Safety and feasibility of intranasal heroin-assisted treatment: 4-week preliminary findings from a Swiss multicentre observational study

Background: Heroin-assisted treatment (HAT) is effective for individuals with severe opioid use disorder (OUD) who do not respond sufficiently to other opioid agonist treatments. It is mostly offered with injectable diacetylmorphine (DAM) or DAM tablets creating a barrier for individuals who need the rapid onset of action but are either unable or unwilling to inject, or primarily snort opioids. To explore another route of administration, we evaluated the safety and feasibility of intranasal (IN) DAM. Methods: This is a multicentre observational cohort study among patients in Swiss HAT. All patients planning to receive IN DAM within the treatment centres were eligible to participate. Participants were either completely switched to IN DAM or received IN DAM in addition to other DAM formulations or opioid agonists. Patients were followed up for four weeks. Sociodemographic characteristics, current HAT regimen, reasons for starting IN DAM, IN DAM doses, number of injection events in the sample, IN DAM continuation rate, and appearance of adverse events and nose-related problems were evaluated. Results: Participants (n = 52) reported vein damage, preference for nasal route of administration, and desire of a stronger effect or for a less harmful route of administration as primary reasons for switching to IN DAM. After four weeks, 90.4% of participants (n = 47) still received IN DAM. Weekly average realised injection events decreased by 44.4% from the month before IN DAM initiation to the month following. No severe adverse events were reported. Conclusions: After four weeks, IN DAM was a feasible and safe alternative to other routes of administration for patients with severe OUD in HAT. It addressed the needs of individuals with OUD and reduced injection behaviour. More long-term research efforts are needed to systematically assess efficacy of and patient satisfaction with IN DAM

Nanomagnetism reveals the intracellular clustering of iron oxide nanoparticles in the organism

International audienceThere are very few methods to investigate how nanoparticles (NPs) are taken up and processed by cells in the organism in the short and long terms. We propose a nanomagnetism approach, in combination with electron microscopy, to document the magnetic outcome of iron oxide-based P904 NPs injected intravenously into mice. The NP superparamagnetic properties are shown to be modified by cell internalization, due to magnetic interactions between NPs sequestered within intracellular organelles. These modifications of magnetic behaviour are observed in vivo after NP uptake by resident macrophages in spleen and liver or by inflammatory macrophages in adipose tissue as well as in vitro in monocyte-derived macrophages. The dynamical magnetic response of cell-internalized NPs is theoretically and experimentally evidenced as a global signature of their local organization in the intracellular compartments. The clustering of NPs and their magnetism become dependent on the targeted organ, on the dose administrated and on the time elapsed since their injection. Nanomagnetism probes the intracellular clustering of iron-oxide NPs and sheds light on the impact of cellular metabolism on their magnetic responsivity

Colon-specific immune microenvironment regulates cancer progression versus rejection

International audienceImmunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset ofpatients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissuespecificfactors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironmentshapes the immune response to CRC is needed to identify mechanisms of resistance toimmunotherapies and guide the development of novel therapeutics.In an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescenceimaging and the immune signatures were assessed at a transcriptional level using NanoString and ata cellular level by flow cytometry. Despite initial tumor growth in all mice, only 25% to 35% of micedeveloped a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor.No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injectedin non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumorsexhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernibleshortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting micepresented an early inflammatory response and an antitumor microenvironment enriched in CD8+ T cells.Taken together, our data demonstrate the role of the colon microenvironment in regulating thebalance between anti or protumor immune responses. While emphasizing the relevance of the CRCorthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancerresponse to immunotherapy

Direct transport vs secondary transfer to level I trauma centers in a French exclusive trauma system: Impact on mortality and determinants of triage on road-traffic victims.

BackgroundTransporting a severely injured patient directly to a trauma center (TC) is consensually considered optimal. Nevertheless, disagreement persists regarding the association between secondary transfer status and outcome. The aim of the study was to compare adjusted mortality between road traffic trauma patients directly or secondarily transported to a level 1 trauma center (TC) in an exclusive French trauma system with a physician staffed prehospital emergency medical system (EMS).MethodsA retrospective cohort study was performed using 2015-2017 data from a regional trauma registry (Traumabase®), an administrative database on road-traffic accidents and prehospital-EMS records. Multivariate logistic regression models were computed to determine the role of the modality of admission on mortality and to identify factors associated with secondary transfer. The primary outcome was day-30 mortality. Results: During the study period, 121.955 victims of road-traffic accident were recorded among which 4412 trauma patients were admitted in the level 1 regional TCs, 4031 directly and 381 secondarily transferred from lower levels facilities. No significant association between all-cause 30-day mortality and the type of transport was observed (Odds ratio 0.80, 95% confidence interval (CI) [0.3-1.9]) when adjusted for potential confounders. Patients secondarily transferred were older, with low-energy mechanism and presented higher head and abdominal injury scores. Among all 947 death, 43 (4.5%) occurred in lower-level facilities. The population-based undertriage leading to death was 0.15%, 95%CI [0.12-0.19].ConclusionIn an exclusive trauma system with physician staffed prehospital care, road-traffic victims secondarily transferred to a TC do not have an increased mortality when compared to directly transported patients

Functional Characterization of a Chimeric Soluble Fas Ligand Polymer with In Vivo Anti-Tumor Activity

Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for th

FAK alternative splice mRNA variants expression pattern in colorectal cancer

International audienceThe Focal adhesion kinase (FAK) is a ubiquitous cytoplasmic tyrosine-kinase promoting tumor progression and metastasis processes by acting in cancer cells and their tumor microenvironment partners. FAK overexpression in primary colon tumors and their metastasis is associated to poor colorectal cancer (CRC) patients' outcome. Eight FAK mRNA alternative splice variants have been described and contribute to additional level of FAK activity regulation, some of them corresponding to overactivated FAK isoforms. To date, FAK mRNA alternative splice variants expression and implication in CRC processes remain unknown. Here, using different human CRC cells lines displaying differential invasive capacities in an in vivo murine model recapitulating the different steps of CRC development from primary tumors to liver and lung metastasis, we identified three out of the eight mRNA variants (namely FAK 0 , FAK 28 and FAK 6) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK 0 and FAK 6 expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK 0 and FAK 6 could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK 28 in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK 0 , the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK 6 or FAK 28 splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis

The C-type lectin DCIR contributes to the immune response and pathogenesis of colorectal cancer

International audienceDevelopment and progression of malignancies are accompanied and influenced by alterations in the surrounding immune microenvironment. Understanding the cellular and molecular interactions between immune cells and cancer cells has not only provided important fundamental insights into the disease, but has also led to the development of new immunotherapies. The C-type lectin Dendritic Cell ImmunoReceptor (DCIR) is primarily expressed by myeloid cells and is an important regulator of immune homeostasis, as demonstrated in various autoimmune, infectious and inflammatory contexts. Yet, the impact of DCIR on cancer development remains largely unknown. Analysis of available transcriptomic data of colorectal cancer (CRC) patients revealed that high DCIR gene expression is associated with improved patients’ survival, immunologically "hot" tumors and high immunologic constant of rejection, thus arguing for a protective and immunoregulatory role of DCIR in CRC. In line with these correlative data, we found that deficiency of DCIR1, the murine homologue of human DCIR, leads to the development of significantly larger tumors in an orthotopic murine model of CRC. This phenotype is accompanied by an altered phenotype of tumor-associated macrophages (TAMs) and a reduction in the percentage of activated effector CD4 + and CD8 + T cells in CRC tumors of DCIR1 - deficient mice. Overall, our results show that DCIR promotes antitumor immunity in CRC, making it an attractive target for the future development of immunotherapies to fight the second deadliest cancer in the world

Safety and feasibility of intranasal heroin-assisted treatment: 4-week preliminary findings from a Swiss multicentre observational study.

BACKGROUND: Heroin-assisted treatment (HAT) is effective for individuals with severe opioid use disorder (OUD) who do not respond sufficiently to other opioid agonist treatments. It is mostly offered with injectable diacetylmorphine (DAM) or DAM tablets creating a barrier for individuals who need the rapid onset of action but are either unable or unwilling to inject, or primarily snort opioids. To explore another route of administration, we evaluated the safety and feasibility of intranasal (IN) DAM. METHODS: This is a multicentre observational cohort study among patients in Swiss HAT. All patients planning to receive IN DAM within the treatment centres were eligible to participate. Participants were either completely switched to IN DAM or received IN DAM in addition to other DAM formulations or opioid agonists. Patients were followed up for four weeks. Sociodemographic characteristics, current HAT regimen, reasons for starting IN DAM, IN DAM doses, number of injection events in the sample, IN DAM continuation rate, and appearance of adverse events and nose-related problems were evaluated. RESULTS: Participants (n = 52) reported vein damage, preference for nasal route of administration, and desire of a stronger effect or for a less harmful route of administration as primary reasons for switching to IN DAM. After four weeks, 90.4% of participants (n = 47) still received IN DAM. Weekly average realised injection events decreased by 44.4% from the month before IN DAM initiation to the month following. No severe adverse events were reported. CONCLUSIONS: After four weeks, IN DAM was a feasible and safe alternative to other routes of administration for patients with severe OUD in HAT. It addressed the needs of individuals with OUD and reduced injection behaviour. More long-term research efforts are needed to systematically assess efficacy of and patient satisfaction with IN DAM