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Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)‐wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short‐ and long‐term survivors of IDH‐wildtype GB (STS and LTS, respectively) by data‐independent acquisition mass spectrometry (DIA‐MS)‐based proteomics, with the aim of identifying such markers. DIA‐MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid‐binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first‐line treatment with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH‐wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH‐wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS.

Erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone‐receptor‐positive, human epidermal growth factor receptor 2‐negative (HR+/HER2−) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three‐color Crystal dPCR™ naica® platform with a two‐step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma‐based monitoring of ERBB2 mutational status in patients with MBC.

Plastic pollution is distributed patchily around the worlds oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

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Pathogenic Leptospira can cause leptospirosis: a widespread, potentially fatal bacterial zoonosis whose risk is mediated by the soil and water features, animal host distributions, meaning the local ecosystem. When human cases of leptospirosis occur, it is challenging to track down their source because ecosystem-level epidemiological knowledge on Leptospira is needed. Between 2016 and 2019 in a focal riparian ecosystem, the human population experienced an outbreak and successive cases of leptospirosis attributable to L. kirschneri and L. interrogans. The epidemiological investigation was carried out using the One Health approach, as described in international health guidelines. As a first step in this process, we investigated leptospiral carriage in the main animal hosts found in the region. We sampled 143 nutrias, 17 muskrats, and 10 Norway rats using convenient trapping. DNA was extracted from their kidneys, lungs, and urine and subjected to real-time PCR (RT-PCR) targeting the Leptospira 16S rDNA and lfb1 genes. In the farms along the river's stretch of interest, we sampled serum from 439 cattle and used a microscopic agglutination test to detect the presence of antibodies against Leptospira. Urine samples were concomitantly obtained from 145 cattle and were used in two analyses: RT-PCR targeting the Leptospira 16S rDNA gene and Leptospira culturing. We found th, wt rodents were the most likely source of the L. interrogans behind the human cases. The cattle tested negative for Leptospira DNA but positive for antibodies against the serogroups implicated in the human cases. We failed to identify the potential source of the L. kirschneri responsible for several human cases of leptospirosis. Our results call for further clarification of the Leptospira maintenance community, which may comprise known maintenance hosts, such as rodents, as well as taxa not commonly considered to be maintenance hosts but that can still spread Leptospira. The resulting research network will collaboratively conduct future eco-epidemiological surveys to illuminate the leptospirosis risks faced by humans and animals within ecosystems.

Abstract Background Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. Results First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p

Abstract Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

Abstract The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5–10 GBq and 25–30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals’ models such as dogs before moving into the clinic.

This study examines the tempo and drivers of penguin diversification by combining genomes from all extant and recently extinct penguin lineages, stratigraphic data from fossil penguins and morphological and biogeographic data from all extant and extinct species. Together, these datasets provide new insights into the genetic basis and evolution of adaptations in penguins.

Abstract Background Information on epidural analgesia delivered to parturient women is frequently incomplete, making it difficult for expectant mothers to make an appropriate choice for their delivery. We assessed the impact of a multimodal information session on epidural analgesia delegated to anesthetic nurses on new-mothers’ satisfaction. Methods We performed a prospective sequential study including parturient women who gave birth with epidural analgesia. During the first period, information on epidural analgesia was delivered by anesthetists during the scheduled anesthesia consultation, according to French standard-of-care. Then, a dedicated information session about epidural analgesia provided by anesthetic nurses was implemented. The primary endpoint was the satisfaction of women with the quality of information received. Main secondary endpoints were knowledge of women about epidural analgesia, anxiety before epidural catheter placement, and satisfaction with delivery. Results 259 and 298 women were included during the first and second periods respectively, among whom 178 and 188 were analyzed. Information on epidural analgesia delivered by anesthetic nurses was associated with improvement of new-mothers’ satisfaction with information received (9 (8–10) vs. 10 (9–10) – p

Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)‐wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short‐ and long‐term survivors of IDH‐wildtype GB (STS and LTS, respectively) by data‐independent acquisition mass spectrometry (DIA‐MS)‐based proteomics, with the aim of identifying such markers. DIA‐MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid‐binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first‐line treatment with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH‐wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH‐wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS. [ABSTRACT FROM AUTHOR]

Erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone‐receptor‐positive, human epidermal growth factor receptor 2‐negative (HR+/HER2−) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three‐color Crystal dPCR™ naica® platform with a two‐step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma‐based monitoring of ERBB2 mutational status in patients with MBC. [ABSTRACT FROM AUTHOR]

BackgroundQuantification of chimerism showing the proportion of the donor in a recipient is essential for the follow-up of hematopoietic stem cell transplantation but can also be useful to document an immune tolerance situation after solid organ transplantation. Historically, chimerism has been quantified from genomic DNA, but with technological advances, chimerism from donor-derived cell-free DNA seems particularly relevant in solid organ transplantation.MethodsThe reference method was until recently the short tandem repeat technique, but new innovative techniques as digital PCR (dPCR) and NGS, have revolutionized the quantification of chimerism, such as the so-called microchimerism analysis. After a short review of chimerism methods, a comparison of chimerism quantification data for two new digital PCR systems (QIAcuity™ dPCR (Qiagen®) and QuantStudio Absolute Q (ThermoFisher®) and two NGS-based chimerism quantification methods (AlloSeq HCT™ (CareDx®) and NGStrack™ (GenDX®)) was performed.ResultsThese new methods were correlated and concordant to routinely methods (r²=0.9978 and r²=0.9974 for dPCR methods, r²=0.9978 and r²=0.9988 for NGS methods), and had similar high performance (sensitivity, reproductibility, linearity).ConclusionFinally, the choice of the innovative method of chimerism within the laboratory does not depend on the analytical performances because they are similar but mainly on the amount of activity and the access to instruments and computer services.

Non-conventional stable isotopes have received increasing attention in the past decade to investigate multi-level ecological connections from individuals to ecosystems. More recently, isotopes from trace and non-nutrient elements, potentially toxic (i.e., Hg), have also been recognized of great significance to discriminate sources, transports, and bioaccumulation, as well as trophic transfers. In contrast, lithium (Li) concentrations and its isotope compositions (δ7Li) remain poorly documented in aquatic ecosystems, despite its possible accumulation in marine organisms, its increasing industrial production, and its demonstrated hazardous effects on biota. Here, we present the first Li isotope investigation of various soft tissues, organs or whole organisms, from marine plankton, bivalves, cephalopods, crustaceans, and fish of different biogeographical regions [North Mediterranean Sea, North Atlantic Ocean (Bay of Biscay), South East Pacific Ocean (New Caledonia), and Southern Indian Ocean (Kerguelen Islands)]. Independently of the considered organisms, δ7Li values range widely, from 4.6‰ (digestive gland of bivalves) to 32.0‰ (zooplankton). Compared to homogeneous seawater (δ7Li ∼ 31.2‰ ± .3‰), marine organisms mostly fractionate Li isotopes in favor of the light isotope (6Li). Within the same taxonomic group, significant differences are observed among organs, indicating a key role of physiology on Li concentrations and on the distribution of Li isotopes. Statistically, the trophic position is only slightly related to the average Li isotope composition of soft tissues of marine organisms, but this aspect deserves further investigation at the organ level. Other potential influences are the Li uptake by ingestion or gill ventilation. Overall, this work constitutes the first δ7Li extensive baseline in soft tissues of coastal organisms from different large geographic areas mostly preserved from significant anthropogenic Li contamination.

Affichée comme une priorité de la gestion du risque d’inondation, la sécurité des populations est rarement évaluée dans les bilans des catastrophes naturelles en France. Plus que les bilans humains, ce sont les dommages socio-économiques qui sont mis en avant comme indicateurs de la prévention. Cet article présente un recueil de données sur les décès liés aux inondations dans le sud de la France (BD Vict-In). 328 victimes ont étérecensées entre 1980 et 2020. L’article présente le profil des personnes décédées et une analyse des circonstances et des lieux de décès. Il ressort que les victimes sont majoritairement des hommes (61%) de la classe d’âge 40-70 ans. 35% des décès sont liés à l’automobile et 31 % ont lieu au domicile. Parmi les comportements dangereux, le franchissement de cours d’eau en véhicule ou à pied (50 cas recensés) ou les refus d’évacuation (24 cas) sont les plus représentés. 29 décès ont eu lieu dans des campings. La cartographie du taux de mortalité montre la forte exposition des arrière-pays méditerranéens qui associent fréquence des épisodes pluvieux, fortes pentes et urbanisation croissante. L’évolution temporelle montre une diminution du nombre de décès par événement mais une augmentation du nombre d’inondations meurtrières.

The use of cephalopod beaks in ecological and population dynamics studies has allowed major advances of our knowledge on the role of cephalopods in marine ecosystems in the last 60 years. Since the 1960’s, with the pioneering research by Malcolm Clarke and colleagues, cephalopod beaks (also named jaws or mandibles) have been described to species level and their measurements have been shown to be related to cephalopod body size and mass, which permitted important information to be obtained on numerous biological and ecological aspects of cephalopods in marine ecosystems. In the last decade, a range of new techniques has been applied to cephalopod beaks, permitting new kinds of insight into cephalopod biology and ecology. The workshop on cephalopod beaks of the Cephalopod International Advisory Council Conference (Sesimbra, Portugal) in 2022 aimed to review the most recent scientific developments in this field and to identify future challenges, particularly in relation to taxonomy, age, growth, chemical composition (i.e., DNA, proteomics, stable isotopes, trace elements) and physical (i.e., structural) analyses. In terms of taxonomy, new techniques (e.g., 3D geometric morphometrics) for identifying cephalopods from their beaks are being developed with promising results, although the need for experts and reference collections of cephalopod beaks will continue. The use of beak microstructure for age and growth studies has been validated. Stable isotope analyses on beaks have proven to be an excellent technique to get valuable information on the ecology of cephalopods (namely habitat and trophic position). Trace element analyses is also possible using beaks, where concentrations are significantly lower than in other tissues (e.g., muscle, digestive gland, gills). Extracting DNA from beaks was only possible in one study so far. Protein analyses can also be made using cephalopod beaks. Future challenges in research using cephalopod beaks are also discussed.

Abstract Oceanic frontal zones have been shown to deeply influence the distribution of primary producers and, at the other extreme of the trophic web, top predators. However, the relationship between these structures and intermediate trophic levels is much more obscure. In this paper we address this knowledge gap by comparing acoustic measurements of mesopelagic fish concentrations to satellite-derived fine-scale Lagrangian Coherent Structures in the Indian sector of the Southern Ocean. First, we demonstrate that higher fish concentrations occur more frequently in correspondence with strong Lagrangian Coherent Structures. Secondly, we illustrate that, while increased fish densities are more likely to be observed over these structures, the presence of a fine-scale feature does not imply a concomitant fish accumulation, as other factors affect fish distribution. Thirdly, we show that, when only chlorophyll-rich waters are considered, front intensity modulates significantly more the local fish concentration. Finally, we discuss a model representing fish movement along Lagrangian features, specifically built for mid-trophic levels. Its results, obtained with realistic parameters, are qualitatively consistent with the observations and the spatio-temporal scales analysed. Overall, these findings may help to integrate intermediate trophic levels in trophic models, which can ultimately support management and conservation policies.

Abstract Technical advances in 3D imaging have contributed to quantifying and understanding biological variability and complexity. However, small, dry‐sensitive objects are not easy to reconstruct using common and easily available techniques such as photogrammetry, surface scanning, or micro‐CT scanning. Here, we use cephalopod beaks as an example as their size, thickness, transparency, and dry‐sensitive nature make them particularly challenging. We developed a new, underwater, photogrammetry protocol in order to add these types of biological structures to the panel of photogrammetric possibilities. We used a camera with a macrophotography mode in a waterproof housing fixed in a tank with clear water. The beak was painted and fixed on a colored rotating support. Three angles of view, two acquisitions, and around 300 pictures per specimen were taken in order to reconstruct a full 3D model. These models were compared with others obtained with micro‐CT scanning to verify their accuracy. The models can be obtained quickly and cheaply compared with micro‐CT scanning and have sufficient precision for quantitative interspecific morphological analyses. Our work shows that underwater photogrammetry is a fast, noninvasive, efficient, and accurate way to reconstruct 3D models of dry‐sensitive objects while conserving their shape. While the reconstruction of the shape is accurate, some internal parts cannot be reconstructed with photogrammetry as they are not visible. In contrast, these structures are visible using reconstructions based on micro‐CT scanning. The mean difference between both methods is very small (10−5 to 10−4 mm) and is significantly lower than differences between meshes of different individuals. This photogrammetry protocol is portable, easy‐to‐use, fast, and reproducible. Micro‐CT scanning, in contrast, is time‐consuming, expensive, and nonportable. This protocol can be applied to reconstruct the 3D shape of many other dry‐sensitive objects such as shells of shellfish, cartilage, plants, and other chitinous materials.

Self-regulation and executive functioning impairments are common in children with fetal alcohol spectrum disorder. Given the high rates of fetal alcohol spectrum disorder identified amongst children living in the remote Fitzroy Valley region of Western Australia, the Alert Program® was identified as a culturally safe intervention for use in local primary schools. Researchers collaborated with Aboriginal Elders, community members, and staff from a Fitzroy Valley primary school to trial the Alert Program®. Teachers were trained to deliver eight Alert Program® lessons to children in class. Self-regulation and executive functioning were measured using teacher and parent/caregiver questionnaires three times. Data were analyzed using repeated-measures ANOVA. Teacher-led delivery of the Alert Program® was feasible in a region with high fetal alcohol spectrum disorder rates. As measured by teacher and parent/caregiver ratings, this curriculum may improve the self-regulation and executive functioning of children for some outcomes and provide sustained effects for some children. This community partnered pilot research, evaluated a school-based program to reduce the behavioral impact of fetal alcohol spectrum disorder, and informed design of a larger trial across eight Aboriginal community schools.

Adeno-associated virus (AAV) vectors are considered efficient vectors for gene transfer, as illustrated by recent successful clinical trials targeting retinal or neurodegenerative disorders. However, limitations as host immune responses to AAV capsid or transduction of limited regions must still be overcome. Here, we focused on locoregional (LR) intravenous perfusion vector delivery that allows transduction of large muscular areas and is considered to be less immunogenic than intramuscular (IM) injection. To confirm this hypothesis, we injected 6 cynomolgus monkeys with an AAV serotype 8 (AAV8) vector encoding for the highly immunogenic GFP driven by either a muscle-specific promoter (n = 3) or a cytomegalovirus (CMV) promoter (n = 3). We report that LR delivery allows long-term GFP expression in the perfused limb (up to 1 year) despite the initiation of a peripheral transgene-specific immune response. The analysis of the immune status of the perfused limb shows that LR delivery induces persisting inflammation. However, this inflammation is not sufficient to result in transgene clearance and is balanced by resident regulatory T cells. Overall, our results suggest that LR delivery promotes persisting transgene expression by induction of Treg cells in situ and might be a safe alternative to IM route to target large muscle territories for the expression of secreted therapeutic factors.

Abstract The aim of this study was to assess the potential impact of the kinetics of serum levels of seven cytokines during induction in acute myeloid leukemia (AML) patients. Indeed, the role of cytokines, in the pathophysiology and response to therapy of AML patients, remains under investigation. Here, we report on the impact of peripheral levels of two cytokines, the Fms‐like tyrosine kinase 3 ligand (FL) and interleukin‐6 (IL‐6), evaluated during first‐line intensive induction. A new risk stratification can be proposed, which supersedes the ELN 2017 classification to predict survivals in AML patients by examining the kinetic profile of these cytokines during the induction phase. It segregates three groups of, respectively, high‐risk, characterized by a stagnation of low FL levels, intermediate risk, with dynamic increasing FL levels and high IL‐6 at day 22, and favorable risk with increasing FL levels but low IL‐6 at day 22.