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Abstract Background Microbrachytherapy enables high local tumor doses sparing surrounding tissues by intratumoral injection of radioactive holmium-166 microspheres (166Ho-MS). Magnetic resonance imaging (MRI) cannot properly detect high local Ho-MS concentrations and single-photon emission computed tomography has insufficient resolution. Computed tomography (CT) is quicker and cheaper with high resolution and previously enabled Ho quantification. We aimed to optimize Ho quantification on CT and to implement corresponding dosimetry. Methods Two scanners were calibrated for Ho detection using phantoms and multiple settings. Quantification was evaluated in five phantoms and seven canine patients using subtraction and thresholding including influences of the target tissue, injected amounts, acquisition parameters, and quantification volumes. Radiation-absorbed dose estimation was implemented using a three-dimensional 166Ho specific dose point kernel generated with Monte Carlo simulations. Results CT calibration showed a near-perfect linear relation between radiodensity (HU) and Ho concentrations for all conditions, with differences between scanners. Ho detection during calibration was higher using lower tube voltages, soft-tissue kernels, and without a scanner detection limit. The most accurate Ho recovery in phantoms was 102 ± 11% using a threshold of mean tissue HU + (2 × standard deviation) and in patients 98 ± 31% using a 100 HU threshold. Thresholding allowed better recovery with less variation and dependency on the volume of interest compared to the subtraction of a single HU reference value. Corresponding doses and histograms were successfully generated. Conclusion CT quantification and dosimetry of 166Ho should be considered for further clinical application with on-site validation using radioactive measurements and intra-operative Ho-MS and dose visualizations. Relevance statement Image-guided holmium-166 microbrachytherapy currently lacks reliable quantification and dosimetry on CT to ensure treatment safety and efficacy, while it is the only imaging modality capable of quantifying high in vivo holmium concentrations. Key Points Local injection of 166Ho-MS enables high local tumor doses while sparing surrounding tissue. CT enables imaging-based quantification and radiation-absorbed dose estimation of concentrated Ho in vivo, essential for treatment safety and efficacy. Two different CT scanners and multiple acquisition and reconstruction parameters showed near-perfect linearity between radiodensity and Ho concentration. The most accurate Ho recoveries on CT were 102 ± 11% in five phantoms and 98 ± 31% in seven canine patients using thresholding methods. Dose estimations and volume histograms were successfully implemented for clinical application using a dose point kernel based on Monte Carlo simulations. Graphical Abstract

To tease apart differences between conventional cage (CC) and cage-free (CF) housing systems, this study focuses on the effects of excreta exposure and age by comparing microbial communities, intestinal permeability, and corticosterone in hens in enriched colonies (EC) and CF housing systems during early- and late-lay. Hens were randomly selected from two rooms of CF (n = 20) and EC (n = 20) at 35 and 76 weeks of age. One hour following an oral gavage of fluorescein isothiocyanate dextran (FITC-D), hens were euthanized, and ileal contents and blood were collected. Serum FITC-D using a fluorescent spectrophotometer and corticosterone using a commercial competitive ELISA kit were analyzed. Following DNA isolation from the ileum contents, the V4 region of the 16S rRNA gene was sequenced. Sequence data were filtered in Mothur v1.43.0, followed by de novo operational taxonomic unit (OTU) clustering and classifying with the SILVA SSU v138 reference database. Serum FITC-D was altered by housing type, age of hens, and the interaction between housing type and age of hens (p < 0.001), with 76-week-old hens housed in EC having the highest FITC-D. Corticosterone increased with age (p = 0.023). Microbial community diversity measurements favored hens housed in the CF housing system as ileal contents tended to have increased species evenness (p = 0.008) and greater alpha diversity (p = 0.006). The majority of the over-representation of OTUs were associated with peak lay.

Abstract Background Cefiderocol is a siderophore-conjugated cephalosporin increasingly used in the management of Achromobacter infections. Testing for cefiderocol susceptibility is challenging with distinct recommendations depending on the pathogens. Objectives We evaluated the performance of commercial tests for testing cefiderocol susceptibility in the Achromobacter genus and reviewed the literature. Methods Diffusion (disks, MIC gradient test strips [MTS], Liofilchem) and broth microdilution (BMD) methods (ComASP™, Liofilchem; UMIC®, Bruker) were compared with the BMD reference method according to the EUCAST guidelines on 143 Achromobacter strains from 14 species with MIC50/90 of ≤ 0.015/0.5 mg/L. A literature search was conducted regardless of method or species. Results None of the methods tested fulfilled an acceptable essential agreement (EA). MTS displayed the lowest EA (30.8%) after UMIC® (49%) and ComASP™ (76.9%). All methods achieved an acceptable bias, with MICs either underestimated using MTS (-1.3%) and ComASP™ (-14.2%) or overestimated with UMIC® (+ 9.1%). Inhibition zone diameters ranged from 6 to 38 mm (IZD50/90=33/30 mm). UMIC® and ComASP™ failed to categorize one or the two cefiderocol-resistant strains of this study as resistant unlike the diffusion-based methods. The literature review highlighted distinct performance of the available methods according to pathogens and testing conditions. Conclusions The use of MTS is discouraged for Achromobacter spp. Disk diffusion can be used to screen for susceptible strains by setting a threshold diameter of 30 mm. UMIC® and ComASP™ should not be used as the sole method but have to be systematically associated with disk diffusion to detect the yet rarely described cefiderocol-resistant Achromobacter sp. strains.

Abstract Crohn’s disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identify a distinct epithelial cell type in both terminal ileum and ascending colon (hereon as ‘LND’) with high expression of LCN2, NOS2, and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, are rare in non-IBD controls but expand in active CD, and actively interact with immune cells and specifically express IBD/CD susceptibility genes, suggesting a possible function in CD immunopathogenesis. Furthermore, we discover early and late LND subpopulations with different origins and developmental potential. A higher ratio of late-to-early LND cells correlates with better response to anti-TNF treatment. Our findings thus suggest a potential pathogenic role for LND cells in both Crohn’s ileitis and colitis.

Abstract Background Achromobacter spp. are opportunistic pathogens, mostly infecting immunocompromised patients and patients with cystic fibrosis (CF) and considered as difficult-to-treat pathogens due to both intrinsic resistance and the possibility of acquired antimicrobial resistance. Species identification remains challenging leading to imprecise descriptions of resistance in each taxon. Cefiderocol is a broad-spectrum siderophore cephalosporin increasingly used in the management of Achromobacter infections for which susceptibility data remain scarce. We aimed to describe the susceptibility to cefiderocol of a collection of Achromobacter strains encompassing different species and isolation sources from CF or non-CF (NCF) patients. Methods We studied 230 Achromobacter strains (67 from CF, 163 from NCF patients) identified by nrdA gene-based analysis, with available susceptibility data for piperacillin–tazobactam, meropenem and trimethoprim–sulfamethoxazole. Minimal inhibitory concentrations (MICs) of cefiderocol were determined using the broth microdilution reference method according to EUCAST guidelines. Results Strains belonged to 15 species. A. xylosoxidans represented the main species (71.3%). MICs ranged from ≤ 0.015 to 16 mg/L with MIC50/90 of ≤ 0.015/0.5 mg/L overall and 0.125/2 mg/L against 27 (11.7%) meropenem-non-susceptible strains. Cefiderocol MICs were not related to CF/NCF origin or species although A. xylosoxidans MICs were statistically lower than those of other species considered as a whole. Considering the EUCAST non-species related breakpoint (2 mg/L), 228 strains (99.1%) were susceptible to cefiderocol. The two cefiderocol-resistant strains (A. xylosoxidans from CF patients) represented 3.7% of meropenem-non-susceptible strains and 12.5% of MDR strains. Conclusions Cefiderocol exhibited excellent in vitro activity against a large collection of accurately identified Achromobacter strains, irrespective of species and origin.

Abstract In multiple myeloma, as in B‐cell malignancies, mono‐ and especially bi‐allelic TP53 gene inactivation is a high‐risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53‐deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (CTPS1), which encodes a CTP synthesis rate‐limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA‐seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP‐B induced cell cycle arrest in early S phase in isogenic NCI‐H929 or XG7 TP53+/+, TP53−/−, and TP53R175H/R175H cells and in a TP53−/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP‐B‐treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP‐B‐induced S‐phase arrested cells synergistically induced cell death in TP53+/+, TP53−/−, and TP53R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase‐mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53−/− NCI‐H929 xenografted NOD‐scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53‐deficient patients.

In recent years, following the groundbreaking achievements of chimeric antigen receptor (CAR) T cell therapy in hematological cancers, and advancements in cell engineering technologies, the exploration of other immune cells has garnered significant attention. CAR-Therapy extended beyond T cells to include CAR natural killer (NK) cells and CAR-macrophages, which are firmly established in the clinical trial landscape. Less conventional immune cells are also making their way into the scene, such as CAR mucosal-associated invariant T (MAIT) cells. This progress is advancing precision medicine and facilitating the development of ready-to-use biological treatments. However, in view of the unique features of natural killer cells, adoptive NK cell immunotherapy has emerged as a universal, allogenic, “off-the shelf” therapeutic strategy. CAR-NK cytotoxic cells present targeted tumor specificity but seem to be devoid of the side effects associated with CAR-T cells. CAR-NK cells appear to be potentially promising candidates for cancer immunotherapy. However, their application is hindered by significant challenges, particularly the limited persistence of CAR-NK cells in the body, which poses a hurdle to their sustained effectiveness in treating cancer. Based upon the foregoing, this review discusses the current status and applications of both CAR-T cells and CAR-NK cells in hematological cancers, and provides a comparative analysis of the structure, genetics, and clinical outcomes between these two types of genetically modified immune cells.

La France est actuellement au premier rang des productions européennes de poulets biologiques. Cette production ne représente toutefois encore que quelques pourcents de la production nationale. L’élevage avicole biologique est souvent considéré comme respectueux du bien-être animal et de l’environnement. Cependant, au-delà de ces images positives que l’élevage avicole biologique et les produits biologiques véhiculent, certaines contraintes déjà identifiées limitent leur développement. Le contact avec la faune sauvage présentant un risque sanitaire, la gestion du parcours, les tensions sur l’environnement dues à une excrétion des déjections sur le parcours difficilement maîtrisables et la sensibilité au contexte économique et aux comportements de consommation sont autant d’obstacles. L’élevage biologique offre néanmoins des opportunités 1) pour l’animal : le parcours facilite l’expression de nombreux comportements et permet la consommation d’insectes et de plantes possédant diverses propriétés (nutritionnelle, médicinales…) ; 2) pour l’éleveur : une amélioration des conditions de travail ainsi qu’une plus grande satisfaction sont mises en avant ; 3) pour l’environnement : le parcours constitue une source de biodiversité. Après une présentation des conditions d’élevage des poulets biologiques en France et en Europe, nous proposons d’identifier les barrières à l’extension de l’élevage biologique et les leviers/opportunités pour les dépasser.

Abstract Introduction The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996–August 1998) and STICLO Italy (April 1999–October 2000), but data were not fully exploited at the time. Methods This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes. Results Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients’ mean and median (25%; 75%) age were 9.2 years (range 3.0–20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic–clonic seizure (GTCS) frequency, versus 7% in the placebo group (P

Abstract Background In juvenile systemic lupus erythematosus (j-SLE) with neuropsychiatric (NP) symptoms, there is a lack of diagnostic biomarkers. Thus, we study whether PET-FDG may identify any metabolic dysfunction in j-NPSLE. Methods A total of 19 18FDG-PET exams were consecutively performed using PET-MRI system in 11 non-sedated patients presenting with j-NPSLE (11-18y) for less than 18 months (m) and without any significant lesion at MRI. Psychiatric symptoms were scored from 0 (none) to 3 (severe) at PET time. PET images were visually analyzed and voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (spm) with an age-matched control group, at threshold set > 50 voxels using both p

Abstract Objectives Stiripentol, fenfluramine, and cannabidiol are licensed add‐on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first‐line add‐on therapies in DS. Methods We conducted a systematic review and frequentist network meta‐analysis (NMA) of randomized controlled trial (RCT) data for licensed add‐on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure‐free); serious adverse events (SAEs); discontinuations due to AEs. Results We identified relevant data from two placebo‐controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: −20% to 22%; p = 0.93] and 6% [−15% to 27%; p = 0.59], respectively), and both were statistically superior (p

Abstract Background Mantle cell lymphoma (MCL) is a chronically relapsing malignancy with deregulated cell cycle progression. We analyzed efficacy, mode of action, and predictive markers of susceptibility to palbociclib, an approved CDK 4/6 inhibitor, and its combination with venetoclax, a BCL2 inhibitor. Methods A panel of nine MCL cell lines were used for in vitro experiments. Four patient derived xenografts (PDX) obtained from patients with chemotherapy and ibrutinib-refractory MCL were used for in vivo proof-of-concept studies. Changes of the mitochondrial membrane potential, energy-metabolic pathways, AKT activity, and pro-apoptotic priming of MCL cells were evaluated by JC-1 staining, Seahorse XF analyser, genetically encoded fluorescent AKT reporter, and BH3 profiling, respectively. MCL clones with gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on sensitivity to palbociclib, and venetoclax. Results Co-targeting MCL cells with palbociclib and venetoclax induced cytotoxic synergy in vitro and in vivo. Molecular mechanisms responsible for the observed synthetic lethality comprised palbociclib-mediated downregulation of anti-apoptotic MCL1, increased levels of proapoptotic BIM bound on both BCL2, and BCL-XL and increased pro-apoptotic priming of MCL cells mediated by BCL2-independent mechanisms, predominantly palbociclib-triggered metabolic and mitochondrial stress. Loss of RB1 resulted in palbociclib resistance, while deletion of CDKN2A or overexpression of CDK4, and MYC genes did not change sensitivity to palbociclib. Conclusions Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion.

Abstract Objective Double‐blind, randomized, and placebo‐controlled trial SP0967 (NCT02477839/2013‐000717‐20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to

Landscape temporal dynamics are a crucial concern in ecology to understand current biodiversity. But historical environmental data are often not easily available. This study assesses for the first time the potential of historical orthophotographs to describe past landscape conditions and determine the temporal lag between landscape changes and biotic communities responses.This method utilizes Gray level Co-occurrence Matrix (GLCM) texture indices computed from black and white orthophotographs to construct continuous metrics of landscape composition. Metrics were first developed using present-day data, i.e. 2015, and calibrated with categorical land cover maps of the Strasbourg Eurometropolis, France. Subsequently, these metrics were applied to historical orthophotographs from 1966, 1976, 1986, and 2000. Plant and bird data from research and citizen science programs were used to estimate the time delay in which these communities respond to evolutions in built areas and high vegetation.Obtained texture-based models reveal that built areas exhibit high contrast and homogeneity, depicted through a linear relation, and that high vegetation display low pixel brightness and high brightness diversity, better described via a nonlinear model. We successfully applied those findings to historical orthophotographs, and revealed dependencies on landscape composition up to 50 years ago for plants and up to 30 years ago for birds, with the time lag and the influence of built and high vegetation areas depending on the selected biodiversity indices.These results demonstrate the utility of archive black and white orthophotographs' texture indices for describing urban landscapes over the past five decades, making them valuable tools for ecological research. These indices are more accessible than categorical data like land cover maps for past years. They have the potential to greatly benefit future studies investigating time lags in landscape ecology, simplifying access to historical landscape features and contributing to sustainable urban planning efforts.

Natural environments of living organisms are often dynamic and multifactorial, with multiple parameters fluctuating over time. To better understand how cells respond to dynamically interacting factors, we quantified the effects of dual fluctuations of osmotic stress and glucose deprivation on yeast cells using microfluidics and time-lapse microscopy. Strikingly, we observed that cell proliferation, survival, and signaling depend on the phasing of the two periodic stresses. Cells divided faster, survived longer, and showed decreased transcriptional response when fluctuations of hyperosmotic stress and glucose deprivation occurred in phase than when the two stresses occurred alternatively. Therefore, glucose availability regulates yeast responses to dynamic osmotic stress, showcasing the key role of metabolic fluctuations in cellular responses to dynamic stress. We also found that mutants with impaired osmotic stress response were better adapted to alternating stresses than wild-type cells, showing that genetic mechanisms of adaptation to a persistent stress factor can be detrimental under dynamically interacting conditions.

ABSTRACTAchromobacter spp. are opportunistic pathogens of environmental origin increasingly isolated in patients with underlying conditions like cystic fibrosis (CF). Despite recent advances, their virulence factors remain incompletely studied, and siderophore production has not yet been investigated in this genus. The aim of this study was to evaluate the production of siderophores in a large collection of Achromobacter spp. and evaluate the variability according to the origin of the strain and species. A total of 163 strains were studied, including 128 clinical strains (CF and non-CF patients) and 35 strains of environmental origin. Siderophores were quantified by the liquid chrome azurol-sulphonate assay. Species were identified by nrdA gene-based phylogeny. Strains were assigned to 20 species, with Achromobacter xylosoxidans being the most represented (51.5% of strains). Siderophore production was observed in 72.4% of the strains, with amounts ranging from 10.1% to 90% siderophore units. A significantly higher prevalence of siderophore-producing strains and greater production of siderophores were observed for clinical strains compared with strains of environmental origin. Highly variable observations were made according to species: A. xylosoxidans presented unique characteristics (one of the highest prevalence of producing strains and highest amounts produced, particularly by CF strains). Siderophores are important factors for bacterial growth commonly produced by members of the Achromobacter genus. The significance of the observations made during this study must be further investigated. Indeed, the differences observed according to species and the origin of strains suggest that siderophores may represent important determinants of the pathophysiology of Achromobacter spp. infections and also contribute to the particular epidemiological success of A. xylosoxidans in human infections.IMPORTANCEAchromobacter spp. are recognized as emerging opportunistic pathogens in humans with various underlying diseases, including cystic fibrosis (CF). Although their pathophysiological traits are increasingly studied, their virulence factors remain incompletely described. Particularly, siderophores that represent important factors of bacterial growth have not yet been studied in this genus. A population-based study was performed to explore the ability of members of the Achromobacter genus to produce siderophores, both overall and in relevant subgroups (Achromobacter species; strain origin, either clinical—from CF or non-CF patients—or environmental). This study provides original data showing that siderophore production is a common trait of Achromobacter strains, particularly observed among clinical strains. The major species, Achromobacter xylosoxidans, encompassed both one of the highest prevalence of siderophore-producing strains and strains producing the largest amounts of siderophores, particularly observed for CF strains. These observations may represent additional advantages accounting for the epidemiological success of this species.

Abstract Background CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites. Aim Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders. Implications Resistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.