[The dynamic brain-network model of PTSD]. / Les sciences des réseaux appliquées à l'étude du Trouble de Stress Post-Traumatique.

The brain is a highly complex system whose functioning is critical for our interaction with the world. Neural elements, from single cells to brain systems, constantly fluctuate in their dynamics, accompanying the plethora of possible exchanges between our environment and ourselves. However, sometimes things go awry. An unfortunate example is post-traumatic stress disorder (PTSD), a debilitating clinical condition that can appear after exposure to a threatening life event. In this work, using complexity as a framework, we aim to introduce the dynamic brain network model of PTSD. We hope this model will allow the generation of novel specific hypotheses concerning brain organization and dynamics in PTSD research. We first introduce how the network framework complements the localizationist approach centered in specific brain regions or subsets of brain regions, with a whole brain approach considering brain regions' dynamic relationships. Then, we review key concepts in network neuroscience, focusing on the importance of the network topology and dynamics to understand the organizational principles of the brain, that is, functional segregation and integration. In the third part, we apply this knowledge to describe the possible trajectories conducting a brain system to present PTSD alterations. Accordingly, we introduce the Dynamic Brain Network Model (DBNM) of PTSD, a concrete framework built on the network approach and resilience theory to study the transition of a brain network from state 1 (e.g., before the traumatic event) to state 2 (e.g., after the traumatic event). To conclude, we provide a summary of metrics for quantifying elements on the DBNM and its potential use in computational models of PTSD.

Title: Les sciences des réseaux appliquées à l'étude du Trouble de Stress Post-Traumatique. Abstract: Cet article expose la manière dont les sciences des réseaux peuvent contribuer à la compréhension du Trouble de Stress Post-Traumatique (TSPT). Nous soulignons l'intérêt de concevoir le cerveau comme un système complexe et dynamique pour affiner la description et la prédiction des réponses cérébrales après exposition à un évènement traumatique. À partir des modèles de résilience au stress et sous le prisme des sciences des réseaux, nous proposons une ligne temporelle du TSPT, partant des facteurs de résilience intrinsèques au réseau, présents avant l'évènement traumatique, jusqu'à la réponse cérébrale ayant lieu après l'évènement traumatique. Dans ce cadre, il est essentiel de considérer la topologie du cerveau et les dynamiques cérébrales dans des processus permettant d'utiliser ces facteurs de résilience. Ainsi, nous proposons un cadre concret, autorisant la formulation d'hypothèses explicites sur des aspects potentiellement critiques de l'organisation et des dynamiques des réseaux cérébraux impliqués dans le TSPT.

TERT Expression Induces Resistance to BRAF and MEK Inhibitors in BRAF-Mutated Melanoma In Vitro.

Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT's telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target.

Association of Time From Primary Diagnosis to First Distant Relapse of Metastatic Melanoma With Progression of Disease and Survival.

Importance: The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable. Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma. Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017. Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (<12 months, 12-24 months, and >24 months). Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment. Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

Timing the spinal cord development with neural progenitor cells losing their proliferative capacity: a theoretical analysis.

In the developing neural tube in chicken and mammals, neural stem cells proliferate and differentiate according to a stereotyped spatiotemporal pattern. Several actors have been identified in the control of this process, from tissue-scale morphogens patterning to intrinsic determinants in neural progenitor cells. In a previous study (Bonnet et al. eLife 7, 2018), we have shown that the CDC25B phosphatase promotes the transition from proliferation to differentiation by stimulating neurogenic divisions, suggesting that it acts as a maturating factor for neural progenitors. In this previous study, we set up a mathematical model linking fixed progenitor modes of division to the dynamics of progenitors and differentiated populations. Here, we extend this model over time to propose a complete dynamical picture of this process. We start from the standard paradigm that progenitors are homogeneous and can perform any type of divisions (proliferative division yielding two progenitors, asymmetric neurogenic divisions yielding one progenitor and one neuron, and terminal symmetric divisions yielding two neurons). We calibrate this model using data published by Saade et al. (Cell Reports 4, 2013) about mode of divisions and population dynamics of progenitors/neurons at different developmental stages. Next, we explore the scenarios in which the progenitor population is actually split into two different pools, one of which is composed of cells that have lost the capacity to perform proliferative divisions. The scenario in which asymmetric neurogenic division would induce such a loss of proliferative capacity appears very relevant.

Sequential nailfold videocapillaroscopy examinations have responsiveness to detect organ progression in systemic sclerosis.

OBJECTIVE: To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these changes are associated with overall disease progression and organ involvements. METHODS: A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions. RESULTS: Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) [hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.07-0.93]. Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR = 4.35, 95% CI: 1.87-10.12), occurrence of new DU (HR = 5.33, 95% CI: 1.69-16.71), lung vascular progression (HR = 18.53, 95% CI: 1.28-78.33), progression of skin fibrosis (HR = 4.22, 95% CI: 1.24-14.36), and worsening of the Medsger severity score (HR = 5.26, 95% CI: 1.78-15.52). CONCLUSION: Significant NVC changes are observed in almost half of the patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression.

Recurrent obstructive acute pyelonephritis: A rare form of Actinotignum (Actinobaculum) schaalii infection in a HIV-1 infected patient.

Actinobaculum schaalii is a rarely reported, anaerobic, Gram-positive bacterium which role as uropathogen is emerging. We report here the case of a 47 year old HIV-1 infected woman presented with five recurrent episodes of obstructive pyelonephritis in the context of multiple renal stones. No bacteria was found until the fifth episode, during which prolonged urinary cultures as well as 16S rDNA sequencing allowed the diagnosis of A. schaalii infection. She had developed a life-threatening condition with severe renal failure. A right nephrectomy was performed and found that the intrarenal stones were attributed to the antiretroviral therapy. The renal parenchyma corresponded to an end-stage renal disease with chronic pyelonephritis without abcesses or granules. The situation improved after six months of amoxicillin therapy.

Intrahepatic hepatitis C virus RNA quantification in microdissected hepatocytes.

BACKGROUND/AIMS: Debate continues on whether serum and intrahepatic HCV viral loads are correlated and if HCV viral load correlates with the severity of liver disease. These difficulties may at least in part be linked to liver cell heterogeneity, when total liver extracts from HCV-infected individuals are tested for HCV RNA quantification. We have therefore investigated the feasibility of quantifying HCV replication using a laser-based microdissection technique. METHODS: We compared the results with those obtained for serum HCV RNA quantification and immunochemistry in the case of HCV antigen detection in the liver. Twenty-one HCV-positive patients with chronic active hepatitis (n=10) or cirrhosis (n=11) were analyzed. RESULTS: A positive correlation (P=0.0019) was observed between HCV RNA quantifications in sera and microdissected cells. Immunohistochemistry demonstrated that HCV antigen hepatocytes were randomly distributed within liver lobules. Their percentage varied in different patients (0-40%), but did not correlate with the HCV viral load. CONCLUSIONS: We have designed a sensitive methodology to evaluate the intrahepatic HCV viral load by combining a standardized RNA quantification method with microdissected hepatocytes from frozen liver needle biopsies. Our results directly demonstrate a positive correlation between serum and intrahepatic viral loads, which therefore provides a reliable reflection of intrahepatic HCV replication.