👤 Eduardo Soriano

Core 1 biomarkers, such as amyloid positron emission tomography, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core 1 biomarkers remains unclear. The goal of this study was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD. Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts. The Core 1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGSs in both populations. The Core 1 PGSs show improved predictive value for AD-related plasma biomarkers and early cognitive changes. APOE ε4 explained more variance in plasma p-tau217 than in plasma p-tau181. PGSs based on Core 1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in non-Hispanic White and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. While the variance in p-tau181 and p-tau217 explained by individual Core 1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core 1 biomarkers may provide an opportunity for developing an integrative Core 1 PGS that more effectively predicts plasma p-tau181 and p-tau217 levels than AD-based PGS. Show less

Tofacitinib, a Janus kinase inhibitor, has been associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). This study evaluated tofacitinib's effects on lipid parameters and the impact of prior biological agents' therapy in RA patients. Thirty female RA patients starting tofacitinib were assessed at baseline and after 3 months. Clinical assessments, health assessment questionnaire (HAQ), disease activity score 28 (DAS28), inflammatory markers, lipid profile, oxidized low-density lipoprotein (LDL), activities of paraoxonase 1 (PON 1), lipoprotein-associated phospholipase A After 3 months, HAQ and DAS28 scores improved significantly. Total cholesterol (TC), HDL-C, non-HDL-C, and HDL capacity to acquire free cholesterol from TGRL increased, while enzyme activities and cholesterol efflux capacity remained unchanged. At baseline, patients with prior biological therapy (n = 19) had lower triglycerides, TC, non-HDL-C, and apolipoprotein (apo) B compared to biologic-naïve patients (n = 11). This group exhibited no lipid changes after tofacitinib, whereas biologic-naïve patients showed atherogenic increases in TC, LDL-C, non-HDL-C, apo B, Lp-PLA Tofacitinib improved disease activity and functional status in RA patients with minimal lipid changes. Patients previously treated with biological agents experienced no significant lipid alterations, while biologic-naïve patients showed atherogenic lipid changes and increased PON 1 activity. Prior biologic therapy may confer a more favorable CV profile before and after tofacitinib treatment. Show less

Clonal mature B-cell lymphoproliferative disorders (B-LPDs) are a heterogeneous group of neoplasia characterized by the proliferation of mature B lymphocytes in the peripheral blood, bone marrow and/or lymphoid tissues. B-LPDs classification into different subtypes and their diagnosis is based on a multiparametric approach. However, accurate diagnosis may be challenging, especially in cases of ambiguous interpretation. Multiparameter flow cytometry (MFC) represents an extensively used technique to detect the presence of different cellular lines in immunology and hematology. MFC results provide an essential contribution to the B-LPDs diagnostic process, even more so considering that panels are constantly integrating novel markers to improve diagnostic accuracy. The aim was to evaluate the contributing role of MFC routinary studies by analyzing the expression and the mean fluorescence intensity (MFI) of CD200, ROR1, and CD43 in various B-LPDs to evaluate their usefulness in the differential diagnosis of these diseases. We retrospectively evaluated 2615 consecutive cases of newly collected samples (mostly from patients with lymphocytosis) analyzed by MFC carried out in the B-LPD diagnostic process referred to the Division of Hematology of the Sapienza University of Rome. We compared the results of CD200, ROR1, and CD43 expression percentage and their MFI between different subtypes of B-LPDs. In chronic lymphocytic leukemia (CLL), CD200, ROR1, and CD43 were always expressed with bright intensity. CLL samples presented high CD200 expression and MFI [CD200%, mean: 100 (range, 24-100); positivity rate: 100%; MFI, median = 125 (range, 10-1200)] statistically higher than mantle cell lymphoma (MCL) (p<0.001), which is usually negative for CD200, and variant hairy cell leukemia (vHCL, according to 2022 ICC) (p<0.001), but comparable with classic HCL (cHCL) (p>0.9). ROR1 resulted expressed in all CLL [ROR1%, mean: 100 (range, 52-100), positivity rate: 100%; MFI, median=50 (range, 10-202)] and MCL cases with comparable MFI (p>0.9). CD43 expression and MFI were significantly higher in CLL [CD43%, mean 99 (range, 59-100); positivity rate: 100%; MFI, median = 130 (range, 41-980)] than in MCL, vHCL, cHCL, and all the others mature B-cell neoplasia (p<0.001). CD200 and CD43 expression and MFI were significantly higher in cHCL compared to vHCL. Among the other mature B-cell neoplasia, CD200 was variably expressed in follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma (LPL). ROR1 and CD43 presented a very low expression percentage in this latter group, being mostly negative. Persistent polyclonal B-cell lymphocytosis (PPBL) resulted in uniformly positive for CD200 and negative for ROR1 and CD43. Our data suggest that evaluating CD200, ROR1, and CD43 antigens and their intensity of expression, along with commonly used markers in MFC routine panels for B-LPDs, might be extremely useful for prompt diagnostic evaluation in the differential diagnosis of these diseases. Show less

The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes. Show less

The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Show less

The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Show less

Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the Show less

To explore the pathophysiology of proliferative verrucous leucoplakia (PVL) through a methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) case-control study. Oral biopsies from ten PVL patients and five healthy individuals were obtained and used to compare their epigenetic patterns. Network biology methods and integrative analyses of MeDIP-seq and RNAseq data were applied to investigate functional relations among differentially methylated genes (DMGs). The value of selected genes as malignant biomarkers was evaluated in a large cohort of oral squamous cell carcinoma (OSCC) patients from TCGA. A total of 4647 differentially methylated regions were found, with a prominent state of hypermethylation in PVL patients. At the gene level, differentially methylated regions (DMRs) covered 826 genes with distinct roles, including transcription factors and binding proteins with functions in cell adhesion, migration, proliferation, regulation of transcription, bone morphogenesis, and cell signalling. Network analysis revealed three major hubs, two of them collecting proteins related to the response of the patients to PVL and treatment and one hub collecting proteins related to PVL and cancer. The integrative analysis revealed 8 genes (ARTN, CD8A, GATA3, HOXD10, MYO7A, OSR2, PLCB1, and SPOCK2) significantly upregulated in PVL compared to control and 5 genes (ANKRD6, DLG2, GPX3, PITX2, and ZNF736) significantly downregulated. The status of de-regulation found for PVL patients was concordant with what was found for OSCC samples compared to normal adjacent tissue. Our findings show the potential of methylation markers in PVL and suggest novel OSCC diagnostic biomarkers which may boost the development of novel epigenetic-based therapies. Show less

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells. Show less

Lingo-1 (also known as Lern1) is a component of the Nogo receptor complex that mediates intracellular signaling in response to myelin associated inhibitors (MAIs): NogoA, MAG, and Omgp. Signaling through Nogo receptor extends to more than its well known role in preventing axon regeneration after lesion in the CNS, being implicated in neuronal functional maturation. Using Lingo-1-deficient mice, it has been demonstrated that Lingo-1 plays relevant roles in oligodendrocyte differentiation during brain development, and that treatment with Lingo-1 antagonists can improve axon regeneration after lesion in adult mice by decreasing MAI mediated signaling. However, a detailed description of the pattern of expression of Lingo-1 protein in correlation with the other partners of Nogo receptor is missing. Here, we show that components of the Nogo receptor complex, Lingo-1, NgR1, p75, and TROY coexist in mouse brain in a defined time window only at later postnatal stages. We have also determined the Lingo-1 distribution showing expression in particular subsets of neurons, but not in myelinating mature oligodendrocytes. Surprisingly, Lingo-1 is expressed at early developmental stages without NgR1, which supports the notion that Lingo-1 may participate in other activities in developing neurons different from oligodendrocyte maturation or axon extension inhibition in the adult. Finally, we propose that the intracellular domain of Lingo-1 contributes to signaling and show that it interacts with the postmitotic neuronal specific zinc finger protein Myt1l, suggesting that Lingo-1 may regulate Myt1l transcription factor activity by affecting its subcellular localization. Show less