Biomedical subjects

Margherita Maioli

Publications and source records attributed to Margherita Maioli.

5 recordsLinked to original sources

PubMed2026

Circulating IGF2BP3 enables risk stratification and predicts treatment response in Ewing sarcoma.

Ewing sarcoma (EWS), the second most common pediatric bone tumor, presents with a markedly heterogeneous clinical spectrum and optimal risk stratification is therefore crucial for improving treatment outcomes. The RNA-binding protein IGF2BP3 is a critical oncogenic driver of EWS malignancy. This study evaluates the clinical utility of circulating IGF2BP3 as a biomarker to predict treatment response and risk of disease progression in patients with EWS. Plasma samples from 60 patients with EWS diagnosed and treated at the IRCCS Rizzoli Orthopedic Institute (Bologna, Italy) were collected at diagnosis before treatment initiation and/or after induction chemotherapy. For 51 of these patients, blood was collected at diagnosis, prior to any treatments. For 25 patients, blood samples were available at diagnosis and before surgical intervention, allowing longitudinal analysis in the same patient. For 9 patients, blood was collected only after preoperative chemotherapy, before surgical intervention. Circulating IGF2BP3 levels were quantified using a highly specific and sensitive ELISA assay. Plasma samples from healthy donors served as controls. IGF2BP3 plasma levels were correlated with IGF2BP3 tumor tissue expression, established clinical risk factors, and cumulative incidence of relapse using univariable and multivariable analyses. Plasma IGF2BP3 levels were significantly elevated in patients with EWS compared with healthy controls, with a subset of patients (22/51, 43.2%) exhibiting clinically relevant concentrations. Circulating IGF2BP3 levels reflected tumor expression of the molecule and provided additional prognostic information beyond standard clinicopathologic features. The prognostic impact of circulating IGF2BP3 was primarily observed in patients with localized disease, in whom elevated levels were identified as a significant adverse prognostic factor for disease-specific survival (hazard ratio, 10.63; 95% CI, 1.27-88.62; P = 0.029). Longitudinal monitoring demonstrated that persistence of IGF2BP3 in plasma after induction chemotherapy was a strong predictor of poor clinical outcomes. Circulating IGF2BP3 represents a valuable biomarker for early risk stratification in EWS, particularly in patients with localized disease. Although this is single-marker assay, the expression of the molecule may impact on the fate of many mRNAs. We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.

Humans↗

PubMed2004

Turning on stem cell cardiogenesis with extremely low frequency magnetic fields.

Modulation of stem cell differentiation is an important assignment for cellular engineering. Embryonic stem (ES) cells can differentiate into cardiomyocytes, but the efficiency is typically low. Here, we show that exposure of mouse ES cells to extremely low frequency magnetic fields triggered the expression of GATA-4 and Nkx-2.5, acting as cardiac lineage-promoting genes in different animal species, including humans. Magnetic fields also enhanced prodynorphin gene expression, and the synthesis and secretion of dynorphin B, an endorphin playing a major role in cardiogenesis. These effects occurred at the transcriptional level and ultimately ensued into a remarkable increase in the yield of ES-derived cardiomyocytes. These results demonstrate the potential use of magnetic fields for modifying the gene program of cardiac differentiation in ES cells without the aid of gene transfer technologies and may pave the way for novel approaches in tissue engineering and cell therapy.

Cell Differentiation↗

PubMed2004

Butyric and retinoic mixed ester of hyaluronan. A novel differentiating glycoconjugate affording a high throughput of cardiogenesis in embryonic stem cells.

Embryonic stem (ES) cells can differentiate into specialized cells, including cardiac myocytes, but the efficiency is typically low and the process is incompletely understood. Achieving a high throughput of cardiogenesis from pluripotent cells is therefore a major requirement for future approaches in cardiac cell therapy. Here, we developed a novel ester of hyaluronan linked to both butyric and retinoic acid (HBR), coaxing pluripotent ES cells into a cardiogenic decision. In mouse ES cells, HBR remarkably increased the expression of GATA-4 and Nkx-2.5, acting as cardiac lineage-promoting genes in different animal species, including humans. HBR also enhanced prodynorphin gene expression and the synthesis and secretion of dynorphin B, an endorphin playing a major role in ES cell cardiogenesis. These effects occurred at the transcriptional level. HBR also primed the expression of cardiac-specific transcripts and highly enhanced the yield of spontaneously beating ES-derived cardiomyocytes. These results demonstrate the potential for chemically modifying the gene program of cardiac differentiation in ES cells without the aid of gene transfer technologies and may pave the way for novel approaches in tissue engineering and myocardial regeneration.

Animals↗

PubMed2003

Protein kinase C signaling transduces endorphin-primed cardiogenesis in GTR1 embryonic stem cells.

The prodynorphin gene and its product, dynorphin B, have been found to promote cardiogenesis in embryonic cells by inducing the expression of GATA-4 and Nkx-2.5, two transcription factor-encoding genes essential for cardiogenesis. The molecular mechanism(s) underlying endorphin-induced cardiogenesis remain unknown. In the present study, we found that GTR1 embryonic stem (ES) cells expressed cell surface kappa opioid receptors, as well as protein kinase C (PKC)-alpha, -beta1, -beta2, -delta, -epsilon, and -zeta. Cardiac differentiation was associated with a marked increase in the Bmax value for a selective opioid receptor ligand and complex subcellular redistribution of selected PKC isozymes. PKC-alpha, -beta1, -beta2, -delta, and -epsilon all increased in the nucleus of ES-derived cardiac myocytes, compared with nuclei from undifferentiated cells. In both groups of cells, PKC-delta and -epsilon were mainly expressed at the nuclear level. The nuclear increase of PKC-alpha, -beta1, and -beta2 was due to a translocation from the cytosolic compartment. In contrast, the increase of both PKC-delta and PKC-epsilon in the nucleus of ES-derived cardiomyocytes occurred independently of enzyme translocation, suggesting changes in isozyme turnover and/or gene expression during cardiogenesis. No change in PKC-zeta expression was observed during cardiac differentiation. Opioid receptor antagonists prevented the nuclear increase of PKC-alpha, PKC-beta1, and PKC-beta2 and reduced cardiomyocyte yield but failed to affect the nuclear increase in PKC-delta and -epsilon. PKC inhibitors prevented the expression of cardiogenic genes and dynorphin B in ES cells and abolished their development into beating cardiomyocytes.

Animals↗

PubMed2003

Dynorphin B is an agonist of nuclear opioid receptors coupling nuclear protein kinase C activation to the transcription of cardiogenic genes in GTR1 embryonic stem cells.

The cardiac differentiation of embryonic stem (ES) cells was found to involve prodynorphin gene and dynorphin B expression and was associated with the interaction of secreted dynorphin B with cell surface opioid receptors coupled with protein kinase C (PKC) signaling and complex subcellular redistribution patterning of selected PKC isozymes. Here, confocal microscopy revealed the presence of immunoreactive dynorphin B-like material in GTR1 ES cells, suggesting that dynorphin peptides may also act intracellularly. Opioid binding sites were identified in ES cell nuclei, with a single dissociation constant in the low nanomolar range. A significant increase in Bmax for a kappa opioid receptor ligand was observed in nuclei isolated from ES-derived cardiomyocytes compared with nuclei from undifferentiated cells. Direct exposure of nuclei isolated from undifferentiated ES cells to dynorphin B or U-50,488H, a synthetic kappa opioid receptor agonist, time- and dose-dependently activated the transcription of GATA-4 and Nkx-2.5, 2 cardiac lineage-promoting genes. Nuclear exposure to dynorphin B also enhanced the rate of prodynorphin gene transcription. These responses were abolished in a stereospecific fashion by the incubation of isolated nuclei with selective opioid receptor antagonists. Nuclei isolated from undifferentiated cells were able to phosphorylate the acrylodan-labeled MARCKS peptide, a high-affinity fluorescent PKC substrate. Exposure of isolated nuclei to dynorphin B induced a remarkable increase in nuclear PKC activity, which was suppressed by opioid receptor antagonists. Nuclear treatment with PKC inhibitors abolished the capability of dynorphin B to prime the transcription of cardiogenic genes.

Animals↗