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Summary: Background: Immune checkpoint inhibitors (ICIs) have demonstrated their efficacy with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials provides for treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after treatment cessation shows sustained response and a low risk of relapse in the months following cessation. To date, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI administration. Methods: We emulated target trials using the cloning, weighting and censoring approach. Each emulation trial aimed to compare the effect of discontinuing versus continuing ICIs at a specific timepoint, among patients still under treatment and with disease control at that time. Patients were from MelBase between 2015 and 2021. Findings: 435 participants in the MelBase cohort were eligible and were included in the 6-month discontinuation emulated trial. The results showed significantly lower OS when treatment was discontinued, than when treatment was prolonged for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8–60.5), and the corresponding restricted mean survival time difference was 8.3 months (95% CI: 4.1–12.7). Neither the 12-month nor the 18-month discontinuation emulated trials showed evidence of benefit of either discontinuing or continuing ICIs at either of these timepoints. The 24-month discontinuation emulated trial results were more in favor of discontinuing than continuing treatment at that time point, with an absolute 48-month survival rate that was 10.5% higher (95% CI 4.4–18.1). Interpretation: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental. Funding: This work was supported by a grant from Bristol Myers Squibb, Merck Sharp Dhome, Pierre Fabre, Novartis, Sun Pharm, Regeneron, Sanofi, Nektar, Therapeutics and Oncyte.

Human language relies on a rich cognitive machinery, partially shared with other animals. One key mechanism, however, decomposing events into causally linked agent-patient roles, has remained elusive with no known animal equivalent. In humans, agent-patient relations in event cognition drive how languages are processed neurally and expressions structured syntactically. We compared visual event tracking between humans and great apes, using stimuli that would elicit causal processing in humans. After accounting for attention to background information, we found similar gaze patterns to agent-patient relations in all species, mostly alternating attention to agents and patients, presumably in order to learn the nature of the event, and occasionally privileging agents under specific conditions. Six-month-old infants, in contrast, did not follow agent-patient relations and attended mostly to background information. These findings raise the possibility that event role tracking, a cognitive foundation of syntax, has evolved long before language but requires time and experience to become ontogenetically available.

The objective of the EU project Resilience for Dairy (R4D) is to develop and strengthen a self-sustainable Thematic Network on resilient dairy farms in 15 European countries. This article focusses on those solutions (practices and techniques) that are assessed contributing to a resilient dairy farming sector. The opinions of experts, farmers, and stakeholders were collected and scored through surveys and in a series of local workshops. Six key contributing knowledge fields are included: economic and social resilience, technical efficiency, environment, animal welfare and health, and societal perception. Assessing these knowledge fields proved to be a good predictor for measuring resilience. Only the impact fields of animal welfare and health and societal perception overlapped each other in response. This study shows differences in the choice of solutions across Europe. Experts from South and East Europe are more positive about the contribution of solutions to resilience than their colleagues from North and West Europe, except for social life items. Expert and farmer/stakeholder opinions differ regarding several of the solutions. Technical efficiency is a leading strategy. Priority topics of interest are communication with society, renewable energy production, strategic hoof trimming, early detection of diseases, monitoring fertility and health, and calf rearing. Besides resilience, attractiveness and readiness of the solutions were also assessed.

Summary: When conversing, humans instantaneously predict meaning from fragmentary and ambiguous mspeech, long before utterance completion. They do this by integrating priors (initial assumptions about the world) with contextual evidence to rapidly decide on the most likely meaning. One powerful prior is attentional preference for agents, which biases sentence processing but universally so only if agents are animate. Here, we investigate the evolutionary origins of this preference, by allowing chimpanzees, gorillas, orangutans, human children, and adults to freely choose between agents and patients in still images, following video clips depicting their dyadic interaction. All participants preferred animate (and occasionally inanimate) agents, although the effect was attenuated if patients were also animate. The findings suggest that a preference for animate agents evolved before language and is not reducible to simple perceptual biases. To conclude, both humans and great apes prefer animate agents in decision tasks, echoing a universal prior in human language processing.

Background and Purpose: Microbeam Radiation Therapy (MRT) aims to deliver higher doses to the target while minimizing radiation damage to healthy tissues using synchrotron x-ray microbeams. Translational MRT research has now started, driven by promising results from preclinical studies. This study aimed to propose a first dose-outcome model by analyzing micrometric dose distributions obtained with high-resolution 3D dose calculations, accounting for the inherent physical dose distribution complexity in MRT. The feasibility of integrating penMRT, our full Monte Carlo multiscale dose calculation algorithm based on PENELOPE into translational research on veterinary patients was also investigated. Material and Methods: Micrometric dose distributions were calculated in tumor-bearing rats and for a veterinary patient with penMRT, for conformal multi-directional MRT treatment plans. Absorbed dose maps were obtained with 0.005 × 0.005 × 1 mm3 voxel sizes. High-resolution dose-volume histograms were extracted and analyzed against radiobiology studies. Results: The complexity of the MRT dose distribution was properly rendered at a micrometer scale on 3D dose maps, with well separated dose regions observed on the differential dose-volume histograms. The median survival time of glioma-bearing rats varied linearly with the volume fraction of the planning target volume that received doses higher than 50 Gy (R2 = 0.98). The feasibility of using penMRT for treatment planning in large volumes has been shown on a veterinary patient. Conclusions: This study demonstrated the significant added value of penMRT for planning and prescribing MRT treatments. It also shed light on the correlation between the high-resolution 3D dose distributions and the treatment outcome.

Abstract Background With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. Methods PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.

Summary: Persistent sodium current (INaP) in the spinal locomotor network promotes two distinct nonlinear firing patterns: a self-sustained spiking triggered by a brief excitation in bistable motoneurons and bursting oscillations in interneurons of the central pattern generator (CPG). Here, we identify the NaV channels responsible for INaP and their role in motor behaviors. We report the axonal Nav1.6 as the main molecular player for INaP in lumbar motoneurons. The inhibition of Nav1.6, but not of Nav1.1, in motoneurons impairs INaP, bistability, postural tone, and locomotor performance. In interneurons of the rhythmogenic CPG region, both Nav1.6 and Nav1.1 equally mediate INaP. Inhibition of both channels is required to abolish oscillatory bursting activities and the locomotor rhythm. Overall, Nav1.6 plays a significant role both in posture and locomotion by governing INaP-dependent bistability in motoneurons and working in tandem with Nav1.1 to provide INaP-dependent rhythmogenic properties of the CPG.

ABSTRACTFluvial and coastal landforms are indicative of landscape river delta evolution over time and provide clues for understanding coastal adjustments to sea-level and fluvial dynamics fluctuations, tectonic displacements, and extreme waves. We have mapped the surface and sub-surface footprints of fluvial and coastal geomorphological features in the Aceh River delta, northern Sumatra, using imagery dataset, vertical facies logging and helicopter electromagnetic surveys. The result is a geomorphological map at the scale of 1:75.000 which outlines the main features of the deltaic plain, including rivers, tidal and buried channels, fluvial levees, beach ridges, swales, tidal flats and lagoons. We compare their spatial distribution to the geometry of buried sediment bodies, revealed by boreholes and resistivity maps. Buried channel belts and floodplain deposits document the former locations of the distributary channels of the Aceh River. Coastal-parallel beach ridges evidence 7–8 km of asymmetric delta progradation since the mid-Holocene sea-level high stand.

BackgroundThe tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment.Patients and methodsPatients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS).Results973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients’ characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively).ConclusionOur study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Background and Aim: One of the key components of the O ne Health approach to epidemic preparedness is raising awareness and increasing the knowledge of emerging infectious diseases, prevention, and risk reduction. However, related research can involve significant risks to biosafety and biosecurity. For this purpose, we organized a multidisciplinary biosafety hands-on workshop to inform and increase the knowledge of infectious diseases and risk mitigation. This study aimed to describe the process and outcome of a hands-on biosafety training program using a One Health a pproach across a multidisciplinary and multi-specialty group in Nigeria. Materials and Methods: A face-to-face hands-on training for 48 participants was organized by the West African Center for Emerging Infectious Diseases (WAC-EID) at the Jos University Teaching Hospital, serving as a lead institution for the Nigeria project site. Topics covered included (1) an overview of the WAC-EID research; (2) overview of infection prevention and control; (3) safety in animal handling and restraint, sample collection, and processing; (4) safety in field studies including rodent, bird and bat handling; (5) safety practices in the collection of mosquito and other arthropod vectors; (6) personal protective equipment training (disinfection, donning and doffing); and (7) safety in sample collection, labeling, and transportation. The program was executed using a mixed method of slide presentations, practical hands-on sessions, and video demonstrations. Pre- and post-course evaluation assessments and evaluation measures were used to assess training. Results: A total of 48 trainees participated in this training, with 12 (25%), 16 (33.3%), 14 (29.2%), 6 (12.5%) categorized as ornithology, entomology, mammalogy, and clinical interest groups, respectively. The pass rate for the pre-test was 29.4%, while for the post-test, it was 57.1%, or a 28% improvement. 88.6% of the trainees rated the training as relevant to them. Conclusion: Didactic and hands-on biosafety training is relevant in this era of zoonotic epidemics and pandemic preparedness. During this training program, there was a clear demonstration of knowledge transfer that can change the current practices of participants and improve the safety of infectious diseases research.

Abstract To perform its propagative and circulative cycle into its insect vector, the flavescence dorée phytoplasma invades different cell types. Clathrin-mediated endocytosis is used by a wide range of bacteria to infect eukaryote cells. Among the insect proteins interacting with the phytoplasma adhesin VmpA, we identified the adaptor protein complex AP-1 and AP-2 suggesting that phytoplasmas could enter the insect cells via clathrin-mediated endocytosis. By infection assays of insect cells in culture, we showed that phytoplasmas entry into Drosophila S2 cells was more efficient than infection of the Euva cell line developed from the insect vector Euscelidius variegatus. Chlorpromazine, cytochalasin D and knockdown of clathrin heavy chain (chc) gene expression using RNA interference inhibited entry of phytoplasmas into S2 cells. During invasion of S2 cells, phytoplasmas were observed very closed to recombinant GFP-labelled clathrin light chain. To verify the role of clathrin in the insect colonization by phytoplasmas, RNAi was performed via artificial feeding of chc dsRNA by the vector E. variegatus. This decreased the expression of chc gene in the midgut and heads of E. variegatus. The chc lower expression correlated to a decreased of midgut and salivary gland cells colonization after the insects had ingested phytoplasmas from infected plants. In conclusion, results indicate that clathrin is important for the FD phytoplasma to enter insect cells and colonize its insect vector.

Andesitic volcanic hydrosystems in Indonesia are mostly hydrogeologically unknown despite their socio-economic importance. The development of robust and easy-to-implement methodologies to conceptualize and quantify the water cycle components becomes a prerequisite for their sustainable management.We developed a lumped hydrological model to mimic the structure and functioning of a previously unknown hydrosystem located on the flanks of the Salak volcano (West Java). The structure of the aquifers was revealed with electrical resistivity tomography. The distinction between springs fed by the extensive artesian aquifer and others fed by shallow perched aquifers was obtained mostly using hydrochemistry. The elevation of the recharge area was identified using isotopic analysis of spring water.After designing the hydrological model structure, we carried out a probabilistic parameters exploration using the multiple-try differential evolution adaptive Metropolis algorithm to calibrate aquifer discharge. Multiple Markov chains allow a better exploration of the parameter values. The Bayesian approach provides the best water cycle simulation with a parameter uncertainty analysis, improving the accuracy and representation of the water cycle appropriate for previously unknown hydrosystems.

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients’ characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

We present explainable machine learning approaches for gaining deeper insights into the solubilization processes of inclusion bodies. The machine learning model with the highest prediction accuracy for the protein yield is further evaluated with regard to Shapley additive explanation (SHAP) values in terms of feature importance studies. Our results highlight an inverse fractional relationship between the protein yield and total protein concentration. Further correlations can also be observed for the dominant influences of the urea concentration and the underlying pH values. All findings are used to develop an analytical expression that is in reasonable agreement with experimental data. The resulting master curve highlights the benefits of explainable machine learning approaches for the detailed understanding of certain biopharmaceutical manufacturing steps.

Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it has been thought that axonal transport of SVPs does not affect synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) increases axonal transport of SVPs and synaptic glutamate release by recruiting the kinesin motor KIF1A. In mice, constitutive HTT phosphorylation causes SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.

BackgroundSatisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity.ObjectiveRILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI.MethodsIn this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period.ConclusionTo the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI.Trial registrationThe clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792.Trial sponsorAssistance Publique-Hôpitaux de Marseille.

During phloem unloading, multiple cell-to-cell transport events move organic substances to the root meristem. Although the primary unloading event from the sieve elements to the phloem pole pericycle has been characterized to some extent, little is known about post-sieve element unloading. Here, we report a novel gene, PHLOEM UNLOADING MODULATOR (PLM), in the absence of which plasmodesmata-mediated symplastic transport through the phloem pole pericycle-endodermis interface is specifically enhanced. Increased unloading is attributable to a defect in the formation of the endoplasmic reticulum-plasma membrane tethers during plasmodesmal morphogenesis, resulting in the majority of pores lacking a visible cytoplasmic sleeve. PLM encodes a putative enzyme required for the biosynthesis of sphingolipids with very-long-chain fatty acid. Taken together, our results indicate that post-sieve element unloading involves sphingolipid metabolism, which affects plasmodesmal ultrastructure. They also raise the question of how and why plasmodesmata with no cytoplasmic sleeve facilitate molecular trafficking.

Autophagosomes are specialized vesicles that target and deliver cargo to the lytic vacuole. Here the authors show that plasma-membrane derived lipid phosphatidylinositol-4-phosphate supports the assembly and expansion of autophagosomes in Arabidopsis