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Les patients avec métastases hépatiques de mélanome ont un pronostic plus défavorable. Ils ne tirent qu’un bénéfice limité des traitements, y compris de l’immunothérapie. Le mécanisme supposé est une tolérance immunitaire systémique dans les modèles précliniques. Une destruction des lésions hépatiques pourrait améliorer la réponse thérapeutique. Nous présentons une série de patients avec un traitement focal par radiothérapie stéréotaxique (RTST) des lésions hépatiques.

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years. There are several described pathogenic mutations that encode functional proteins; however, these proteins, which include the protein resulting from the “common” TPIE105Dmutation, are unstable due to active degradation by protein quality control (PQC) pathways. Previous work has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI Df in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a human embryonic kidney (HEK) stable knock-in model expressing the common TPI Df protein fused with green fluorescent protein (HEK TPIE105D-GFP). To directly address the need for lead TPI Df therapeutics, these cells were developed into an optical drug discovery platform that was implemented for high-throughput screening (HTS) and validated in 3-day variability tests, meeting HTS standards. We initially used this assay to screen the 446-member National Institutes of Health (NIH) Clinical Collection and validated two of the hits in dose–response, by limited structure–activity relationship studies with a small number of analogs, and in an orthogonal, non-optical assay in patient fibroblasts. The data form the basis for a large-scale phenotypic screening effort to discover compounds that stabilize TPI as treatments for this devastating childhood disease.

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years. There are several described pathogenic mutations that encode functional proteins; however, these proteins, which include the protein resulting from the “common” TPIE105Dmutation, are unstable due to active degradation by protein quality control (PQC) pathways. Previous work has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI Df in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a human embryonic kidney (HEK) stable knock-in model expressing the common TPI Df protein fused with green fluorescent protein (HEK TPIE105D-GFP). To directly address the need for lead TPI Df therapeutics, these cells were developed into an optical drug discovery platform that was implemented for high-throughput screening (HTS) and validated in 3-day variability tests, meeting HTS standards. We initially used this assay to screen the 446-member National Institutes of Health (NIH) Clinical Collection and validated two of the hits in dose–response, by limited structure–activity relationship studies with a small number of analogs, and in an orthogonal, non-optical assay in patient fibroblasts. The data form the basis for a large-scale phenotypic screening effort to discover compounds that stabilize TPI as treatments for this devastating childhood disease.

La méthode Halliwick, créée en Angleterre en 1949 par J. McMillan, ingénieur, qui a proposé ses services à l’école de natation Halliwick pour jeunes filles paralysées cérébrales, est basée sur les propriétés physiques de l’eau et consiste en un programme en dix points (TPP) pour l’initiation à la nage ; la WSTH est un moteur d’apprentissage dans l’eau qui facilite la gestion des mouvements et activités de la vie journalière sur terre. Elle est en accord avec le développement moteur normal de l’enfant, les niveaux d’évolution motrice, la Classification Internationale du Fonctionnement, du handicap et de la santé proposée par l’OMS en 2001 ainsi qu’avec la santé positive de Huber (2011). Plusieurs études scientifiques attestent de l’efficacité de la méthode Halliwick et de la WSTH sur la motricité. Quatre études de terrains, publiées, ont comparé WSTH à la thérapie aquatique classique, randomisées, pour une population de paralysés cérébraux : (1) sur la spasticité (mesure coude/poignet/genou/cheville), la WSTH montre une diminution hautement significative, spécifiquement au poignet et cheville après WSTH ; résultats significatifs pour la thérapie aquatique classique ; (2) sur les amplitudes articulaires, les mesures montrent une augmentation significative proximalement surtout aux membres supérieurs après WSTH ; (3) sur le redressement actif du tronc, la WSTH montre une action très hautement significative en thoracique 12, significative en thoracique 8 et cervicale 7 ; non significative en thérapie aquatique classique ; (4) sur le contrôle de tête, les résultats sont, après WSTH, hautement significatifs en flexion/extension/inclinaisons et significatifs en rotations ; ils sont non significatifs pour la thérapie aquatique classique.

La radiothérapie stéréotaxique est une technique innovante de radiothérapie externe, permettant de délivrer de fortes doses de rayonnement en une fraction unique ou en quelques fractions, avec une précision maximale. Cette technique peu invasive peut être proposée pour la prise en charge des métastases de cancer de prostate, permettant d’obtenir un excellent contrôle local. Différentes situations de cancer de prostate oligométastatique peuvent être identifiées, selon l’atteinte synchrone ou métachrone, d’une part, et selon le statut d’hormonosensibilité, d’autre part. Les modalités modernes d’imagerie, et particulièrement les nouveaux traceurs utilisés en médecine nucléaire ont permis de mieux sélectionner les patients oligométastatiques. Les données de la littérature, bien que préliminaires, suggèrent qu’un traitement focal des oligométastases de cancer de prostate par radiothérapie stéréotaxique pourrait avoir un impact sur le pronostic des patients et permettre dans certains cas une épargne thérapeutique, avec un profil de toxicité favorable. Les indications thérapeutiques doivent être proposées au cas par cas chez des patients rigoureusement sélectionnés.

Joule energy loss due to resistive heating is omnipresent in today’s electronic devices whereas quantum-mechanical dissipation is largely unexplored. Here, we experimentally observe a suppression of the Joule dissipation in Bi2Te3due to topologically protected surface states. Instead, a different type of dissipation mechanism is observed by pendulum atomic force microscopy, which is related to single-electron tunnelling resonances into image potential states that are slightly above the Bi2Te3surface. The application of a magnetic field leads to the breakdown of the topological protection of the surface states and restores the expected Joule dissipation process. Nanomechanical energy dissipation experienced by the cantilever of the pendulum atomic force microscope provides a rich source of information on the dissipative nature of the quantum-tunnelling phenomena on the topological insulator surface, with implications for coupling a mechanical oscillator to the generic quantum material.

Intermittent rivers and ephemeral streams (IRES) may represent over half the global stream network, but their contribution to respiration and carbon dioxide (CO2) emissions is largely undetermined. In particular, little is known about the variability and drivers of respiration in IRES sediments upon rewetting, which could result in large pulses of CO2. We present a global study examining sediments from 200 dry IRES reaches spanning multiple biomes. Results from standardized assays show that mean respiration increased 32‐fold to 66‐fold upon sediment rewetting. Structural equation modeling indicates that this response was driven by sediment texture and organic matter quantity and quality, which, in turn, were influenced by climate, land use, and riparian plant cover. Our estimates suggest that respiration pulses resulting from rewetting of IRES sediments could contribute significantly to annual CO2emissions from the global stream network, with a single respiration pulse potentially increasing emission by 0.2–0.7%. As the spatial and temporal extent of IRES increases globally, our results highlight the importance of recognizing the influence of wetting‐drying cycles on respiration and CO2emissions in stream networks. Sediment respiration in intermittent rivers and ephemeral streams increases substantially in response to rewettingRespiration pulses are driven by sediment properties, which, in turn, are influenced by climate and catchment characteristicsEffects of wetting‐drying cycles on respiration and CO2emissions in stream networks need consideration in upscaling and modeling efforts

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Since there is no common genetic alteration causing resistance to venetoclax in CLL and B cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole exome sequencing, methylated DNA immunoprecipitation sequencing and genome wide CRISPR/Cas9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMApromoter which is methylated upon venetoclax treatment, mediating PUMAdownregulation on transcript and protein level. PUMAexpression and sensitivity towards venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher OXPHOS and ATP production, resembling the metabolic phenotype that is seen upon venetoclax resistance. While PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity towards both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive DLBCL in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

La radiothérapie stéréotaxique (SBRT) joue un rôle important dans la prise en charge des patients oligométastatiques. Dans la littérature, peu de données spécifiques au mélanome oligométastatique sont disponibles.

Perennial rivers and streams make a disproportionate contribution to global carbon (C) cycling. However, the contribution of intermittent rivers and ephemeral streams (IRES), which sometimes cease to flow and can dry completely, is largely ignored although they represent over half the global river network. Substantial amounts of terrestrial plant litter (TPL) accumulate in dry riverbeds and, upon rewetting, this material can undergo rapid microbial processing. We present the results of a global research collaboration that collected and analysed TPL from 212 dry riverbeds across major environmental gradients and climate zones. We assessed litter decomposability by quantifying the litter carbon-to-nitrogen ratio and oxygen (O2) consumption in standardized assays and estimated the potential short-term CO2emissions during rewetting events. Aridity, cover of riparian vegetation, channel width and dry-phase duration explained most variability in the quantity and decomposability of plant litter in IRES. Our estimates indicate that a single pulse of CO2emission upon litter rewetting contributes up to 10% of the daily CO2emission from perennial rivers and stream, particularly in temperate climates. This indicates that the contributions of IRES should be included in global C-cycling assessments. Rewetting of plant litter accumulated in dry riverbeds releases pulses of CO2, reveals a global analysis of intermittent rivers and ephemeral streams.

AimsWe aimed to retrospectively assess the accuracy and safety of CT navigated pedicle screws and to compare accuracy in the cervical and thoracic spine (C2-T8) with (COMB) and without (POST) prior anterior surgery (anterior cervical discectomy or corpectomy and fusion with ventral plating: ACDF/ACCF).Patients and MethodsA total of 592 pedicle screws, which were used in 107 consecutively operated patients (210 COMB, 382 POST), were analysed. The accuracy of positioning was determined according to the classification of Gertzbein and Robbins on post-operative CT scans.ResultsHigh accuracy was achieved in 524 screws (88.5%), 192 (87.7%) in the cervical spine and 332 (89%) in the thoracic spine, respectively. The results in the two surgical groups were compared and a logistic regression mixed model was performed to analyse the risk of low accuracy. Significantly lower accuracy was found in the COMB group with 82.9% versus91.6% in the POST group (p = 0.036). There were no neurological complications, but two vertebral artery lesions were recorded. Three patients underwent revision surgery for malpositioning of a screw. Although the risk of malpositioning of a screw after primary anterior surgery was estimated to be 2.4-times higher than with posterior surgery alone, the overall rates of complication and revision were low.ConclusionWe therefore conclude that CT navigated pedicle screws can be positioned safely although greater caution must be taken in patients who have previously undergone anterior surgery.Cite this article: Bone Joint J2017;99-B:1373–80.

Les améliorations technologiques récentes et notamment la généralisation de la reconstruction itérative ont permis d’abaisser l’irradiation d’un scanner thoracique jusqu’à s’approcher de celle délivrée par une radiographie thoracique de face et de profil. Ce scanner thoracique Ultra-Basse Dose ou ULD présente une qualité d’image volontairement dégradée mais restant diagnostique dans de nombreuses situations cliniques. Ainsi, son efficacité est déjà validée pour le dépistage et le suivi des nodules parenchymateux solides, pour le diagnostic et le suivi des pneumopathies infectieuses et pour le dépistage des complications pleurales secondaires à l’exposition à l’amiante. Ses limites sont l’analyse des structures médiastinales, l’obésité sévère (IMC>35) et la détection des lésions interstitielles. S’il remplace le scanner thoracique standard dans ces indications validées, et ce d’autant plus volontiers dans les situations où la dose d’irradiation est un problème majeur (sujets jeunes, examens itératifs, dépistage), il se présente aussi de plus en plus comme une alternative de première intention à la radiographie thoracique, en apportant plus d’informations à un coût radique similaire.

AbstractIn industrialised areas, teleost fish are often exposed to anthropogenic changes of the water quality. These often have negative effects on species with a narrow ecological range. Species with a wider ecological range, such as the three-spined stickleback (Gasterosteus aculeatusLinneaus, 1758), might benefit if water quality alteration reduces interspecific competition and/or parasite infection pressure. In the present study, we investigated sticklebacks in an inland brook, in which the inlet of warm and salty coal mine drainage water increases water temperature and changes the brook from freshwater to brackish (approx. 20 mS cm−1) conditions. We collected sticklebacks up- and downstream of the saltwater inlet (henceforth called freshwater and saltwater sites or habitats) in monthly intervals from April to October 2010, and monitored their body condition parameters and parasite infections. In particular during spring, the water temperature was higher (3.7–4.5°C) in the saltwater habitat and juvenile sticklebacks occurred earlier and grew faster compared to juveniles in the freshwater habitat. In the saltwater habitat, fewer parasite species were detected compared to the freshwater situation (7 vs. 10). Moreover, parasite index, which peaked in young-of-the-year sticklebacks in September, was lower in sticklebacks from the saltwater site. The present study suggests that changes of freshwater conditions by the inlet of warm and salty coal mine drainage water match the adaptive range of three-spined sticklebacks, which grew faster and had lower parasite burden in the altered habitat.

La cohorte RAMSES (NCT04077528) a été créée en septembre 2019 pour évaluer les modalités d’utilisation, les bénéfices et les risques associés aux différentes stratégies d’utilisation des traitements de palier 5 chez les patients asthmatiques sévères.