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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.

The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting in an increased assembly of paraspeckles foci both in vitro and in human skin tissues. RNA-seq analysis associated with global DNA binding profile (ChIRP-seq) revealed that NEAT1 associates with the promoter of key epithelial transcription factors sustaining their expression during epidermal differentiation. These molecular events might explain the inability of NEAT1-depleted keratinocytes to undergo the proper formation of epidermal layers. Collectively, these data uncover the lncRNA NEAT1 as an additional player of the intricate network orchestrating epidermal morphogenesis. The transcription factor ΔNp63 is a master regulator of epithelial development and integrity of stratified epithelial tissues. Here, the authors unveiled the lncRNA NEAT1 as an additional player of the highly complex regulatory network by which ΔNp63 controls epidermal homeostasis.

The growing incidence of breast cancer over time suggests that environmental factors might contribute to the underlying causes of the disease. Mercury, a toxic metal classified as a Substance of Very High Concern, accumulates in the body through contaminated food, air, water, and soil, raising concerns about its role in tumor biology. The main aim of this study was to identify the possible associations between in situ mercury bioaccumulation and the molecular features of breast cancer. To achieve this, a total of 26 breast cancer cases were analyzed using an integrated approach that combined DNA and RNA sequencing, histological analysis, and inductively coupled plasma mass spectrometry (ICP-MS) to assess mercury bioaccumulation. Mercury was detected in 72% of the cases. A significant positive correlation was found between mercury bioaccumulation and CXCR4 expression in breast cancer tissues. Bioinformatic analysis further revealed that CXCR4 expression was significantly higher in metastatic tissues compared to primary tumors. These findings suggest that mercury accumulation may influence tumor biology through the CXCR4-CXCL12 signaling pathway, highlighting a potential mechanism by which mercury contributes to breast cancer progression.

Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole‐genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan‐Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine‐learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning. Since the publication of The Cancer Genome Atlas data in 2013, the advances in the sequencing techniques allowed us to study cancer through whole‐genome sequencing and multiomics approaches. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine learning approaches will be the next step towards personalized approaches for cancer medicine.

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.

Breast cancer is the second leading cause of cancer-related deaths among women, largely due to the progression of a significant fraction of primary tumours to the metastatic stage. Here, we show that zinc-finger protein 750 (ZNF750) opposes the migration and invasion of breast cancer cells by repressing a prometastatic transcriptional programme, which includes genes involved in focal adhesion and extracellular matrix interactions, such as LAMB3 and CTNNAL1. Mechanistically, ZNF750 recruits the epigenetic modifiers KDM1A and HDAC1 to the promoter regions of LAMB3 and CTNNAL1, influencing histone marks and transactivating these genomic sites. Gene expression analysis in cancer patient datasets indicated that ZNF750 and its targets were negative prognostic factors in breast cancer. Together, our findings shed light on the molecular mechanism by which ZNF750 regulates cell migration and invasion, suggesting a role in breast cancer metastasis.

Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell–cell and cell–matrix adhesion programmes. However, limited knowledge exists on the relevant cell–cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell–cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell–cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.

Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to the acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain‐of‐function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to the acquisition of the lethal phenotype. Here, by integrating a p53R270H‐dependent transcriptomic analysis with chromatin accessibility (ATAC‐seq) profiling, we shed light on the molecular basis of a p53 mutant‐dependent drug‐tolerant phenotype in pancreatic cancer. p53R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates in phenotypic evolution of the cancer. We specifically focused on the p53R270H‐dependent regulation of the tyrosine kinase receptor macrophage‐stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53R270H‐dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of the evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in the acquisition of a lethal phenotype by fine‐tuning the chromatin landscape. This study reports that chromatin accessibility is influenced by p53 mutants at the genomic site of macrophage stimulating 1 receptor (a key player of PDAC chemoresistance), promoting the transcription of the gene. This molecular axis influences drug resistance phenotype in PDAC cell lines, and it is a negative prognostic factor in patients. Thus, our work suggests that interaction between genetic and epigenetic events underlies the basis of PDAC evolution.

Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and triggers further liver fibrosis and even cirrhosis. Emerging macrophage-targeting strategies have shown efficacy in both preclinical and clinical studies. Increasing evidence indicates that metabolic rewiring provides substrates for epigenetic modification, which endows monocytes/macrophages with prolonged “innate immune memory”. Therefore, it is reasonable to conceive novel therapeutic strategies for metabolically reprogramming macrophages and thus mediate a homeostatic or reparative process for hepatic inflammation management and liver regeneration.

The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow “real-time” understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.