Search Results (1,982)

This review summarizes the impact of insecticide resistance in urban pests and its implications for ‘One Health’ systems. Mosquitoes are the major vector of human disease via blood feeding, followed by houseflies and cockroaches via physical contact, and finally bed bugs, ants, and termites, which are not typically disease vectors. Besides overt disease, other impacts in the context of One Health include nuisance biting and resultant infections, as well as allergic reactions. Control of urban pests is still primarily achieved with insecticides, which have continually improved over time. However, their use has selected for the evolution of resistance to several compound classes across broad geographical areas and multiple species. Resistance results from several types of mechanisms: altered inherited behavioral repertoires that reduce chemical exposure, modified target sites, increased metabolism, and reduced penetration, which have recently been shown to have several specific underlying causes. Overall, the literature portrays a complex resistance landscape that highlights the importance of comprehensive, multifaceted approaches to maintain effective control. New technologies and approaches for resistance management are also discussed, with emphasis on improved chemical control measures via novel synergists and insecticides from both natural and synthetic sources. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several accessory proteins that modulate host cellular pathways and contribute to immune evasion and disease severity. Among them, ORF8 has emerged as a key immunomodulatory factor; however, its impact on host post-transcriptional regulatory networks remains poorly defined. In this study, we investigated how ORF8 expression reshapes the microRNA (miRNA) landscape of lung epithelial cells and how these changes translate into functional proteomic alterations. Using A549 cells transduced with ORF8 and control cells, we performed small RNA sequencing to identify differentially expressed miRNAs, followed by integrative analysis with quantitative proteomic data. ORF8 expression induces extensive remodeling of the miRNA profile, with coordinated upregulation and downregulation of miRNAs involved in inflammatory signaling, interferon regulation, apoptosis, autophagy and epithelial homeostasis. Integration of miRNA and proteomic datasets revealed inverse regulatory relationships linking ORF8-associated miRNAs to proteins involved in immune defense, stress responses and epithelial integrity. Selected miRNA alterations were validated by RT–qPCR, and the junctional protein plakoglobin (JUP) was experimentally confirmed as a representative downregulated target. Collectively, our findings identify ORF8 as a factor associated with coordinated miRNA-mediated post-transcriptional reprogramming in lung epithelial cells. This network-based regulatory framework provides new insight into how SARS-CoV-2 accessory proteins may influence host responses and highlights miRNA networks as potential contributors to viral pathogenesis and host immune dysregulation. Full article

NPM1-mutated acute myeloid leukemia (AML) represents one of the most frequent and biologically distinct AML entities, characterized by the aberrant cytoplasmic localization of the NPM1 mutant protein. The recent advances in molecular biology and translational research have progressively redefined the clinical management of this disease. This narrative review summarizes the evolution of NPM1-mutated AML over the last two decades, focusing on the transition from immunohistochemical observations to modern genetics-based and measurable residual disease (MRD)-driven approaches. We discuss the biological role of mutant NPM1, the prognostic impact of co-occurring genetic alterations, and the integration of molecular monitoring into routine clinical practice. Particular attention is given to the prognostic and therapeutic implications of the co-mutational landscape. We also discuss emerging targeted therapies directed against key pathogenic pathways, including the menin–KMT2A axis and nuclear export machinery. Despite significant advances in risk stratification and treatment, considerable heterogeneity in clinical outcomes persists among patients with NPM1-mutated AML, indicating that genomic information obtained at diagnosis alone is insufficient to fully capture prognostic differences. Future advances will likely depend on the integration of genetic, transcriptional, and broader cellular-state information to better define biologically relevant disease states and guide more personalized therapeutic strategies. Full article

Male infertility is a multifactorial condition in which conventional semen analysis provides limited insight into the molecular mechanisms underlying sperm dysfunction. Inflammatory and oxidative processes are major contributors to impaired male reproductive function, acting through interconnected alterations in redox homeostasis, immune activation, and protein integrity. Because mature spermatozoa have minimal transcriptional and translational capacity, oxidative and inflammatory damage to proteins may persist and substantially affect motility, capacitation, fertilization competence, and reproductive outcomes. This review examines how sperm proteomics can characterize the molecular landscape of inflammatory and oxidative injury in male infertility. Particular attention is given to pre-analytical variables, sperm purification, protein extraction, bottom-up LC–MS/MS workflows, data-dependent and data-independent acquisition, quantitative strategies, and targeted or orthogonal validation. Proteomic evidence identifies coordinated remodeling of flagellar and motility proteins, Ca²⁺-signaling networks, mitochondrial bioenergetics, antioxidant defenses, membrane-associated pathways, and proteins involved in sperm–oocyte interaction. These signatures may improve mechanistic patient stratification and support the development of biomarker panels linked to clinically relevant endpoints. Nevertheless, routine implementation remains limited by methodological heterogeneity, inadequate standardization, small study populations, and insufficient prospective validation. Integrating proteomic signatures with redox, inflammatory, clinical, and reproductive outcome data may facilitate the transition from descriptive semen assessment and empirical treatment toward mechanism-based precision andrology. Full article

Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare and very aggressive pediatric myelodysplastic/myeloproliferative neoplasm with molecular heterogeneity and constitutive activation of the RAS signaling pathway. The aim of this study was to identify the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic targets of mutations that affect receptor tyrosine kinases (RTKs) and RAS pathways in JMML. Methods: We collected tumor and matched buccal swab samples from 35 patients with JMML and performed whole-exome sequencing. Variants were called using GATK-Mutect2 and annotated with ANNOVAR. Mutational profiling, co-occurrence analysis, protein domain mapping, and driver gene identification were performed using maftools and OncodriveCLUST. DGIdb was used to explore drug–gene interactions, MutationalPatterns was used for the characterization of mutational signatures, and the clusterProfiler package was used for the functional enrichment analyses. Results: Alteration of the RTK-RAS pathway was found in 77.1% of patients. PTPN11 (23%), NRAS (20%), and KRAS (14%) were the most frequently altered genes, followed by PTEN (11%) and FLT3, ROS1, FGFR4, ERBB2, and EGFR (9% each). Domain mapping of protein sequences identified the grouping of mutations within the conserved functional domains of the proteins. The alterations in receptor tyrosine kinase genes demonstrated a significant degree of co-occurrence, while the alterations in canonical JMML genes showed mutual exclusivity. PTPN11, NRAS, ROS1, and FGFR4 were top driver genes based on driver gene analysis. Functional enrichment analysis revealed significant enrichment of receptor tyrosine kinase signaling, Ras/MAPK and PI3K-AKT pathways. The mutational signatures were mostly SBS5-like, with enrichment of C>T transitions, indicative of endogenous mutational processes. Drug–gene interaction analysis identified EGFR, ALK, ROS1, ERBB2, FLT3, FGFR4, and PDGFRA as highly interconnected and potentially actionable therapeutic targets. Conclusions: These findings expand the molecular landscape of JMML and underscore the importance of aberrant RTK-RAS signaling in disease pathogenesis. The identification of recurrent and potentially druggable RTK alterations provides a rationale for future precision medicine approaches in JMML. Full article

Cancer progression and therapeutic resistance are shaped by reciprocal dynamic interactions between malignant cells and the metabolically altered tumor microenvironment (TME). Tumor-associated hypoxia, glucose and amino acid competition, extracellular acidity, lactate accumulation, adenosine, prostaglandin E2 (PGE2) and other metabolic signals can remodel immune cell function and determine whether inflammation is tumoricidal or tumor-supportive. Although B lymphocytes have traditionally been viewed as antibody-producing cells, tumor-infiltrating B (TIL-B) cells comprise functionally heterogeneous populations that can act as antigen-presenting cells, cytokine and chemokine producers, antibody-secreting cells, cytotoxic effectors, regulatory B cells (Bregs) and organizers of tertiary lymphoid structures (TLSs). Their functional state is strongly influenced by the metabolic and spatial context in which they reside. This review focuses on the intersection of B cell biology and tumor immunometabolism, emphasizing how hypoxia, lactate, nutrient limitation, adenosine, PGE2, kynurenine and B cell-derived γ-aminobutyric acid (GABA) may shape B cell states and their interactions with myeloid and lymphoid cells. We discuss how metabolically conditioned Bregs and immunoglobulin (Ig)A-skewed humoral responses can contribute to immune suppression, whereas metabolically competent antigen-presenting, IgG-biased and TLS-associated B cell responses may support effective anti-tumor immunity. Importantly, the effects are tumor type- and context-dependent: B cell/TLS signatures are associated with favorable outcomes in several breast, lung and other solid tumors, whereas B cell-centered immune landscapes can be suppressed or neutral in pancreatic cancer and IgA-dominated responses may be unfavorable in selected malignancies. We further examine how these states may influence sensitivity or resistance to immune checkpoint blockade, chemotherapy, radiotherapy and cellular therapies. Finally, we highlight B cell metabolic pathways as potential therapeutic entry points and identify priorities for spatial metabolomics and prospective interventional studies. Full article

Background/Objectives: Pleural and peritoneal mesothelioma (PL and PE) are aggressive diseases, accounting for 68.0–92.4% and 6.9–24.1% of all cases. To improve both diagnosis and management of these patients, a deeper knowledge and characterization of the molecular background are necessary. Although molecular profiling of PL has been largely investigated in recent years, much less is known about the genomic landscape of PE, due to its rarity. Here, we aim to compare gene expression profiling of pleural and peritoneal mesothelioma to underline main differences and to identify new potential histotype-specific biomarkers. Methods: We performed a gene expression analysis of 32 epithelioid PL and 21 epithelioid PE cases, diagnosed from 2017 to 2023 at the University Hospital of Pisa, using an nCounter custom panel including 117 target genes known for their crucial role in cancer. Results: PE, compared to PL, showed different expression levels of genes related to extracellular matrix modification (ECM), as collagen alteration, pro-inflammatory and angiogenic response (mediated by NF-κB). In detail, in PE we observed a significant upregulation of metalloproteinase-1 (MMP1), E-selectin (SELE), pappalysin-1 (PAPPA), estrogen receptor-2 (ESR2) and transportin-2 (TNPO2); and a downregulation of pyruvate kinase (PKM). Furthermore, BAP1 loss was associated with distinct gene deregulation in PE and PL; the only exception was ASS1 upregulation, which was observed in both histologies. These insights may help refine the utility of BAP1 as a biomarker. Conclusions: Deregulated genes in PE deserve further investigation as potential biomarkers, according to their biological role. In fact, MMPs and PAPPA impact migration ability and angiogenic response of mesothelioma, while PKM and ESR2 are usually investigated for their involvement in reprogramming of energy metabolism. The identification of histotype-specific biomarkers is warranted to improve mesothelioma management. Full article

The hypothalamus is a central regulator of systemic energy balance and glucose homeostasis, yet how type 2 diabetes (T2D) alters its cellular and regulatory landscape remains incompletely understood. Here, we integrated single-nucleus RNA sequencing (snRNA-seq) with bulk ATAC-seq to characterize hypothalamic remodeling in an HFD/STZ-induced T2D mouse model. High-resolution snRNA-seq revealed pronounced cell type-specific alterations involving several neuronal subpopulations, including Gal.Nts.Npy, Nxph4.Adcyap1, and Lmx1a.Gpr149.Tcf4 neurons, together with substantial changes in oligodendrocyte-lineage cells. Increased Npy expression was accompanied by greater tissue-level chromatin accessibility at the Npy locus, providing convergent evidence for activation of the hypothalamic Npy regulatory axis. Pseudotime analysis further showed increased representation of a transcriptionally distinct Cntnap2-positive oligodendrocyte-lineage state, together with reduced representation of canonical myelination-associated states. Ligand–receptor analysis predicted reduced signaling across selected neuron–oligodendrocyte interactions and altered communication among glial populations. Collectively, these findings reveal coordinated neuronal, oligodendrocyte-lineage, intercellular signaling, and chromatin-accessibility alterations in the diabetic hypothalamus, and identify the Npy regulatory axis and Cntnap2-positive oligodendrocyte-lineage state as candidate features for further mechanistic investigation. Full article

Therapeutic failure in esophageal squamous cell carcinoma (ESCC) can arise as tumor cells and their microenvironment adapt to sustained treatment pressure. The lactate–lactylation axis may connect altered metabolism with adaptive treatment responses through changes in protein and chromatin regulation. However, how this axis contributes to therapeutic adaptation in ESCC and how its mechanistic evidence should be interpreted across different biological contexts remain incompletely defined. Here, we review lactate sources, the regulatory landscape of lysine lactylation, and emerging evidence linking this axis to heterogeneous treatment responses in ESCC. Studies in ESCC implicate several lactylation-related processes in therapeutic adaptation. These include poly(ADP-ribose) polymerase 1 (PARP1) K654 lactylation in DNA damage responses, signal transducer and activator of transcription 3 (STAT3) K631 and nudix hydrolase 21 (NUDT21) K23 lactylation in programmed cell death susceptibility, and the NIPA-like domain containing 1 (NIPAL1)–histone H3 lysine 18 lactylation(H3K18la) and hypoxia-inducible factor 1α (HIF-1α) K172la axes in immune microenvironment remodeling. The strength of evidence differs across individual mechanisms. Several site-specific lactylation events have been identified in ESCC models or patient-derived specimens and supported by functional validation, whereas the role of lactylation-associated pathways in predicting immunotherapy response requires further clinical investigation. Therefore, the lactate–lactylation axis is best viewed as an emerging metabolic–epigenetic network that connects cellular metabolic states with adaptive treatment phenotypes rather than as a universal resistance mechanism. Integrating longitudinal clinical cohorts, multi-omics profiling, and mechanistic studies will be critical for defining how lactate–lactylation signatures may support patient stratification and precision therapeutic strategies in ESCC. Full article

The Natura 2000 site “Bosco Pantano di Policoro e Costa Ionica Foce Sinni” (SPA/SCI IT9220055), located along the Ionian Arc, is one of the remaining areas in Southern Italy characterized by the coexistence of a lowland forest and coastal dune habitats. The interaction between coastal dynamics and hydrological processes generates high environmental heterogeneity, supporting a complex habitat mosaic. The aim of this study is to document the vegetation composition and characterize the plant landscape of the coastal belt, assessing habitat conservation status and impact of the main pressures and threats. To this end, phytosociological analyses and vegetation transects were employed to identify the plant communities and describe their distribution along the sea–inland gradient. Floristic and structural diversity were assessed using the Shannon, Simpson, and HDUNE indices. The results highlight the high environmental heterogeneity of the study area and the occurrence of numerous habitat types of Community interest. The analyses also identified the main pressures affecting the area, particularly coastal erosion and alterations to the hydrological regime, causing the simplification of the vegetation mosaic. These processes represent the main conservation concerns for the reserve’s habitats and underline the need for management strategies aimed at maintaining hydrological balance and the natural dynamics of dune systems. Full article

Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma arising from smooth muscle cells. It has a high metastatic potential and limited therapeutic options. Despite advances in oncology, the molecular landscape of LMS remains incompletely understood, particularly regarding the genetic and epigenetic alterations that affect key signaling pathways. This review summarizes the current knowledge of mechanisms driving LMS pathogenesis, including somatic mutations in genes such as TP53 and RB1, chromosomal instability, dysfunction of DNA damage response and repair, aberrant DNA methylation, histone modifications, and non-coding RNAs. Emerging treatment strategies include inhibitors of PI3K/AKT/mTOR and CDK4/6 signaling, epigenetic drugs, immunotherapy, and combinations of these approaches. However, the coexistence of multiple genetic abnormalities complicates diagnosis, prognosis, and therapeutic selection. Companion diagnostic tools that test candidate therapies ex vivo or in vitro may help exclude potentially ineffective targeted treatments. Full article

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders driven mainly by somatic mutations in JAK2, CALR or MPL, but their clinical phenotype is also shaped by chronic inflammation, immune dysregulation, vascular complications and microenvironmental remodeling. Emerging evidence suggests that the gut microbiota may contribute to this inflammatory and immunometabolic landscape; however, the current literature remains heterogeneous and its translational relevance is still insufficiently defined. This critical narrative review maps the available evidence linking the gut microbiota, microbial metabolites and systemic microbial signatures to MPN biology. We distinguish direct human MPN data from indirect mechanistic evidence derived from studies of intestinal barrier dysfunction, thrombo-inflammation, hematopoietic regulation, allogeneic hematopoietic cell transplantation and infection risk. Across human MPN cohorts, the most consistent findings are not uniform changes in global microbial diversity, but rather alterations in specific immunoregulatory taxa, particularly reduced Firmicutes/Faecalibacterium-related communities and dysbiotic signatures associated with JAK2V617F status. Mechanistically, dysbiosis and impaired intestinal barrier integrity may facilitate low-grade endotoxemia, TLR4/NF-κB activation, cytokine amplification, endothelial activation and platelet priming. In parallel, microbial metabolites may influence hematopoietic stem cell programs, the bone marrow niche, megakaryopoiesis and thrombopoiesis. Treatment exposure and diet are relevant modifiers of the microbiota–inflammation axis, although available interventional data remain preliminary. Mendelian randomization and multi-omics studies provide hypothesis-generating evidence for microbiota–metabolome–MPN interactions, but require longitudinal validation, functional studies and contamination-aware analytical pipelines, especially for low-biomass blood and bone marrow samples. Microbiota-targeted strategies, including nutritional interventions and fecal or washed microbiota transplantation, represent promising but still investigational approaches, particularly in immunocompromised or post-transplant settings. Future studies should integrate microbiome, metabolome, genome, proteome, inflammatory biomarkers and clinical outcomes while controlling for diet, antibiotics, treatment exposure and driver mutation status. Such an approach may clarify whether the microbiota is a biomarker, mediator or therapeutic target in MPNs. Full article

Genetic alterations are closely associated with prostate cancer development and progression, but the RNA-derived transcriptional allele landscape of prostate cancer and cancer stem cells (CSCs) remains poorly understood. To characterize cancer-associated transcriptional alleles, we analyzed bulk and single-cell RNA sequencing (RNA-seq) data from primary human prostate cancer cells and their matched benign epithelial cells from non-cancerous regions of the same patients. Sequencing reads were aligned to the human reference genome (hg38) using STAR, and sequence variants were annotated with ANNOVAR. Most detected transcriptional alleles were located in noncoding regions, particularly within 3′ and 5′ untranslated regions, with single-nucleotide variants predominating and C>T substitutions occurring most frequently. Comparison of cancer and matched benign samples identified 223 genes carrying cancer-associated transcriptional alleles consistently detected across three independent patients. Seven of these genes showed differential expression between CSC and non-CSC populations, while 19 contained non-synonymous alleles, including 11 that are predicted to have potentially damaging effects. We identified ATF6 and KDM3A as candidate genes of potential functional interest. Single-cell RNA-seq analyses revealed differences in the number and distribution of detected transcriptional alleles between culture conditions, with 2D cancer cultures detecting more total, coding, and non-synonymous alleles than CSC-enriched 3D spheroids. CSC populations also exhibited fewer detected transcriptional alleles than non-CSC populations. Our findings provide a framework for characterizing transcriptional allele heterogeneity within the prostate cancer cellular hierarchy and identify candidate CSC-associated alterations for further investigation and functional validation. Finally, the cancer–benign matched strategy used in this study provides additional molecular evidence supporting the malignant origin of the tumor-derived cancer cells. Full article

Cutaneous melanoma remains a global health challenge. Although BRAF/MEK-targeted therapies and immune checkpoint inhibitors (ICIs) have improved outcomes in advanced disease, durable responses remain difficult to achieve for most patients. Therapeutic resistance represents the central barrier to long-term disease control. This review comprehensively examines the molecular and immunologic mechanisms underlying melanoma resistance and integrates these insights with emerging pharmaceutical strategies designed to overcome them. We explore the genetic landscape of melanoma, including oncogenic alterations in BRAF, NRAS, NF1, CDKN2A, and PTEN, and explain how dysregulation of the MAPK and PI3K/AKT/mTOR signaling axes drives therapeutic escape. Phenotypic plasticity is discussed as a critical epigenetic driver of drug tolerance. The tumor microenvironment (TME) is examined as an active co-conspirator in resistance, encompassing immunosuppressive cell populations, cancer-associated fibroblasts, and metabolic competition. Resistance mechanisms to targeted therapy, including MAPK reactivation, bypass signaling, transcriptional reprogramming, and metabolic rewiring, are reviewed alongside tumor-intrinsic and tumor-extrinsic mechanisms of ICI resistance. Emerging therapeutic strategies are surveyed, including next-generation RAF and ERK inhibitors, dual-pathway blockade, and metabolic therapies targeting oxidative phosphorylation. Innovations in molecular imaging, liquid biopsy, and artificial intelligence-driven biomarker discovery are highlighted as pivotal tools for real-time resistance monitoring and adaptive treatment. By linking mechanistic insights with translational advances, this review advocates for combination strategies and adaptive clinical frameworks to achieve more durable disease control in melanoma. Full article

Cervical, ovarian, and endometrial cancers comprise biologically distinct malignancies with substantial heterogeneity in their molecular alterations, metabolic dependencies, immune landscapes, and therapeutic responses. Despite advances in surgery, chemotherapy, radiotherapy, targeted therapies, and immunotherapy, these cancers remain major causes of cancer-related morbidity and mortality worldwide. Signal Transducer and Activator of Transcription 3 (STAT3) is frequently activated in these tumor types, where its biological and clinical relevance varies according to disease context, histological subtype, and molecular characteristics. In addition to tumor-intrinsic functions regulating proliferation, survival, angiogenesis, and stemness, STAT3 participates in dynamic interactions between malignant cells and the tumor microenvironment (TME), integrating inflammatory, metabolic, and stromal signals. Persistent STAT3 activation has been associated with immunosuppressive changes involving macrophage polarization, myeloid-derived suppressor cell expansion, dendritic cell dysfunction, regulatory T-cell accumulation, and impaired cytotoxic lymphocyte activity, although the extent and mechanisms of these effects differ among tumor types and experimental contexts. Metabolic alterations, including enhanced glycolysis, lactate accumulation, and hypoxia, may further interact with STAT3-dependent signaling and influence communication between tumor and stromal or immune compartments. In this review, we examine STAT3 as a signaling node linking tumor metabolism with immune regulation in cervical, ovarian, and endometrial cancers, while emphasizing disease- and subtype-specific differences. We summarize current evidence on STAT3-mediated tumor–microenvironment communication and discuss emerging STAT3-targeted therapeutic strategies. Finally, we highlight challenges related to biological heterogeneity, the lack of validated predictive biomarkers, and patient stratification that currently limit the clinical translation of STAT3-directed approaches. Full article