGROUND AND PURPOSE: Advances in functional neuroimaging studies have led to the need for improved anatomical precision to face with more and more specific challenges. Nevertheless, functional magnetic resonance imaging (MRI) (fMRI) suffers from geometrical distortions, which limit the matching between functional and anatomical data necessary to interpret fMRI results. The "FieldMap" method is the most widely used technique to correct for geometrical distortions but in some cases cannot be applied or provides unsatisfactory results. The objective of this study is thus to provide a very simple alternative method for distortion correction and to demonstrate its efficiency. METHODS: This correction relies on the nonlinear registration of echo-planar imaging (EPI) acquisitions onto their corresponding undistorted non-EPI T2 Star volume, and was tested on two independent groups of subjects undertaking the same paradigm but scanned with distinct EPI sequences. RESULTS: This procedure was found to considerably decrease the mismatch between functional and anatomical data in both groups, as revealed through several quantitative and qualitative measures on both EPI volumes and activation maps. CONCLUSION: This study describes a simple, rapid, and easily implementable method to significantly improve neuroanatomical accuracy of fMRI results localization, which may be relevant for future neuroimaging studies.

International audience; Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging.

atrophy rates with 90% power. Results: The FTLD cohort exhibited significantly greater whole-brain atrophy rates than controls using both manual segmentation (p 0.029) and the automated BSI (p 0.001). The BBSI and VBSI techniques significantly reduced variability of results compared with manual segmentation and were used as the primary outcome for the following analyses. Pairwise comparisons of all three FTLD subgroups with controls demonstrated significantly higher whole-brain atrophy rates (bvFTLD, p 0.040; SD, p 0.001; and PNFA, p 0.023). Ventricular expansion rates were also significantly greater than controls for the whole FTLD cohort (p 0.001) and for the SD (p 0.001) and PNFA (p 0.001) subgroups, but not bvFTLD (p 0.226), potentially due to the pathogenetic heterogeneity of bvFTLD patients. In future multi-centre clinical trials, using the BBSI would require 221 FTLD patients (with similar numbers per subgroup) to detect a 30% reduction in atrophy rate with 90% power. Conclusions: Whole-brain and ventricular BSI measurements show promise as biomarkers of disease progression in FTLD and could be utilised as outcome measures of treatment effects in future clinical trials of disease-modifying therapies.

While the hippocampus is constantly reported as the site of earliest and highest structural alteration in Alzheimer's disease (AD), findings regarding the metabolic status of this region are rather heterogeneous. It has been proposed that only a time-consuming individual region-of-interest (ROI) approach would allow the detection of hypometabolism in this complex and small area. Our main goal with this study is to assess whether more automatic and clinically useful methods would be sensitive enough when considering other methodological confounds. From a single PET data set collected in 28 patients with amnestic Mild Cognitive Impairment (aMCI) and 19 controls, we assessed the effects of partial volume effect (PVE) correction, scaling (using vermis or global means), and analysis method (individual ROI versus more automatic template-based ROI or voxel-based approaches) on hippocampal hypometabolism detection in aMCI. PVE correction and scaling both showed a significant effect on group comparison, while the analysis method (individual versus template-based ROI) surprisingly did not. Hippocampal metabolic decrease was significant in all vermis-scaled conditions, and more so after PVE correction. Our findings highlight the crucial relevance of using reference-region-based (instead of global) scaling, and the higher sensitivity of PVE-corrected PET measures, to detect hippocampal hypometabolism in aMCI. They also show that hippocampal metabolic decline can be detected using template-based ROI as well as voxel-based methods. These findings have clinical relevance since they support the validity of more automatic and time-saving approaches to assess hippocampal metabolism changes in aMCI and early AD.

During stress-induced increase in abdominal pressure, urinary continence is maintained by urethral closure mechanisms. Active urethral response has been studied in dogs and rats. Such an active urethral response is also believed to occur in humans during stress events. We aimed to investigate urethral closure mechanisms during sneezing in cats. Urethral pressures along the urethra (UP1–UP4), with microtip transducer catheters with UP4 positioned in the distal urethra where the external urethral sphincter (EUS) is located, and intravesical pressure were measured, and abdominal wall, anal sphincter (AS), levator ani (LA), and EUS electromyograms (EMGs) were recorded during sneezing under closed-abdomen and open-abdomen conditions in eight anesthetized adult female cats. Proximal and middle urethral response induced by sneezing was not different from bladder response. Distal urethral response was greater compared with proximal and middle urethral and bladder response. In the open-abdomen bladder, proximal and middle urethral responses were similarly decreased and distal urethral response was unchanged compared with the closed-abdomen bladder. Bladder and urethral responses were positively correlated to sneeze strength. EUS, LA, and AS EMGs increased during sneezing. No urine leakage was observed, regardless of the strength of sneeze. In cats urethral closure mechanisms are partly passive in the proximal and middle urethra and involve an active component in the distal urethra that is believed to result from EUS and possibly LA contractions. Because central serotonin exerts similar effects on the lower urinary tract in cats and humans, the cat may represent a relevant model for pharmacological studies on continence mechanisms.