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In 2022, the number of foodborne outbreaks in Europe increased by 43.9%, highlighting the need to improve surveillance systems and design outbreak predictive tools. This review aims to assess the scientific literature describing wastewater surveillance to monitor foodborne pathogens in association with clinical data. In the selected studies, the relationship between peaks of pathogen concentration in wastewater and reported clinical cases is described. Moreover, details on analytical methods to detect and quantify pathogens as well as wastewater sampling procedures are discussed. Few papers show a statistically significant correlation between high concentrations of foodborne pathogens in wastewater and the occurrence of clinical cases. However, monitoring pathogen concentration in wastewater looks like a promising and cost-effective strategy to improve foodborne outbreak surveillance. Such a strategy can be articulated in three steps, where the first one is testing wastewater with an untargeted method, like shotgun metagenomic, to detect microorganisms belonging to different domains. The second consists of testing wastewater with a targeted method, such as quantitative polymerase chain reaction, to quantify those specific pathogens that in the metagenomic dataset display an increasing trend or exceed baseline concentration thresholds. The third involves the integrated wastewater and clinical data analysis and modeling to find meaningful epidemiological correlations and make predictions.

In the PRIMA project ArtiSaneFood, the microbiological parameters of several artisanal cheeses produced in the Mediterranean area have been quantified. In this pilot study, we selected four of these artisanal cheese products from Italy, Portugal, Spain, and Morocco to investigate and compare their microbiomes in terms of taxonomy composition, presence of reads of foodborne pathogens, as well as virulence and antimicrobial resistance genes. Lactococcus, Streptococcus and Lactobacillus were the most represented genera in the Portuguese and Spanish cheeses, Streptococcus in the Italian cheese, and Enterococcus, Klebsiella, Escherichia, and Citrobacter in the Moroccan products. The correlation analysis indicated a negative association between the abundance of some lactic acid bacteria (i.e., Lactococcus, Lactobacillus, Streptococcus, and Leuconostoc) and foodborne pathogenic genera, like Escherichia and Salmonella. The analysis of pathogen abundance, virulence factors, and antimicrobial resistance genes showed a strong clusterization based on the cheese type, confirming that the presence of potential human health risk determinants was higher in the artisanal products derived from unpasteurized milk that underwent spontaneous fermentation.

Abstract FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis.

Traditional heat treatments in the dairy industry are known for their high water and energy consumption, and more economically and environmentally friendly solutions are being sought. Infrared (IR) technology offers advantages in energy efficiency and environmental sustainability; however, its effectiveness in milk processing, particularly in pathogen inactivation, remains relatively unexplored. In this study, homogenized raw milk was subjected to IR treatment, and its impact on Listeria monocytogenes, Salmonella spp., and Enterobacteriaceae was assessed. Results indicate that the IR treatment effectively reduces the microbial load, achieving levels of inactivation comparable to conventional pasteurization methods (around 6 Log10 CFU/mL). Moreover, the treatment maintains milk pH levels, suggesting minimal alteration to its composition. Further research is needed to explore the full extent of IR treatment on milk sanitation efficacy, deeply exploring IR technology to fully assess its applicability and integration into dairy processing practices. Despite regulatory challenges, the Wir System Milk shows promise as a cost-effective and eco-friendly alternative for raw milk treatment.

Dry-aged meat is gaining popularity among food business operators and private consumers. The process is carried out in aerobic conditions by hanging beef carcasses or placing subprimal or primal cuts in a dedicated cabinet for several weeks or even months while controlling the environment through the management of process parameters such as temperature, relative humidity, and airflow. In this review, we present a critical evaluation of the literature to evaluate tools to manage the process to guarantee food safety and identify critical control points, as well as good hygienic and manufacturing practices. In controlled aging conditions, only Listeria monocytogenes and Yersinia enterocolitica can multiply, while a reduction in the number of Salmonella spp. and Escherichia coli O157:H7 is generally reported. Enterobacteriaceae usually decrease on the surface of the meat during maturation; thus, for the purpose of the hygienic evaluation of the production process, a count no higher than that of unmatured meat is expected. Besides, various studies report that the total bacterial count and the spoilage microorganisms significantly increase on the surface of the meat, up to 5-6 Log CFU/g in the absence of visible spoilage. Bacteria of the Pseudomonas genus tend to progressively replace other microorganisms during maturation; thus, the total mesophilic or psychrophilic bacterial load is not a good indicator of process hygiene for matured meat. Critical parameters for the control of the process are temperature, relative humidity, and ventilation, which should be monitored during the process. For this reason, equipment designed and certified for dry aging must be used, and the manufacturer must validate the process. Food business operators must apply general good manufacturing practices (GMP) and good hygiene practices (GHP) for meat processing and some GMP and GHP specific for dry aging. Several research needs were identified, among them the evolution of the populations of L. monocytogenes and Y. enterocolitica and the microbiology of the inner parts of the dry-aged meat.

In this pilot study, we compared the metagenomic profiles of different types of artisanal fermented meat products collected in Italy, Greece, Portugal, and Morocco to investigate their taxonomic profile, also in relation to the presence of foodborne pathogens and antimicrobial resistance genes. In addition, technical replicates of the same biological sample were tested to estimate the reproducibility of shotgun metagenomics. The taxonomic analysis showed a high level of variability between different fermented meat products at both the phylum and genus levels. Staphylococcus aureus was identified with the highest abundance in Italian fermented meat; Escherichia coli in fermented meat from Morocco; Salmonella enterica in fermented meat from Greece; Klebsiella pneumoniae and Yersinia enterocolitica in fermented meat from Portugal. The fungi Aspergillus, Neosartoria, Emericella, Penicillum and Debaryomyces showed a negative correlation with Lactococcus, Enterococcus, Streptococcus, Leuconostoc and Lactobacillus. The resistome analysis indicated that genes conferring resistance to aminoglycoside, macrolide, and tetracycline were widely spread in all the samples. Our results showed that the reproducibility between technical replicates tested by shotgun metagenomic was very high under the same conditions of analysis (either DNA extraction, library preparation, sequencing analysis, and bioinformatic analysis), considering both the degree of overlapping and the pairwise correlation.

ABSTRACT: This systematic review aimed to compile the available body of knowledge about microbiome-related nutritional interventions contributing to improve the chicken health and having an impact on the reduction of colonization by foodborne pathogens in the gut. Original research articles published between 2012 and 2022 were systematically searched in Scopus and PubMed. A total of 1,948 articles were retrieved and 140 fulfilled the inclusion criteria. Overall, 73 papers described 99 interventions against colonization by Escherichia coli and related organisms; 10 papers described 15 interventions against Campylobacter spp.; 36 papers described 54 interventions against Salmonella; 40 papers described 54 interventions against Clostridium perfringens. A total of 197 microbiome-related interventions were identified as effective against one or more of the listed pathogens and included probiotics (n = 80), prebiotics (n = 23), phytobiotics (n = 25), synbiotics (n = 12), organic acids (n = 12), enzymes (n = 4), essential oils (n = 14) and combination of these (n = 27). The identified interventions were mostly administered in the feed (173/197) or through oral gavage (11/197), in the drinking water (7/197), in ovo (2/197), intra amniotic (2/197), in fresh or reused litter (1/197) or both in the feed and water (1/197). The interventions enhanced the beneficial microbial communities in the broiler gut as Lactic acid bacteria, mostly Lactobacillus spp., or modulated multiple microbial populations. The mechanisms promoting the fighting against colonization by foodborne pathogens included competitive exclusion, production of short chain fatty acids, decrease of gut pH, restoration of the microbiome after dysbiosis events, promotion of a more stable microbial ecology, expression of genes improving the integrity of intestinal mucosa, enhancing of mucin production and improvement of host immune response. All the studies extracted from the literature described in vivo trials but performed on a limited number of animals under experimental settings. Moreover, they detailed the effect of the intervention on the chicken gut without details on further impact on poultry meat safety.

Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.

Abstract Background Arginine is an essential amino acid for chickens and feeding diets with arginine beyond the recommended levels has been shown to influence the growth performance of broiler chickens in a positive way. Nonetheless, further research is required to understand how arginine supplementation above the widely adopted dosages affects metabolism and intestinal health of broilers. Therefore, this study was designed to assess the effects of arginine supplementation (i.e., total arginine to total lysine ratio of 1.20 instead of 1.06–1.08 recommended by the breeding company) on growth performance of broiler chickens and to explore its impacts on the hepatic and blood metabolic profiles, as well as on the intestinal microbiota. For this purpose, 630 one-day-old male Ross 308 broiler chicks were assigned to 2 treatments (7 replicates each) fed a control diet or a crystalline L-arginine-supplemented diet for 49 d. Results Compared to control birds, those supplemented with arginine performed significantly better exhibiting greater final body weight at D49 (3778 vs. 3937 g; P

Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.

Dry-aging is a process during which meat is stored within maturation chambers at low temperatures and low relative humidity, resulting in improved tenderness and flavor development. The cuts are exposed to the atmosphere by hanging them or setting them on racks in the maturation chamber without any protective packaging. Animals and humans are usually the major sources of bacterial food contamination in the meat industry, but other routes might be involved. Therefore, procedures to reduce or eliminate pathogens from surfaces are crucial for an effective hazard analysis critical control point program in the food industry and other environments. This study aimed to assess the survival of Listeria monocytogenes, Escherichia coli, Salmonella spp., and Staphylococcus aureus on the inner surface of dry aging chambers. Moreover, we tested the efficacy of alkaline electrolyzed water (REW) for its eventual application within a procedure aimed at reducing foodborne pathogens during meat storage. Environmental conditions inside the dry aging cabinet determine a reduction of circa 3 log CFU/cm2 of the considered microorganisms on the inner surface in 24 hours. Additionally, the nebulization of alkaline electrolyzed water with the smoking system increased the count reduction in 24 hours due to environmental conditions for L. monocytogenes (~1 log CFU/cm2) and for S. aureus (~2 log CFU/cm2). In this context, the use of REW can be justified for routine cleaning procedures of the surfaces, with the added value of being safe to handle, not containing environmental pollutants, and making it unnecessary to rinse surfaces due to its instability.

The capacity of utilising a single cell protein (SCP) ingredient coming from Corynebacterium glutamicum was assessed on adult grey mullet (Mugil cephalus) reared in captive conditions. The experiment was carried out using triplicate groups of grey mullet of 68 g average initial body weight. Three diets, SCP0, SCP10 and SCP20 with increasing inclusion of SCP (0%, 10% and 20%) in substitution of soybean, poultry and fish meal were formulated to contain 30% protein, 10% fat and 18.5 Mj/kg feed of digestible energy. After 113 days, fish fed SCP diets presented significantly lower growth performance and a significant lower activity of the alkaline proteases and aminopeptidases compared to fish fed diet without SCP inclusion. Gut microbiota appeared modulated by SCP inclusion being dominated at the phylum level by Fusobacteria in fish fed SCP0 (51.1%), while in fish fed SCP10 (67.3%) and SCP20 (53.2%) Proteobacteria was dominant. Data evinces a deficiency in the protein utilisation as a cause of the poor growth performance in fish fed the SCP diets. A hypothesis has been proposed that an incomplete SCP cell-wall lysis accounts for this outcome because of the particular organisation of the digestive system of grey mullet (which lack of an acidic stomach digestion) and the failing in the development of a functional gizzard (no access to sand in captive conditions). Even though the outcomes of this research were quite unexpected, they will improve our knowledge on the digestive system of flathead grey mullet and provide some theoretical basis for an improved development of low FM and SBM aquafeed for the species.

Nowadays functional ingredients have a significant potential for improving current low fish meal (FM) aquafeed formulation in sustaining growth and enhancing animal robustness for Mediterranean aquaculture. Among them, nucleotides (NT) and nucleic acids (NA) drew attention for their application in the last two decades. NT are organic molecules involved in many life-supporting pathways, and are the building blocks of NA, which stand as genetic repositories. NT are naturally present in organic ingredients, and among them FM is known to be one of the highest NT sources. When this NT source is seriously limited, fish might be under the minimum NT requirements, especially in fast growing life stages of carnivorous species. Hence, a trial on European sea bass juveniles was carried out, testing two dietary FM levels (FM10, FM20 as 10% and 20% FM, respectively) supplemented with 500 mg kg-1 yeast-originate NT or NA dose over 80 days. Thereafter, fish were exposed to one week of sub-optimal thermal and dissolved oxygen condition (30°C and 4.0 mg/L O2) to further explore the effect of NT and NA inclusion on immune response and gut microbiome alteration. At the end of the growth period NT increased feed intake at both FM dietary levels. FM20 combined with NA and NT further improved growth performance, enhancing lipid efficiency and increased anti-inflammatory TGF-β. After sub-optimal environmental conditions both NT and NA exerted prebiotic functions on gut microbiome by promoting beneficial lactic acid bacteria such as Weissella and Leuconostoc. At the same time NT in 10% FM diet increased the abundance of Bacillus taxon. In conclusion, the combination of NT/NA included at 500 mg kg-1 was able to promote growth when included in 20% FM level, assuming higher nutritional NT requirement when combined with 10% FM. On the other hand, NT/NA added in 10% FM upregulate proinflammatory IL-1β and favor beneficial gut bacterial taxa.

Little attention has been paid to the biological role of arginine and its dietary supplementation in broilers under heat stress (HS) conditions. Therefore, the main aim of this study was to assess the response of broilers to arginine supplementation and cyclic HS, with a focus on liver, pectoral muscle, and blood metabolic profiles and the cecal microbiota. Day-old male Ross 308 broilers (n = 240) were placed in 2 rooms with 12 pens each for a 44-day trial. Pens were assigned to one of two groups (6 pens/group/room): the control group (CON) was given a basal diet in mash form and the treated group (ARG) was fed CON diet supplemented with crystalline L-arginine. The total arginine:lysine ratio of CON diet ranged between 1.02 and 1.07, while that of ARG diet was 1.20. One room was constantly kept at thermoneutral (TN) conditions, while the birds in the other room were kept at TN conditions until D34 and subjected to cyclic HS from D35 onwards (∼34°C; 9:00 A.M.–6:00 P.M.). Blood, liver, Pectoralis major muscle, and cecal content were taken from 2 birds per pen (12 birds/group/room) for metabolomics and microbiota analysis. Growth performance data were also collected on a pen basis. Arginine supplementation failed to reduce the adverse effects of HS on growth performance. Supplemented birds showed increased levels of arginine and creatine in plasma, liver, and P. major and methionine in liver, and reduced levels of glutamine in plasma, liver, and P. major. HS altered bioenergetic processes (increased levels of AMP and reduced levels of fumarate, succinate, and UDP), protein metabolism (increased protein breakdown to supply the liver with amino acids for energy production), and promoted the accumulation of antioxidant and protective molecules (histidine-containing dipeptides, beta-alanine, and choline), especially in P. major. Arginine supplementation may have partially counterbalanced the effects of HS on energy homeostasis by increasing creatine levels and attenuating the increase in AMP levels, particularly in P. major. It also significantly reduced cecal observed diversity, while HS increased alpha diversity indices and affected beta diversity. Results of taxonomic analysis at the phylum and family level are also provided.

T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL involving the malignant expansion of T-cell progenitors. It is driven by a number of different possible genetic lesions, including mutations in genes encoding for ribosomal proteins (RPs). These are structural constituents of ribosomes, ubiquitous effectors of protein synthesis. Albeit the R98S mutation in RPL10, recurring with a higher frequency among RP mutations, has been extensively studied, less is known about the contribution of mutations occurring in other RPs. Alterations affecting translational machinery may not be well tolerated by cells, and there may be a selective pressure that determines the emergence of mutations with a compensatory effect. To explore this hypothesis, we sequenced the exomes of a cohort of 37 pediatric patients affected by T-ALL, and analyzed them to explore the co-occurrence of mutations in genes involved in ribosome biogenesis (including RPs) and translational control, and in known T-ALL driver genes. We found that some of the mutations in these sub-classes of genes tend to cluster together in different patients, indicating that their co-occurrence may confer some kind of advantage to leukemia cells. In addition, our sequencing highlighted the presence of a novel mutation in RPL10, namely the Q123R, which we found associated with a defect in protein synthesis. Our findings indicate that genetic alterations involving ribosome biogenesis and translational control should be carefully considered in the context of precision medicine in T-ALL.

Listeria monocytogenes is an ubiquitous pathogen isolated from different host species including fish, crustaceans, and molluscs, but it is rarely a pathogenic microorganism to marine reptiles. In particular, only two cases of fatal disseminated listeriosis have been described in the loggerhead sea turtle (Caretta caretta). In this study, we describe a lethal case of L. monocytogenes infection in a loggerhead sea turtle. The turtle was found alive, stranded on a beach in North-eastern Italy, but perished soon after being rescued. The autoptic examination revealed that heart, lung, liver, spleen, and urinary bladder were disseminated with multiple, firm, 0.1–0.5 mm sized, nodular, white-green lesions. Microscopically, these lesions corresponded with heterophilic granulomas with Gram+ bacteria within the necrotic center. Furthermore, the Ziehl–Neelsen stain was negative for acid-fast organisms. Colonies isolated from heart and liver were tested through MALDI-TOF for species identification, revealing the presence of L. monocytogenes. Whole Genome Sequencing on L. monocytogenes isolates was performed and the subsequent in silico genotyping revealed the belonging to Sequence Type 6 (ST 6); the virulence profile was evaluated, showing the presence of pathogenicity islands commonly observed in ST 6. Our results further confirm that L. monocytogenes should be posed in differential diagnosis in case of nodular lesions of loggerhead sea turtles; thus, given the zoonotic potential of the microorganism, animals should be treated with particular caution. In addition, wildlife animals can play an active role as carriers of possibly pathogenetic and virulent strains and contribute to the distribution of L. monocytogenes in the environment.

Fermented goat milk is an artisanal beverage with excellent nutritional properties. There are limited data on its physicochemical properties, fatty acids, phenolic acids, and on any insight on microbiota. The aim of this research was to conduct a pilot study to compare these parameters in raw cow and goat milk before and after spontaneous fermentation in a clay pot and glass container at 37 °C for 24 h. Both types of milk and fermentation containers significantly affected the pH, acidity, proximate composition, viscosity, and whiteness index of fermented milks. A total of 17 fatty acids were identified in fermented milks, where palmitic, stearic, and myristic were the main saturated acids, and oleic and linoleic acids were the main unsaturated ones. These profiles were primarily influenced by the type of raw milk used. Three to five phenolic acids were identified in fermented milks, where quinic acid was the major phenolic compound, and salviolinic acid was identified only in raw goat milk. Preliminary metataxonomic sequencing analysis showed that the genera Escherichia spp. and Streptococcus spp. were part of the microbiota of both fermented milks, with the first genus being the most abundant in fermented goat milk, and Streptococcus in cow’s milk. Moreover, Escherichia abundance was negatively correlated with the abundance of many genera, including Lactobacillus. Overall, the results of this pilot study showed significant variations between the physicochemical properties, the fatty and phenolic acids, and the microbial communities of goat and cow fermented milk, showing the opportunity to further investigate the tested parameters in fermented goat milk to promote its production.

BackgroundSDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent. Here we sought to evaluate the presence and prevalence of SDHA variants in the germline lineage in a population of SDHA-deficient GIST.MethodsGermline SDHA status was assessed by Sanger sequencing on a series of 14 patients with gastric SDHA-deficient GIST.ResultsAll patients carried a germline SDHA pathogenic variant, ranging from truncating, missense, or splicing variants. The second hit was the loss of the wild-type allele or an additional somatic mutation. One-third of the patients were over 50 years old. GIST was the only disease presentation in all cases except one, with no personal or familial cancer history. Seven metastatic cases received a multimodal treatment integrating surgery, loco-regional and medical therapy. The mean follow-up time was of 10 years, confirming the indolent clinical course of the disease.ConclusionSDHA germline variants are highly frequent in SDHA-deficient GIST, and the disease may occur also in older adulthood. Genetic testing and surveillance of SDHA-mutation carriers and relatives should be performed.

Primary cardiac sarcomas are considered rare malignant entities associated with poor prognosis. In fact, knowledge regarding their gene signature and possible treatments is still limited. In our study, whole-transcriptome sequencing on formalin-fixed paraffin-embedded (FFPE) samples from one cardiac osteosarcoma and one cardiac leiomyosarcoma was performed, to investigate their mutational profiles and to highlight differences and/or similarities to other cardiac histotypes. Both cases have been deeply detailed from a pathological point of view. The osteosarcoma sample presented mutations involving ATRX, ERCC5, and COL1A1, while the leiomyosarcoma case showed EXT2, DNM2, and PSIP1 alterations. Altered genes, along with the most differentially expressed genes in the leiomyosarcoma or osteosarcoma sample versus the cardiac angiosarcomas and intimal sarcomas (e.g., YAF2, PAK5, and CRABP1), appeared to be associated with cell growth, proliferation, apoptosis, and the repair of DNA damage, which are key mechanisms involved in tumorigenesis. Moreover, a distinct gene expression profile was detected in the osteosarcoma sample when compared to other cardiac sarcomas. For instance, WIF1, a marker of osteoblastic differentiation, was upregulated in our bone tumor. These findings pave the way for further studies on these entities, in order to identify targeted therapies and, therefore, improve patients’ prognoses.

The Serum Response Factor (SRF) is a transcription factor that regulates the expression of a wide set of genes involved in cell proliferation, migration, cytoskeletal organization and myogenesis. Accumulating evidence suggests that SRF may play a role in carcinogenesis and tumor progression in various neoplasms, where it is often involved in different fusion events. Here we investigated SRF rearrangements in soft tissue tumors, along with a gene expression profile analysis to gain insight into the oncogenic mechanism driven by SRF fusion. Whole transcriptome analysis of cell lines transiently overexpressing the SRF::E2F1 chimeric transcript uncovered the specific gene expression profile driven by the aberrant gene fusion, including overexpression of SRF-dependent target genes and of signatures related to myogenic commitment, inflammation and immune activation. This result was confirmed by the analysis of two cases of myoepitheliomas harboring SRF::E2F1 fusion with respect to EWSR1-fusion positive tumors. The recognition of the specific gene signature driven by SRF rearrangement in soft tissue tumors could aid the molecular classification of this rare tumor entity and support therapeutic decisions.