132 research outputs found
Phenotypic and functional characterization of endothelial progenitor cells isolated from peripheral blood of renal cell carcinoma patients
Endothelial progenitor cells (EPCs) are mobilized from either bone marrow or
arterial walls to restore blood perfusion to ischemic organs and establish the vascular
network within growing tumors [1]. The Ca2+ machinery plays a key role in EPC
activation and might serve a molecular target for novel therapies of highly angiogenic
tumors, such as renal cell carcinoma (RCC) [1]. The Ca2+ toolkit is remodelled in
EPCs isolated from RCC patients (RCC-EPCs) as respect to healthy donors [2]. The
present study was undertaken to evaluate for the first time the functional properties
of EPCs isolated from tumor patients by focusing on RCC-EPCs. We extended our
analysis at microscopic level by monitoring the sub-cellular structure of RCC-EPCs
relative to their Ca2+ signalling fingerprint. Our results showed a striking functional
and ultrastructural difference between RCC-EPCs and their normal counterparts,
which might be the basis for designing novel, more specific anti-angiogenic treatments
HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation
Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor
prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class
I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine
(G)/taxol (T) doublet chemotherapy treatment.
Methods: Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28
PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis,
clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic
mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting
dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative
stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing
PDAC cells.
Results: We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly
used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through
the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers
the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation
and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing
proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of
FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostatinducing
oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid
cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression
with poor progression free survival in PDAC chemotherapy-treated patients
Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance
Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a
devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus
cetuximab (CX) is one of the standard first-line treatments in this disease. However, this
therapeutic regimen is often associated with high toxicity and resistance, suggesting that
new combinatorial strategies are needed to improve its therapeutic index. In our study,
we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic
agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet
in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in
HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to
equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and
pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different
3D-self-assembled spheroid models, suggesting the ability of the combined approach
to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced
DNA damage in combination treatment by reducing the mRNA expression of ERCC
Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular
concentration via upregulation at transcriptional level of CDDP influx channel copper
transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export.
Valproic acid also induced a dose-dependent downregulation of epidermal growth factor
receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways
and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known
mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription
of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also
in vivo in both heterotopic and orthotopic models, demonstrating that the combined
treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall,
the introduction of a safe and generic drug such as VPA into the conventional treatment
for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants
further clinical evaluation. A phase II clinical trial exploring the combination of VPA and
CDDP/CX in R/M HNSCC patients is currently ongoing in our institute
Sexual Dysfunction in People with Multiple Sclerosis: The Role of Disease Severity, Illness Perception, and Depression
Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS
Phenotypic and functional characterization of endothelial progenitor cells isolated from peripheral blood of renal cell carcinoma patients
Endothelial progenitor cells (EPCs) are mobilized from either bone marrow or arterial walls to restore blood perfusion to ischemic organs and establish the vascular network within growing tumors [1]. The Ca2+ machinery plays a key role in EPC activation and might serve a molecular target for novel therapies of highly angiogenic tumors, such as renal cell carcinoma (RCC) [1]. The Ca2+ toolkit is remodelled in EPCs isolated from RCC patients (RCC-EPCs) as respect to healthy donors [2]. The present study was undertaken to evaluate for the first time the functional properties of EPCs isolated from tumor patients by focusing on RCC-EPCs. We extended our analysis at microscopic level by monitoring the sub-cellular structure of RCC-EPCs relative to their Ca2+ signalling fingerprint. Our results showed a striking functional and ultrastructural difference between RCC-EPCs and their normal counterparts, which might be the basis for designing novel, more specific anti-angiogenic treatments
COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context
Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon
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