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BackgroundRadiolabeled-antibodies usually display non-specific liver accumulation that may impair image analysis and antibody biodistribution. Here, we investigated whether Fc silencing influenced antibody biodistribution. We compared recombinant 89Zr-labeled antibodies (human IgG1 against different targets) with wild-type Fc and with mutated Fc (LALAPG triple mutation to prevent binding to Fc gamma receptors; FcγR). After antibody injection in mice harboring xenografts of different tumor cell lines or of immortalized human myoblasts, we analyzed antibody biodistribution by PET-CT and conventional biodistribution analysis.ResultsAccumulation in liver was strongly reduced and tumor-specific targeting was increased for the antibodies with mutated Fc compared with wild-type Fc.ConclusionAntibodies with reduced binding to FcγR display lower liver accumulation and better tumor-to-liver ratios. These findings need to be taken into account to improve antibody-based theragnostic approaches.

Background/Objectives: Tumor-associated antigens are not tumor-specific antigens but proteins that are overexpressed by tumor cells and also weakly expressed at the surface of healthy tissues. Therefore, some side effects are observed when targeted by therapeutic antibodies, a phenomenon named “on-target, off-tumor toxicity”. As tumors generate an acidic microenvironment, we investigated whether we could generate pH-dependent antibodies to increase their tumor specificity. For this proof-of-concept study, we selected the tyrosine kinase receptor AXL because we already developed several antibodies against this target. Methods: To generate a pH-dependent anti-AXL antibody, we performed classical panning of a single-chain variable fragment (scFv) library using phage display at an acidic pH throughout the process. Results: After the third round of panning, 9 scFvs, among the 96 picked clones, bound to AXL at acidic pH and showed very low binding at a neutral pH. After reformatting them into IgG, two clones were selected for further study due to their strong pH-sensitive binding. Using molecular docking and alanine scanning, we found that their binding strongly depended on two histidine residues present on AXL at positions 61 and 116. Conclusions: To conclude, we set-up an easy process to generate pH-dependent antibodies that may increase their tumor-binding specificity and potentially decrease toxicity towards healthy tissues.

Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure–toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug–drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.

Shortly after the Deepwater Horizon oil spill began in April 2010, a widely spaced passive acoustic monitoring array was deployed in the northeastern Gulf of Mexico to document the impacts of this unprecedentedly large and deep offshore oil spill on oceanic marine mammals. The array was subsequently maintained for over a decade. Here we document decadal density declines for seven of eight monitored species groups, including sperm whales (up to 31%), beaked whales (up to 83%), and small delphinids (up to 43%). Declines were observed both within and outside of the surface oil footprint. Though not conclusively linked to the oil spill, the broad spatial and temporal scale of these declines observed for disparate marine mammal species is consistent with Deepwater Horizon impacts. These declines have exceeded and outlasted post-spill damage assessment predictions, suggesting that the offshore ecosystem impacts of Deepwater Horizon may have been larger than previously thought. Whale and delphinid numbers in the Gulf of Mexico have declined by up to 83% in the ten years following the Deepwater Horizon oil spill, according to analysis of passive acoustic monitoring data.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with distressed behaviors and psychological challenges. This study aims to evaluate the change in health-related quality of life (HRQoL), anxiety, and sleep quality in autistic individuals prescribed cannabis-based medicinal products (CBMPs). This observational case series analyzed data from the UK Medical Cannabis Registry on autistic adults treated with CBMPs. Demographic and clinical data were collected at baseline, with patient-reported outcome measures assessed up to 18 months. Primary outcomes included changes in anxiety (GAD-7), sleep quality (SQS), and HRQoL (EQ-5D-5L). Secondary outcomes included the incidence of adverse events. Statistical significance was indicated by p < 0.050. One-hundred and thirty individuals met the inclusion criteria. GAD-7 (p < 0.001) and SQS (p < 0.001) scores improved from baseline to 18 months. EQ-5D-5L index values showed improvement from baseline (0.43 ± 0.30) to 18 months (0.51 ± 0.32, p < 0.001), and PGIC scores increased from 1 month (5.43 ± 1.49) to 18 months (5.65 ± 1.32, p = 0.013). Twenty-five participants (19.23%) reported a total of 232 (178.46%) adverse events, with most being mild (n = 88; 67.69%) or moderate (n = 99; 76.15%). Treatment with CBMPs was associated with improvements in HRQoL, anxiety, and sleep outcomes in autistic patients over an 18-month period. Given the absence of a control group, these findings represent associations rather than proven treatment effects. Further high-quality randomized controlled trials are needed to confirm the long-term efficacy and safety of CBMPs in ASD.

Barriers and Facilitators for Adhesion of Healthcare Professionals in Integrated Care for Older Patients: A Qualitative Assessment Based on the French National Experiment: ‘Health Pathway of Seniors for Preserved Autonomy’ (PAERPA)Introduction: Integrated care is a particularly promising approach in geriatrics – a field in which the medical, psychological and social issues are often complex. The uptake of integrated care by healthcare professionals (HCPs) is essential but varies markedly. The objective of the present study of healthcare professionals was to identify barriers to and facilitators of commitment to integrated care for seniors.Methods: We performed a two-step, qualitative study, comprising (i) six qualitative, semi-directive series of interviews with HCPs (hospital practitioners, family physicians, nurses and pharmacists) who agreed or disagreed to take part in the French national “Health Pathway of Seniors for Preserved Autonomy” (PAERPA) pilot program; and (ii) an analysis of the pooled results, in order to identify common concerns among the healthcare professionals.Results: We identified four key “barrier” and “facilitator” topics shared by HCPs who had committed to the pilot program and those who had not: (i) awareness of and/or interest in geriatric medicine and team working, (ii) the presence of a care coordinator; (iii) the provision of information about the program and about the patient, and communication between HCPs, and (iv) personal benefits for the HCPs and the patients.Key conclusions: The four key topics identified in this large qualitative study of several healthcare professions should be considered during the design and dissemination of integrated care pathways for older patients.

Although officially created, the protected reserve of Ngiri remains virtual, existing only on paper, many reasons can explain this hypothesis: - The insufficient national regulations, at least at the time of the establishment of this protected reserve, which had the effect of not having any application at the local level. - Conflicts of administrative and community interest arising from the overlapping of different laws or measures. - The authorities' lack of interest in safeguarding biodiversity or the priorities given to other aspects of environmental management (development of fishing). - The local situation too complicated due to various conflicts between fishermen and eco-guards. - The lack of qualified personnel, of means, in particular financial resources, to implement measures for the sustainable management of the reserve. - The lack of skills in assessing the state of the environment and planning management. - The poor definition of the limits of the protected reserve, thus reducing its interest for the fauna and flora. - The very significant human pressure on the outskirts and the lack of ecological corridors to connect the reserve. - The lack of economic valuation of the said reserve.

The ability of consumers to adjust their diet in response to resource shifts is a key mechanism allowing the persistence of populations and underlying species’ adaptive capacity. Yet on coral reefs, one of the marine habitats most vulnerable to global change, the extent to which species alter their diet remains poorly understood. Here, we integrated DNA-based gut content analyses (metabarcoding), otolith analysis, body condition, and field surveys to test how diet can mediate effects of habitat degradation on two invertivorous fishes: Chaetodon capistratus, a browser, and Hypoplectrus puella, an active predator. Metabarcoding revealed significant dietary variation in both species across a habitat gradient. However, the response was more pronounced in the browser, whose diet was anthozoan-dominated on healthy reefs, whereas annelid-dominated on degraded reefs. We found reduced growth and body condition on degraded reefs in the browser but not the active predator. Our results reveal that dietary versatility can serve as a mechanism to cope with degraded environments, but that species differ as to whether these changes are sufficient to buffer from changes in habitat. We detected intraspecific dietary variation across sites that suggests food webs and energy flow differ at relatively small scales between healthy and degraded reefs.