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Novel Diffuse Midline Glioma‐on‐Chip Recapitulating Tumor Biophysical Microenvironment to Assess the Heterogeneity of Response to Therapies
No full textInternational audienceDespite significant efforts, Diffuse Midline Gliomas (DMGs) remain incurable. Although promising results are obtained in preclinical studies, most approaches have failed to improve survival in these young patients. In this context, by integrating elements of the biophysical tumor microenvironment known to regulate the response to therapies, a new preclinical tool is developed to better evaluate the efficacy of antitumoral strategies. For this purpose, a novel DMG-on-Chip (DoC) is engineered composed of a 3D dense tumor disk embedded in an extracellular matrix, which is accessible for real-time monitoring using wide-field phase contrast or confocal fluorescence microscopy. By driving the oxygen supply within the chip solely in a radial manner, a hypoxia gradient is established that can be associated with changes in DMG cell phenotype, proliferation, and rewiring of metabolic and stress transcriptomic signatures. Finally, DoC is used to analyze the spatial heterogeneity of the response of DMG cell lines and patient-derived 3D cultures to treatments through cell segmentation. Altogether, these interdisciplinary characterizations validate the new tool as an interesting healthcare solution to understand how cell responses are modulated by biophysical or biochemical cues in the tumor microenvironment
Global burden of chikungunya virus infections and the potential benefit of vaccination campaigns
No full textInternational audienceThe first vaccine against chikungunya virus (CHIKV) has now been licensed; however, due to a limited knowledge of the underlying global burden, its potential to reduce disease burden remains unknown. We used data from seroprevalence studies, observed cases and mosquito distributions to quantify the underlying CHIKV burden in 180 countries and territories, and we explored the potential impact of vaccination campaigns. We estimate that 104 countries have experienced CHIKV transmission, covering 2.8 billion people, and that, in epidemic settings, the mean duration between outbreaks is 6.2 years, with 8.4% of the susceptible population infected per outbreak. Globally, there are 35 million annual infections, mainly in Southeast Asia, Africa and the Americas. Assuming a vaccine efficacy against disease of 70% and a protection against infection of 40%, vaccinating 50% of individuals over 12 years of age in places and times where the virus circulates would avert 4,436 infections, 0.34 deaths and 17 disability-adjusted life years per 100,000 doses used. These findings highlight the global burden of chikungunya and the potential of CHIKV vaccination campaigns
Recent and convergent reversion to serotype Ogawa in the AFR12 sublineage of Vibrio cholerae O1 El Tor in Cameroon
No full textInternational audienceSince 1971, Cameroon has experienced several outbreaks of cholera due to strains of the seventh pandemic Vibrio cholerae O1 El Tor (7PET) lineage originating from South Asia. Over the last 6 years, more than 26,000 cholera cases have been reported. The aim of this study was to perform a genomic characterization of the V. cholerae O1 isolates collected during recent cholera outbreaks in Cameroon. We investigated the virulence, antimicrobial resistance (AMR) signatures and phylogenetic relationships of 164 clinical V. cholerae isolates representative of the successive outbreaks collected between 2018 and 2023. A phylogenomic analysis of more than 1,700 7PET genomes – including 45 from isolates collected in Cameroon between 1971 and 2011 – was performed to place the recent 7PET strains in a broader phylogenetic context. We found that all the recent Cameroonian isolates studied belonged to genomic wave 3 of the 7PET lineage. They clustered together within the AFR12 sublineage (which was identified for the first time in Cameroon in 2009) and with contemporary isolates from other countries in the same region. Serotyping and genome analysis revealed a reversion from serotype Inaba (all isolates between 2018 and 2019) to Ogawa (all isolates between 2021 and 2023) in two different strains originating from different regions of Cameroon. Finally, the AFR12 isolates studied here were less resistant to antimicrobial drugs than the AFR12 isolates identified in Cameroon between 2009 and 2011 due to a 10 kb deletion in the integrative conjugative element conferring multidrug resistance, ICE Vch Ind5, resulting in the loss of four AMR genes ( strA , strB , floR and sul2 ). Our findings confirm the complementarity between traditional microbiological methods and microbial genomics for monitoring circulating 7PET strains and tracking their evolution and the development of AMR
Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia.
No full textInternational audienceRecent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule–targeted agents, antibody–drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy
Occupational Exposure to Engine Exhausts and Prostate Cancer Risk
No full textInternational audienceBackground: Some engine exhausts (EEs) have been classified as carcinogens and/or can have hormone-modulating properties that could play a role in prostate cancer development.Objective: We investigated associations between lifetime occupational exposure to various EEs and prostate cancer risk, overall and for aggressive cancers.Methods: In a population-based case-control study conducted in Montreal, Canada, 1,924 incident histologically-confirmed prostate cancer cases (436 aggressive) and 1,989 population controls were recruited. Socio-demographics, lifestyle factors and a detailed occupational history were collected during in-person interviews. Industrial hygienists conducted evaluations of intensity, frequency and reliability of exposure to EEs resulting from the combustion of several fuels (any diesel, light- and heavy-duty diesel, leaded and unleaded gasoline, propane and jet fuel) in each job held ≥ 2 years. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated for exposure to each EE, in association with prostate cancer risk, adjusting for age and then for potential lifestyle and occupational confounders, accounting for a 5-year latency period. As most associations were not linear, we fitted functions for changes in percentile distributions based on natural cubic splines.Results: There was no evidence of associations between exposure to the various EEs and overall prostate cancer. However, for high-grade cancers, based on the fully-adjusted model, a change from the 25th to the 75th percentile of the exposure distribution of any diesel EE yielded an OR of 1.24 (95%CI 0.96-1.61), and of 1.27 (95% CI 0.80-2.01) for a change from the 75th to the 95th percentile. These increases reflected exposure to diesel EE from light-duty vehicles, associated with similar ORs. For leaded gasoline EE, a change from the 75th to the 95th percentile resulted in an age-adjusted OR of 1.36 (95%CI 0.88-2.11), which was attenuated to 1.12 (95%CI 0.63-2.02) after full adjustment. There were no associations with EE from unleaded gasoline, diesel from heavy-duty vehicles, jet fuel and propane.Conclusion: There was suggestive evidence for a deleterious role of occupational exposure to EE resulting from the combustion of any diesel, light-duty diesel and from leaded gasoline in the development of aggressive prostate cancer. Results were independent from prostate cancer screening patterns
Development and evaluation of a triplex real-time PCR assay for enhanced plague diagnostics in Madagascar
No full textInternational audienceBackground: The plague, caused by Yersinia pestis, remains a critical public health issue, particularly in endemic regions like Madagascar. Rapid and accurate detection of this pathogen is essential for effective outbreak management and timely intervention. Following the urban plague outbreak of 2017, a new molecular diagnostic algorithm was developed and introduced into routine use. However, certain cases required combining real-time and conventional polymerase chain reaction (PCR) methods. While effective, this approach often delayed obtaining conclusive results, an issue that can hinder swift outbreak responses. The aim of this study is to design and optimize a three-target real-time PCR assay (qPCR) for the detection of Y. pestis in clinical samples. Methods: The assay targeted three genes: caf1, pla, and yopM, located on the plasmids pMT1, pPCP1, and pCD1, respectively. Conducted at the Institut Pasteur de Madagascar (IPM), the study evaluated the assay using both pure bacterial cultures and clinical samples, including 50 bubonic aspirates and 50 respiratory specimens. Results: Using bacteriology technique as the reference standard, the triplex qPCR demonstrated a sensitivity of 100% (89–100%) and a specificity of 82%. The positive predictive value (PPV) was 73% and the negative predictive value (NPV) was 100% (91–100%). The coefficient of agreement kappa was 0.74, with a p-value of <0.0001. Notably, the new assay resolved 100% of previously inconclusive cases from the duplex qPCR test targeting only pla and caf1.Discussion: While a new plague diagnostic algorithm has been set up after the outbreak in 2017, the present study suggests a real-time PCR assay based on three genes to improve the speed and accuracy of plague diagnostic. Furthermore, this new technique is a valuable tool for managing plague outbreaks and supporting field diagnostics not only in Madagascar but also in countries with plague.Conclusions: The developed triplex assay to molecularly diagnose Y. pestis in human samples improves the standard already in place and allows to resolve ambiguities previously associated with inconclusive results from duplex qPCR tests, thereby reinforcing the reliability and accuracy of this new technique. Implementing this new method into routine will enable a faster, more effective response to plague outbreaks by reducing the time needed to confirm plague cases and limiting the spread of the diseases. This new technique is also flexible and can be undertaken close to human cases with adequate biosecurity and biosafety measures.Author’s summary: Plague, a severe infectious disease caused by the bacterium Yersinia pestis, remains a significant public health concern in Madagascar, where seasonal outbreaks continue to occur. Rapid and accurate diagnosis is critical for timely treatment and outbreak control. Current diagnostic methods, including bacteriology and rapid diagnostic tests, often face limitations in speed, sensitivity and/ or specificity especially in remote settings. In this study, we developed and evaluated a new molecular diagnostic tool: a triplex real-time PCR assay that simultaneously detects three genes from Y. pestis (pla, caf1, and yopM). This approach enhances diagnostic accuracy while reducing turnaround time. The assay was validated using clinical samples collected in Madagascar and showed high sensitivity (100%) and negative predictive value (100%), outperforming conventional techniques. It is important to notice that this technique resolved previously inconclusive results produced by standard molecular methods. Our findings demonstrate that this triplex qPCR is a robust, rapid, and reliable diagnostic tool that can improve plague detection, especially in outbreak settings. Moreover, its implementation could significantly strengthen public health responses and laboratory capacities in endemic regions like Madagascar
An anthropological analysis of the acceptability and feasability of expanding community-based malaria management to all ages in Madagascar: levers and challenges for national scale-up
No full textDespite significant progress in reducing malaria effects in recent decades, malaria remains a major challenge in Madagascar. Geographic and financial barriers often prevent individuals from seeking prompt care. Community health workers (CHWs) in many countries, including Madagascar, provide malaria case management services to children under 5 years old although typically do not treat older children and adults, leaving a gap for those living far from health facilities. To determine the efficacy of expanding malaria community case management (mCCM) to community members of all ages, a cluster randomized trial was conducted in one district of Madagascar from November 2020 to December 2021. Qualitative surveys were conducted to describe the acceptability and feasibility of this intervention among beneficiaries and health workers. For this purpose, 89 semi-structured interviews and 12 focus groups were conducted in intervention and control arms of the study to assess understanding of malaria, behaviors related to care-seeking for fever, perceptions of CHW roles, and acceptability and feasibility of the age-expanded mCCM. Two major findings emerged. First, stakeholders found age-expanded mCCM to be consistent with existing CHW roles and practices. Age-expanded mCCM induced a recognition of adults' susceptibility to malaria and led to a more accurate understanding of malaria. Second, structural and community-based challenges were not fully resolved by age-expanded mCCM, and some, such as the question of the cost of care, emerged after its implementation. Despite the fact that age-expanded mCCM was acceptable to beneficiaries and CHWs, successful scale-up will require addressing structural challenges and socio-demographic inequalities
Allogenic Stem Cells in Anal Fistulas of Crohn’s Disease: From Promising Premises to Real Life Experience
No full textInternational audienceBackground Allogenic adipocyte stem cells represent an unprecedented opportunity for regenerative therapy to treat Crohn anal fistulas. Apart from the results of one 8-year-old trial, scientific evidence remains scarce. Methods Data from consecutive patients treated with darvadstrocel for Crohn anal fistulas were reviewed at 6 first tertiary reference centers. The judgment criteria combined asymptomatic status plus clinical occlusion of the fistula tract and MRI-confirmed healing of the tract (no inflammation and/or disappearance of the tract). Both clinical and MRI-confirmed healing of the tract defined a deep remission. Clinical remission was defined by an absence of complaint, occlusion of all external openings, and no fistula discharge. Results A total of 116 patients were extracted (median follow-up after cell stem injection: 11 [6-14] months). No severe adverse events were reported after surgery except for subsequent anal surgery in 29 (25%) patients. Fifty-one (44%) patients had clinical remission defined by the absence of complaints, the occlusion of all external openings, and the presence of no fistula discharge. Deep remission was observed in 23 (29%) patients. Patients with clinical remission more often received combined therapy (immunosuppressant antitumor necrosis factors) than those with no improvement (31 of 51 [61%] vs 23 of 65 [35%]; P = .007). Regression analysis showed that high fistulas (odds ratio, 3.8 [1.1-12.5]; P = .03) and younger age (<38 years, odds ratio, 2.3 [1.0-58;4]; P = .02) were associated with a better outcome. Conclusions Allogeneic stem cell treatment of Crohn’s anal fistulas results in complete remission in less than half of patients, with a significant reintervention rate
Molecular characterization of enteroviruses circulating among pigs and goats in two Central African countries, Cameroon and the Central African Republic
No full textInternational audienceTo date, data on animal enteroviruses (EVs) are scarce, especially in Central Africa. The aim of this study was to characterize EVs among pigs and goats in Cameroon and the Central African Republic (CAR). A total of 226 pig and goat faecal samples collected in two previous studies carried out in Cameroon and CAR were pooled and screened with molecular assays targeting EV-Es, EV-Fs and EV-Gs. EV genomes were amplified by RT-PCR and their sequences were obtained by Illumina sequencing and de novo assembly. Based on the capsid sequences, 27 EV-G sequences were identified and assigned to 11 virus types, while no EV-E or EV-F was observed. Phylogenetic analysis revealed that the EV-Gs detected in Central Africa do not form specific clusters compared to EV-Gs previously reported in other continents. This suggests a worldwide circulation of EV-Gs, which is likely due to the massive international trade of live animals. One human EV, EV-C99, which belongs to the species Enterovirus C, was detected in pigs. This is the third detection of such an event in a similar context, reinforcing the hypothesis that some EV-Cs could be infecting pigs. Our work provides new data on the genetic diversity of EVs circulating among domestic animals in Central Africa
From Genes to Pathways: A Curated Gene Approach to Accurate Pathway Reconstruction in Teleost Fish Transcriptomics
No full textInternational audienceInterpreting the vast amounts of data generated by high‐throughput sequencing technologies can often present a significant challenge, particularly for non‐model organisms. While automated approaches like GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses are widely used, they often lack specificity for non‐model organisms. To bridge this gap, we present a manually curated gene list tailored for teleost fish transcriptomics. This resource focuses on key biological processes crucial for understanding teleost fish physiology, development, and adaptation, including hormone signaling, various metabolic pathways, appetite regulation, digestion, gastrointestinal function, vision, ossification, osmoregulation, and pigmentation. Developed through collaborative efforts of specialists in diverse fields, the list prioritizes genes with established roles in teleost physiology, experimental evidence, and conservation across species. This curated list aims to provide researchers with a reliable starting point for transcriptomic analyses, offering a carefully evaluated set of genes relevant to current research priorities. By streamlining the process of gene selection and interpretation, this resource supports the broader teleost fish research community in designing and analyzing studies that investigate molecular responses to developmental and environmental changes. We encourage the scientific community to collaboratively expand and refine this list, ensuring its continued relevance and utility for teleost fish research