👤 David Martino

In this study, we applied microarray, bioinformatics, and qRT-PCR techniques to identify miRNAs and their target genes in plasma obtained from acute ischemic stroke patients and matching controls. Microarray analyses were performed with 24-h acute ischemic stroke vs. healthy individuals and CV-risk factors matched control group plasma samples. Statistical analysis of gene expression was performed using TAC and R, with a focus on robust methods suitable for the small sample size, and miRNA target prediction was conducted using a previously established in-house wizbionet R package. Top non-coding regulators of ischemia (miR-18a-5p, miR-4467, miR-199a-5p and miR-3135b) and their predicted target genes (ANKRD12, HIF1A, GNAI2, GRIN1) were detected via qRT-PCR. 146 upregulated and 258 downregulated differentially expressed RNAs were detected by microarray analysis. Using the multiMiR R package for target prediction, 67 upregulated and 125 downregulated mRNAs were mapped. Functional enrichment analysis revealed that upregulated miRNAs were associated with pathways like BDNF and IL-2 signaling, while downregulated miRNAs were linked to neurodevelopmental and NGF pathways. MiR-18a-5p and miR-199a-5p were significantly elevated in stroke patients at both day 1 and day 7 compared to healthy individuals and CV-matched controls ( Our integrated miRNA/mRNA analysis identified distinct molecular signatures in acute ischemic stroke, with 146 upregulated and 258 downregulated RNAs, implicating key neuroinflammatory and neuroprotective pathways, including BDNF, IL-2, and NGF signaling. Among the validated candidates, miR-199a-5p, miR-3135b, miR-4467, and miR-18a-5p demonstrated diagnostic potential, while miR-4467, together with GNAI2 and HIF1A, showed post-stroke dynamic relevance, reflecting early transcriptomic adaptations following ischemic injury. [Image: see text] The online version contains supplementary material available at 10.1186/s12920-025-02302-5. Show less

Chia (Salvia hispanica L.) is a functional food that can help control the metabolic changes caused by unbalanced diets. The aim of this study was to investigate the effects of chia flour (CF) and chia oil (CO) on satiety, inflammation, and antioxidant potential in the brain of rats fed a high-fat high-fructose diet (HFHF). Male Wistar rats were divided into two groups: AIN-93M (n = 8) and HFHF (n = 24) for 8 wk. Subsequently, HFHF-fed animals were subdivided (n = 8) into: HFHF, HFHF+CF, and HFHF+CO for 10 wk. Gene expression of satiety and inflammation-related proteins was analyzed by RT-qPCR; leptin and adiponectin levels were quantified by ELISA; and antioxidant potential was assessed via SOD and CAT activity. In silico analysis was performed using molecular docking, and the correlations were evaluated via Pearson's analyses. The HFHF+CO group showed higher POMC/CART gene expression, as well as reduced leptin levels compared to the HFHF+CF and AIN-93M groups. Both chia flour and oil reduced NPY, LEP-r, and NF-κB gene expressions compared to the HFHF group. The HFHF+CF group showed increased Nrf2 gene expression compared to the HFHF group. All main phenolic acids found in chia flour showed good interactions with the analyzed markers LEP-r, MC4R, and NPY-Y1. Main positive correlations were observed beteween adiponectin and SOD, phenolics consumption and ALA, MC4R and NPY, NPY and AgRP, and AgRP and MC4R. Thus, this study highlights chia flour and oil as potential modulators of satiety and inflammatory response in the brain, in addition to reinforcing the antioxidant effect of flour. Show less

Ischemic stroke is a severe medical condition characterized by diminished blood flow to the brain, resulting in a shortage of oxygen and nutrients. During ischemia, neurons surrounding the cerebral infarct initiate macroautophagy. However, the implications of this activation for neuronal cell survival are still debated. The identification of new autophagy modulators could aid in understanding autophagy's role in brain ischemia and lay the groundwork for innovative therapeutic strategies aimed at minimizing brain damage in this life-threatening neurological emergency. In this study, we developed a robust and sensitive screening platform to identify autophagy modulators from a library of bioactive compounds. Selected compounds underwent further Show less

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia. It is caused by loss-of-function variants in the genes encoding the lipoprotein lipase (LPL) enzyme and its cofactors, which severely impair the hydrolysis of triglycerides (TG). Its main complication is represented by acute pancreatitis (AP), a potentially life-threatening condition. Conventional TG-lowering therapies are poorly effective in FCS, thus requiring the search of novel treatments. Lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), has demonstrated efficacy in reducing TG levels in FCS. However, it is associated with hepatic side effects, namely liver fat accumulation. Here we present a case study of a 71-year-old female patient with genetically confirmed FCS, baseline TG level of 2300 mg/dL (25.97 mmol/L) and a history of AP, who was treated with lomitapide for almost 5 years. The treatment allowed a marked reduction of TG (about 90%) and no recurrence of AP. However, hepatic monitoring during treatment revealed a progressive worsening of liver fat accumulation as detected by magnetic resonance imaging (MRI), which was associated with pronounced increases in liver transaminases and liver stiffness (up to 15 kPa). Due to these hepatic adverse events, it was decided to discontinue therapy with lomitapide. An MRI scan repeated after 70 days of drug withdrawal revealed complete resolution of fatty liver disease associated with normalization of liver stiffness (4.1 kPa) and liver transaminases. This case demonstrates the reversibility of lomitapide-induced fatty liver and underscores the importance of regular monitoring of the liver safety during lomitapide to guide timely interventions. Show less

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling, including depletion of PUFAs from the phospholipids, phosphatidylserine, and phosphatidylethanolamine. These lipidomic alterations were accompanied by an increase induction of inflammatory and stimulator of interferon genes (STING)-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated patient-derived-AML survival; however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death. Show less

Bladder cancer (BC) is the tenth most common cancer, with urothelial carcinoma representing about 90% of all BC, including neoplasms and carcinomas of different grades of malignancy. Urinary cytology has a significant role in BC screening and surveillance, although it has a low detection rate and high dependence on the pathologist's experience. The currently available biomarkers are not implemented into routine clinical practice due to high costs or low sensitivity. In recent years, the role of lncRNAs in BC has emerged, even though it is still poorly explored. We have previously shown that the lncRNAs Metallophosphoesterase Domain-Containing 2 Antisense RNA 1 (MPPED2-AS1), Rhabdomyosarcoma-2 Associated Transcript (RMST), Kelch-like protein 14 antisense (Klhl14AS) and Prader Willi/Angelman region RNA 5 (PAR5) are involved in the progression of different types of cancers. Here, we investigated the expression of these molecules in BC, first by interrogating the GEPIA database and observing a different distribution of expression levels between normal and cancer specimens. We then measured them in a cohort of neoplastic bladder lesions, either benign or malignant, from patients with suspicion of BC undergoing transurethral resection of bladder tumor (TURBT). The total RNA from biopsies was analyzed using qRT-PCR for the expression of the four lncRNA genes, showing differential expression of the investigated lncRNAs between normal tissue, benign lesions and cancers. In conclusion, the data reported here highlight the involvement of novel lncRNAs in BC development, whose altered expression could potentially affect the regulatory circuits in which these molecules are involved. Our study paves the way for testing lncRNA genes as markers for BC diagnosis and/or follow-up. Show less

Glioblastoma (GBM) is the most aggressive and lethal neoplasia of the central nervous system in adults. Based on the molecular signature genes, GBM has been classified in proneural, neural, mesenchymal and classical subtypes. The Metallophosphoesterase-domain-containing protein 2 ( Show less

Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. We sought to investigate genetic susceptibility to PA. Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10 This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression. Show less

Through microarray analyses, we identified the Mpped2 gene as differentially expressed in two neuroblastoma cell lines induced to differentiation with all-trans retinoic acid. Mpped2 codes for a new metallophosphodiesterase protein, the expression of which inhibits cell proliferation and soft agar colony formation in SH -SY5Y cells. This inhibition is concomitant to an increased proportion of the cells in G0/G1 phase and enhanced caspase 3 activation, effects not seen for the other phosphodiesterases. A Mpped2-null mutation (H67R) abrogates these functions, which indicates that the biochemical activity of Mpped2 is advantageous for cancer suppression. Expression analyses in the "Los Angeles" and "Essen" neuroblastoma gene-array data sets show that increased expression of Mpped2 is associated with good patient prognosis according to Kaplan-Meier analyses. Tumorigenic assays in mice show that overexpression of Mpped2 improves survival rate, substantially impairs tumor growth and induces neuronal differentiation. Altogether, these data show that Mpped2 expression impairs neuroblastoma tumorigenesis, and they establish a basis for future therapeutic applications. Show less