Despite decades of concern over the carcinogenic potential of agricultural pesticides, toxicological studies relying on single endpoints have yet to establish a definitive link between environmental pesticide exposure and cancer in real-world contexts. Here we use an integrative spatial Bayesian framework that merges high-resolution environmental pesticide risk modelling with comprehensive cancer registry data to map pesticide-linked cancer clusters in Peru with unprecedented precision. Our process-based model, encompassing 31 key pesticide active ingredients, together with an innovative stratification of cancer cases by developmental lineage, reveals a robust spatial association between environmental pesticide exposure risk and cancer incidence. In pesticide-associated cancer hotspots, exposomic profiling of liver tissue-a primary target of chemical carcinogens-uncovers a distinct transcriptomic signature of pesticide exposure, implicating a non-genotoxic mode of action that disrupts core regulatory circuitries sustaining cell identity. Collectively, these findings strongly support a mechanistic link between pesticide exposure and cancer, challenging assumptions of human non-carcinogenicity derived from reductionist experimental models. This study redefines the exposome as a lineage-conditioned, mechanistically tractable framework and shows how complex pesticide mixtures can contribute to carcinogenic trajectories, with profound and far-reaching implications for global health policy and socio-ecological equity.

Human papillomavirus-induced cancers result from a synergy between genetic mutations and epigenetic reprogramming. The latter affects both the viral and host genomes, resulting in methylomic signatures, histone alterations and aberrant regulation of non-coding RNAs. These mechanisms contribute to tumor progression and provide new biomarkers for screening, risk stratification, and therapeutic monitoring. In a context where, despite vaccination campaigns, the incidence of HPV-positive cancers remains high particularly for oropharyngeal sites, the integration of these markers into precision medicine approaches appears essential. Future strategies will likely rely on a combination of vaccination, screening based on robust epigenetic panels, and the development of targeted epigenetic therapies, either alone or in combination with immunotherapy, to improve the prevention and management of HPV-associated cancers.

BackgroundBreast and cervical cancers are among the most frequent malignancies in women worldwide and represent a growing public health concern in sub-Saharan Africa (SSA). In Gabon, national screening programs have been established, but their effectiveness remains poorly documented, particularly outside the capital city, Libreville. This study, therefore, aimed to describe the screening outcomes and associated factors for breast abnormalities and suspected cervical lesions at the Centre Hospitalier Universitaire Amissa Bongo (CHUAB) in Franceville, Gabon.MethodsWe conducted a retrospective cross-sectional study that included all women who attended routine screening at CHUAB between 2015 and, 2016 and, 2018 and 2021. Data were retrieved from hospital registries and medical records. All women underwent both clinical breast examination (CBE) and visual inspection with acetic acid (VIA). Sociodemographic, reproductive, and clinical variables were analyzed to determine their associations with screening outcomes using univariable and exploratory multivariable logistic regression models.ResultsA total of 1,328 women were included in the study, with a mean age of 35.4 ± 10.8 years. In univariable analysis, women aged 45–73 years had lower odds of cervical screening positivity compared with those aged 14–25 years (OR = 0.52, 95% CI: 0.29–0.90; p = 0.021). In exploratory multivariable analysis, non-Gabonese nationality and employment in the public sector were associated with cervical screening positivity. Regarding breast abnormalities, an age at first pregnancy between 30 and 39 years was associated with higher odds of screening positivity in univariable analysis (OR = 3.90, 95% CI: 1.07–11.4; p = 0.021); however, no factors remained statistically significant in the adjusted model.ConclusionThis study offers one of the first accounts of routine breast and cervical cancer screening outcomes in a semi-urban setting in south-eastern Gabon. VIA and CBE detected a measurable proportion of women with suspected cervical lesions and breast abnormalities, underscoring the value of these simple and accessible screening approaches in resource-limited settings. Strengthening follow-up systems, improving data management, and expanding screening coverage could further enhance cancer control among women in Gabon.

Host molecular and genetic factors regulating SARS-CoV-2 entry are increasingly recognized as key determinants of infection susceptibility and disease severity. However, the combined impact of transcriptional and genetic variation in these pathways remains incompletely defined. This study aimed to identify clinically relevant biomarkers associated with COVID-19 outcomes by integrating gene expression and genetic variability analyses of major viral entry factors. We analyzed the expression and genetic variability of key SARS-CoV-2 entry-related genes (ACE2, TMPRSS2, FURIN, and NRP1) in 184 severe patients, 182 benign cases, and 180 healthy controls. Gene expression was quantified by qRT-PCR, and six SNPs (rs2285666, rs2070788, rs1475908, rs4702, rs4932178, rs1412115) were genotyped using TaqMan assays. TMPRSS2 and FURIN were significantly overexpressed in severe COVID-19 patients (p < 0.05) and positively correlated with platelet count (r = 0.34–0.36, p < 0.05). FURIN expression also correlated with viral load (r = 0.40, p = 0.007). Genetically, the TMPRSS2 rs1475908 GG genotype was associated with higher gene expression (p = 0.009), while the A allele conferred protection against disease severity (OR = 0.53, 95

Ampullary carcinoma (AC) is a rare epithelial cancer, representing around 0.2% of all gastrointestinal malignancies worldwide, with an estimated incidence of 0.73 per 100,000 people. The rarity of AC, combined with the intricate anatomy of its site of origin, often complicates histopathological diagnosis. Recent advances in molecular research, however, have begun to illuminate its underlying biological complexity. In this study, we present the first comprehensive single-cell transcriptomic atlas of AC, encompassing both malignant epithelial populations and the tumor immune microenvironment (TIME). We identified upregulation of oncogenic drivers previously linked to AC, along with an AC-specific transcriptional program featuring potential biomarkers for minimally invasive diagnostics. Furthermore, we characterized an immunosuppressive TIME, enriched in anti-inflammatory-like tumor-associated macrophages (TAMs) and T cell subsets with limited antitumor activity. Collectively, these findings provide a foundational resource for the identification and validation of candidate biomarkers for early detection and targeted therapies in AC.

Guinea has the highest incidence of hepatocellular carcinoma (HCC) in Sub-Saharan Africa (> 21 cases/100,000 habitants/year). This high incidence is largely attributed to the combination of a high prevalence of chronic hepatitis B virus (HBV) infection and significant exposure to aflatoxin B1 (AFB1), a known carcinogen. However, the clinical presentation of HCC in Guinea has not been well-documented to date. We conducted a retrospective analysis of 216 HCC cases from patients who received care between 2015 and 2023 at the Donka University Hospital in Conakry, the main tertiary care institution of the country. Demographical, clinical, and biological data were extracted from medical records and analyzed using both descriptive and inferential statistics. The median age of patients was relatively young, at 43.0 years (IQR = 34.5–55.0) with a male-to-female ratio of 3.1 (162/54). Half of the male patients were younger than 41 years. Chronic HBV infection was the predominant risk factor accounting for 75.0

Background:HDV, a defective virus dependent on hepatitis B for assembly, can lead to severe liver diseases and an increased risk of progressing to complications such as hepatocellular carcinoma. Given the high prevalence of HDV in Gabon, especially in central Africa, understanding the epidemiology and associated risks is crucial. Aim:This study aimed to assess the serological and molecular features of HDV among HBsAg-positive patients in the urban and rural areas of Gabon. Method:The study was conducted from April 2019 to December 2022 in the Franceville area and from January to June 2023 in the Libreville area. We enrolled 145 newly diagnosed HBsAg-positive individuals in Franceville (101) and Libreville (44). Plasma samples were collected for serological and molecular analyses, including tests for HDV antibodies and RNA detection. Result:The results showed an overall HDV prevalence of 26.2%, with higher rates in Libreville (18/44; 40.9%) compared to Franceville (20/101; 19.8%). Molecular analysis identified the circulation of genotypes I, VII, and VIII, with a predominance of replicative forms. The prevalence of replicative HDV RNA activity was 29.4%, indicating a need for accessible treatment options. Demographic analysis revealed a predominantly male population with an average age of 40. Conclusion:These findings provide valuable insights into the epidemiology of HDV in Gabon and emphasise the importance of targeted interventions and further research to address public health challenges associated with HDV infection in the region.

Background. Hepatitis delta (HDV), a major contributor to severe liver disease, remains highly prevalent in Moldova, despite its declining incidence in Western Europe. Intrafamilial transmission plays a significant role in disease spread, yet has not been thoroughly investigated in Moldova. Understanding its impact is crucial for implementing targeted public health interventions to reduce early-onset liver cirrhosis. Aim. The study aims to assess the impact of intrafamilial HDV transmission on disease progression, particularly its role in accelerating liver cirrhosis onset. Materials and methods. In this comparative cross-sectional study, we describe the demographic, clinical and biological characteristics of 224 HDV-infected patients with chronic hepatitis or liver cirrhosis, attending care in three Moldovan centers. These patients were compared with 100 hepatitis B virus (HBV) -mono-infected subjects. Results. The age of liver cirrhosis onset was similar (48-49 years) in both HDV and HBV monoinfected patients. All delta-infected patients were anti-HBe and HBV DNA detectable much less frequently (28%) than in mono-infected ones (76-92%, P<1.0E-09). Most clinical and biological parameters were significantly worsened in the case of HDV infection. Familial transmission was much more prevalent in HDV than in HBV infection (39% vs 23%, P=0.0036). Amongst patients with HDV those with intrafamilial contamination developed liver cirrhosis significantly earlier than others (40.5±9.3years vs 46.9±8.7years, P=0.053) suggesting a direct association between familial exposure and accelerated disease progression and presented more frequently detectable HDV RNA in their plasma (98.7% vs 89.2%, P=0.0094). Patients from Southern Moldova were significantly more likely to have familial transmission than patients from other parts of the (39.2% vs 17.7%, P=0.0010). Conclusions. Hepatitis delta remains a critical public health concern in Moldova, particularly due to early cirrhosis onset in intrafamilial cases. Given these findings, early screening of HDV in HBsAg-positive individuals and preventive interventions in high-risk families should be prioritized to reduce severe liver disease burden and improve linkage to treatment.

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10−9). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma.

Introduction: Interactions between host and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are incompletely understood. Studies have highlighted the roles of L-dopa decarboxylase (DDC), interferon-inducible truncated isoform of angiotensin-converting enzyme 2 (dACE2), and immunomodulatory hypoxia-regulated gene erythropoietin (EPO) in viral infections. This study investigated the expression levels of DDC, dACE2, and EPO in 136 coronavirus disease 2019 (COVID-19) patients and 88 controls. Methodology: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to quantify mRNA levels of DDC, dACE2, and EPO; and the SARS-CoV-2 viral load in nasopharyngeal swabs. Results: Significantly elevated levels of dACE2 (p = 0.003), DDC (p = 0.004), and EPO (p = 0.006) were observed in patients compared to controls. No correlation with the viral load (DDC: r = 0.12, p = 0.136; EPO: r = 0.02, p = 0.802; dACE2: r = 0.05, p = 0.491), and no associations with age or gender (all p > 0.05) were noted. There were positive correlations between DDC and dACE2 mRNA levels in infected (r = 0.31, p = 0.0002) and uninfected individuals (r = 0.25, p = 0.015); and between DDC and EPO in infected (r = 0.22, p = 0.008) and uninfected individuals (r = 0.27, p = 0.010). There was a positive correlation between dACE2 and EPO mRNA levels in both groups (infected: r = 0.22, p = 0.007; uninfected: r = 0.38, p = 0.0002). Conclusions: DDC, dACE2, and EPO may contribute to COVID-19 pathogenesis through mechanisms independent of viral load, age, or gender.

In the original publication [...].

The TGF-β signaling pathway regulates critical cellular processes, including extracellular matrix production, cell migration, and embryonic development. Although TGF-β exhibits tumor-suppressive effects in early carcinogenesis, it promotes tumor progression in advanced stages. Inhibitors targeting the TGF-β type I receptor (ALK-5)—such as vactosertib and galunisertib—disrupt SMAD-dependent signaling and show therapeutic potential against tumor growthIn this study, we employed structure-based virtual screening (SBVS) of the NANPDB and ZINC compound libraries to identify novel ALK-5 inhibitors. Six top candidates were selected, including tricin (a flavonoid) and ZINC000059217525 (agomelatine), which exhibited strong binding affinities to key catalytic residues (Lys232, Glu245, Ser280) in the ALK-5 active site. Molecular dynamics (MD) simulations confirmed ligand-induced conformational stability of ALK-5, while binding free energy calculations revealed these compounds had the most favorable ΔG values. Four additional candidates showed promising interactions with the ALK-5 hinge region and comparably low binding energies. ADME-Tox profiling indicated favorable pharmacokinetic and safety properties for all six compounds.Our results identify tricin and agomelatine as promising ALK-5 inhibitors with potential anticancer activity, warranting further experimental validation.

Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.

BACKGROUND AND AIMS:Genetic factors, including polymorphisms in the TNFRSF13B gene, which regulates humoral immunity, can influence susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aims to investigate the association between two polymorphisms, rs12603708 and rs3751987, and SARS-CoV-2 susceptibility, disease severity, and humoral immune responses in a Moroccan population. MATERIALS AND METHODS:A total of 303 unvaccinated COVID-19 patients (151 severe cases and 152 asymptomatic/moderate cases) and 150 individuals from a SARS-CoV-2-negative group were included in the analysis. Genotyping was performed using TaqMan SNP assays. SARS-CoV-2 antibodies targeting the nucleocapsid protein and IgG antibodies specific to the receptor-binding domain (RBD) were quantified using chemiluminescence microparticles immunoassay. Complete blood counts and C-reactive protein levels were evaluated using an automated platform. RESULTS:Our analysis revealed that the A/A genotype of rs12603708 significantly increased the risk of SARS-CoV-2 infection in both codominant (p = 0.0055; OR = 3.74; adjusted p value = 0.022) and recessive (p = 0.0049; OR = 3.17; adjusted p value = 0.022) models, as well as the risk of severe disease (p = 0.014; OR = 3.43; adjusted p value = 0.049). For rs3751987, the G/G genotype was linked to higher susceptibility to infection (p = 0.0011; OR = 2.91; adjusted p value = 0.008), while the G/A genotype appeared protective (p = 0.0007; OR = 0.45; adjusted p value = 0.008). No association was found between rs3751987 and disease severity. Analysis of IgG anti-N and anti-RBD levels revealed no significant associations with either polymorphism (p > 0.05). CONCLUSION:These findings highlight the role of TNFRSF13B polymorphisms in SARS-CoV-2 susceptibility and severity, while their impact on humoral immune responses appears limited.

Pierre Tiollais, a French physician-biologist, died on August 5, 2024, at 89. He is celebrated for cloning and sequencing the hepatitis B virus (HBV) genome and developing one of the first recombinant HBV vaccines. Professor at the Pasteur Institute and the University Paris VII (now University Paris Cité), Pierre Tiollais has played a key role in the application of molecular biology and genetic engineering in medical research, notably in the fight against HBV and human immunodeficiency virus (HIV). His work has helped saving millions of lives through vaccination campaigns. Pierre Tiollais was also renowned for his benevolent mentorship and commitment to the scientific community.

In the published publication [...]

The persistent evolution of SARS-CoV-2 highlights the crucial role of genomic surveillance in tracking emerging variants and guiding public health interventions. We performed whole-genome sequencing on 235 SARS-CoV-2-positive samples collected across Morocco between 2021 and 2024 to characterize viral evolution and variant dynamics. Our analysis revealed a temporal shift in variant prevalence that paralleled global trends: initial co-circulation of Alpha and Delta variants, followed by complete replacement by Omicron and its sub-lineages in 2022. Phylogenetic reconstruction identified key mutations associated with enhanced immune evasion and transmissibility, demonstrating the virus’s adaptive capacity. These findings underscore the critical importance of sustained genomic surveillance for monitoring viral evolution, informing vaccine and therapeutic strategies, and guiding public health responses. Our results advocate for expanded collaborative surveillance networks to proactively address threats from SARS-CoV-2 and other betacoronaviruses.

(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. The analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT medulloblastoma, 13 of which are involved in Wnt pathway regulation: RNF43, LEF1, NKD1, AXIN2, DKK4, DKK1, LGR6, FGFR2, NXN, TCF7L1, STK3, YAP1, and NFATC4. The ROC curve analysis of the combined expression of these 13 WNT-related LEF1 targets yielded an area under the curve (AUC) of 1.00, indicating 100% specificity and sensitivity for predicting the WNT subtype in the PBTA medulloblastoma cohort. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma.