Publications by authors named "Giulia Piaggio"

72 Publications

Reduction of Cell Proliferation by Acute CHO Exposure.

Cancers (Basel) 2021 Oct 5;13(19). Epub 2021 Oct 5.

Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

Endogenous acetaldehyde production from the metabolism of ingested alcohol exposes hematopoietic progenitor cells to increased genotoxic risk. To develop possible therapeutic strategies to prevent or reverse alcohol abuse effects, it would be critical to determine the temporal progression of acute ethanol toxicity on progenitor cell numbers and proliferative status. We followed the variation of the cell proliferation rate in bone marrow and spleen in response to acute ethanol intoxication in the MITO-Luc mouse, in which NF-Y-dependent cell proliferation can be assessed in vivo by non-invasive bioluminescent imaging. One week after ethanol administration, bioluminescent signals in bone marrow and spleen decreased below the level corresponding to physiological proliferation, and they progressively resumed to pre-treatment values in approximately 4 weeks. Boosting acetaldehyde catabolism by administration of an aldehyde dehydrogenase activity activator or administration of polyphenols with antioxidant activity partially restored bone marrow cells' physiological proliferation. These results indicate that in this mouse model, bioluminescent alteration reflects the reduction of the physiological proliferation rate of bone marrow progenitor cells due to the toxic effect of aldehydes generated by alcohol oxidation. In summary, this study presents a novel view of the impact of acute alcohol intake on bone marrow cell proliferation in vivo.
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http://dx.doi.org/10.3390/cancers13194999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508324PMC
October 2021

Long-Term Persistence and Relevant Therapeutic Impact of High-Titer Viral-Neutralizing Antibody in a Convalescent COVID-19 Plasma Super-Donor: A Case Report.

Front Immunol 2021 23;12:690322. Epub 2021 Aug 23.

Department of Research, Technological Innovation & Advanced Diagnostics, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.

A convalescent, non-severe, patient with COVID-19 was enrolled as a hyper-immune plasma voluntary donor by the Immuno-Hematology and Transfusion Unit of the Regina Elena National Cancer Institute in Rome, under the TSUNAMI national study criteria. During a nearly 6-month period (May-October 2020), the patient was closely monitored and underwent four hyperimmune plasma collections. Serum SARS-CoV-2 (anti-S + anti-N) IgG and IgM, anti-S1 IgA, and neutralizing titers (NTs) were measured. Anti-SARS-CoV-2 antibody levels steadily decreased. No correlation was found between anti-S/anti-N IgG and IgM levels and viral NT, measured by either a microneutralization test or the surrogate RBD/ACE2-binding inhibition test. Conversely, NTs directly correlated with anti-S1 IgA levels. Hyperimmune donor plasma, administered to five SARS-CoV-2 patients with persistent, severe COVID-19 symptoms, induced short-term clinical and pathological improvement. Reported data suggest that high NTs can persist longer than expected, thus widening hyperimmune plasma source, availability, and potential use. RBD/ACE2-binding inhibition test is confirmed as a convenient surrogate index for neutralizing activity and patients' follow-up, suitable for clinical settings where biosafety level 3 facilities are not available. IgA levels may correlate with serum neutralizing activity and represent a further independent index for patient evaluation.
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http://dx.doi.org/10.3389/fimmu.2021.690322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419417PMC
September 2021

The diagnostic applicability of A-type Lamin in non-muscle invasive bladder cancer.

Ann Diagn Pathol 2021 Oct 17;54:151808. Epub 2021 Aug 17.

Laboratory of Proteins Engineering and Bioactive Molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia. Electronic address:

Purpose: Lamin A is a major component of the nuclear lamina maintaining nuclear integrity, regulation of gene expression, cell proliferation, and apoptosis. Its deregulation in cancer has been recently reported to be associated with its prognosis. However, its clinical significance in non-muscle invasive bladder cancer (NMIBC) remains to be defined.

Material/methods: Immunohistochemical staining and RT-qPCR were performed to screen the expression patterns of Lamin A/C protein and Lamin A mRNA respectively in 58 high and low grade NMIBC specimens.

Results: Lamin A/C protein was expressed only in the nucleus and less exhibited in NMIBC tissues compared to non-tumoral ones. On the other side, Lamin A mRNA was up-regulated in NMIBC compared to controls. Nevertheless, both expression patterns (protein and mRNA) were not correlated to clinical prognosis factors and were not able to predict the overall survival of patients with high-grade NMIBC.

Conclusions: The deregulation of A-type Lamin is not associated with the prognosis of NMIBC, but it could serve as a diagnostic biomarker distinguishing NMIBC patients from healthy subjects suggesting its involvement as an initiator event of tumorigenesis in our cohort.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151808DOI Listing
October 2021

Lower response to BNT162b2 vaccine in patients with myelofibrosis compared to polycythemia vera and essential thrombocythemia.

J Hematol Oncol 2021 07 29;14(1):119. Epub 2021 Jul 29.

Hematology Unit, Department of Research and Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

In a population of 42 Philadelphia negative myeloproliferative neoplasm patients, all on systemic active treatment, the likelihood of responding to anti-SARS-CoV-2 BNT162b2 vaccine at 2 weeks after the second dose was significantly lower in the ten patients with myelofibrosis compared to the 32 with essential thrombocythemia (n = 17) and polycythemia vera (n = 15) grouped together, both in terms of neutralizing anti-SARS-CoV-2 IgG titers and seroprotection rates (32.47 AU/mL vs 217.97 AU/mL, p = 0.003 and 60% vs 93.8%, p = 0.021, respectively). Ruxolitinib, which was the ongoing treatment in five patients with myelofibrosis and three with polycythemia vera, may be implicated in reducing vaccine immunogenicity (p = 0.076), though large prospective study is needed to address this issue.
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http://dx.doi.org/10.1186/s13045-021-01130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319901PMC
July 2021

Neutrophil extracellular traps in cancer: not only catching microbes.

J Exp Clin Cancer Res 2021 Jul 14;40(1):231. Epub 2021 Jul 14.

SAFU Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.

Neutrophils are the most abundant type of white blood cells circulating throughout the bloodstream and are often considered the frontline defenders in innate immunity. However, neutrophils are increasingly being recognized as having an important role in tumorigenesis and carcinogenesis due to their aberrant activation by molecules released into the tumor microenvironment. One defensive response of neutrophils that is aberrantly triggered during the neoplastic process is called NETosis, where activated neutrophils expel their DNA and intracellular contents in a web-like structure known as a neutrophil extracellular trap (NET). In cancer, NETosis has been linked to increased disease progression, metastasis, and complications such as venous thromboembolism. NET structures released by neutrophils can also serve as a scaffold for clot formation, shining new light on the role of neutrophils and NETosis in coagulation-mediated diseases.Here, we review current available knowledge regarding NET and the related NETosis process in cancer patients, with an emphasis on pre-clinical and clinical data fostering the identification and validation of biomarkers of NET with a predictive/prognostic role in cancer patients treated with immunotherapy agents. NETosis biomarkers, e.g., citH3, may integrate correlates of immunogenicity currently available (e.g., PD-L1 expression, TMB, TILs) and help select the subsets of patients who may most benefit from the use of the therapeutic weapons under discussion.
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http://dx.doi.org/10.1186/s13046-021-02036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281578PMC
July 2021

H-Ras gene takes part to the host immune response to COVID-19.

Cell Death Discov 2021 Jun 25;7(1):158. Epub 2021 Jun 25.

Medical Oncology Sant'Andrea Hospital, University La Sapienza, via di Grottarossa 1035-1039, 00189, Rome, Italy.

Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.
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http://dx.doi.org/10.1038/s41420-021-00541-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256395PMC
June 2021

Early Onset of SARS-COV-2 Antibodies after First Dose of BNT162b2: Correlation with Age, Gender and BMI.

Vaccines (Basel) 2021 Jun 22;9(7). Epub 2021 Jun 22.

Scientific Direction, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), 00144 Rome, Italy.

Background: The first goal of the study was to analyse the antibody titre 21 days after the first dose of the BNT162b2 vaccine in a group of 252 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and body mass index (BMI).

Methods: Participants had a nasopharyngeal swab for SARS-CoV-2 and were assessed for the presence of SARS-CoV-2 antibodies at baseline and 21 days after the BNT162b2 priming dose.

Results: First dose of BNT162b2 activated immune responses in 98% of the participants. Five HWC had no increase in antibody titre 21 days after the first dose. Antibody titre was greater in young (<38 years) vs. older participants (<38 vs. 47-56 = 0.002; <38 vs. >56 = 0.001). Higher antibody levels were detected in underweight vs. pre-obesity group ( = 0.026) and in normal-weight vs. pre-obesity group ( = 0.007). This association was confirmed after adjusting for age ( = 0.0001) and gender ( = 0.00001).

Conclusions: Our study demonstrates that a single dose of BNT162b2 activates the immune response, and being young and normal-weight correlate positively with this response. Larger specifically designed clinical trials are needed to validate these results.
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http://dx.doi.org/10.3390/vaccines9070685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310011PMC
June 2021

Initial observations on age, gender, BMI and hypertension in antibody responses to SARS-CoV-2 BNT162b2 vaccine.

EClinicalMedicine 2021 Jun 4;36:100928. Epub 2021 Jun 4.

Scientific Direction, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), Rome, Italy.

Background: Literature data suggests that age, gender and body mass index (BMI) could be associated with difference in immune responses to vaccines. The first goal of the study was to analyze the antibody titre seven days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCWs). The second goal was to analyze how antibody titre changes in correlation with age, gender, BMI and hypertension.

Methods: An immunogenicity evaluation was carried out among HCWs vaccinated at the Istituti Fisioterapici Ospitalieri (IFO), Rome, Italy. All HCWs were asked to be vaccinated by the Italian national vaccine campaign at the beginning of 2021. 260 vaccinated HCWs were enrolled in the study. All eligible participants were assigned to receive the priming dose in two weeks' time and the booster dose exactly 21 days thereafter. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine. Quantitative measurements of IgG antibodies against S1/S2 antigens of SARS-CoV-2 were performed with a commercial chemiluminescent immunoassay. Presence of SARS-Cov-2 in nasopharyngeal swab was determined by commercial RT-PCR testing.

Findings: 248 HWCs were analyzed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response. The geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7) was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with <0.0001. Multivariate linear regression analysis of AU/mL by age, gender and BMI multivariate was performed by the inclusion of covariates. This analysis demonstrated that age (<0.0001) and gender ( = 0.038) are statistically associated with differences in antibody response after vaccination, whereas BMI and hypertension have no statistically significant association ( = 0.078 and  = 0.52 respectively).

Interpretation: 99.5% of HCW developed a humoral immune response and female and young participants seem to have an increased capacity to mount humoral immune responses. BMI and hypertension seem not associated with difference in immune response to the vaccine.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2021.100928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177433PMC
June 2021

Fifth-week immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution.

J Hematol Oncol 2021 05 17;14(1):81. Epub 2021 May 17.

Hematology Unit, Department of Research and Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose.

Methods: Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively.

Results: At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed.

Conclusions: BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).
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http://dx.doi.org/10.1186/s13045-021-01090-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128283PMC
May 2021

In Vivo Imaging of Thyroid Cancer with Tc-TR1401 and Tc-TR1402: A Comparison Study in Dogs.

J Clin Med 2021 Apr 26;10(9). Epub 2021 Apr 26.

Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, "Sapienza" University of Rome, 00161 Rome, Italy.

Differentiated thyroid cancer (DTC) cells may lose NIS expression and iodine uptake, but usually express TSH receptors (TSHR). Therefore, the aim of our study was to compare two radiolabeled superagonist TSH analogues for DTC imaging. These analogues (namely TR1401 and TR1402) have a higher TSHR binding affinity than recombinant human TSH (Thyrogen). Radiolabeling was performed with technetium-99m using an indirect method via HYNIC conjugation and was followed by in vitro quality controls and binding assay on TSHR-positive cell lines (ML-1). An in vitro binding assay was also performed and compared with radiolabeled human recombinant TSH. In vivo imaging was performed in four dogs with spontaneous follicular thyroid carcinoma with solid poorly differentiated areas with Tc-TR1401 SPECT/CT, Tc-TR1402 SPECT/CT, and [F]FDG PET/CT on different days within 2 weeks. TR1401 and TR1402 were labeled with high specific activity (8.3 ± 1.2 MBq/µg) and retention of their biological activity and structural integrity. Both agonists were able to efficiently bind TSHR receptors expressed by cell lines with dissociation constants (Kd) of 2.7 nM for Tc-TR1401 and 0.5 nM for Tc-TR1402 compared with Tc-Thyrogen (Kd = 8.4 nM). In tumor-targeting experiments, a focal uptake was observed in dogs with spontaneous intraglandular thyroid carcinoma, in which TSHR expression was confirmed by immunohistochemistry. Tc-TR1402 provided higher T/B than Tc-TR1401 and [F]FDG (12.9 ± 1.3, 10.2 ± 0.7, and 3.8 ± 0.6, respectively; all < 0.001). Given these results, Tc-TR1402 appears to be a useful tool for in vivo imaging of thyroid cancer.
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http://dx.doi.org/10.3390/jcm10091878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123688PMC
April 2021

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies.

J Transl Med 2021 04 1;19(1):139. Epub 2021 Apr 1.

Department of Clinical and Molecular Medicine, Sapienza University, Via di Grottarossa, 1035/1039, 00189, Rome, Italy.

Background: Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies.

Methods: Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant'Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC).

Results: Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3.

Conclusions: Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.
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http://dx.doi.org/10.1186/s12967-021-02805-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016508PMC
April 2021

MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo.

Sci Rep 2021 01 12;11(1):671. Epub 2021 Jan 12.

UOSD SAFU, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

We developed a novel reporter transgenic zebrafish model called MITO-Luc/GFP zebrafish in which GFP and luciferase expression are under the control of the master regulator of proliferation NF-Y. In MITO-Luc/GFP zebrafish it is possible to visualize cell proliferation in vivo by fluorescence and bioluminescence. In this animal model, GFP and luciferase expression occur in early living embryos, becoming tissue specific in juvenile and adult zebrafish. By in vitro and ex vivo experiments we demonstrate that luciferase activity in adult animals occurs in intestine, kidney and gonads, where detectable proliferating cells are located. Further, by time lapse experiments in live embryos, we observed a wave of GFP positive cells following fin clip. In adult zebrafish, in addition to a bright bioluminescence signal on the regenerating tail, an early unexpected signal coming from the kidney occurs indicating not only a fin cell proliferation, but also a systemic response to tissue damage. Finally, we observed that luciferase activity was inhibited by anti-proliferative interventions, i.e. 5FU, cell cycle inhibitors and X-Rays. In conclusion, MITO-Luc/GFP zebrafish is a novel animal model that may be crucial to assess the spatial and temporal evolution of cell proliferation in vivo.
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http://dx.doi.org/10.1038/s41598-020-79530-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804000PMC
January 2021

Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma.

Cancer Lett 2021 02 26;499:220-231. Epub 2020 Nov 26.

Department of Molecular Medicine, University La Sapienza, Roma, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, University La Sapienza, Roma, Italy. Electronic address:

Aberrant activation of the Hedgehog (Hh) pathway leads to the development of several tumors, including medulloblastoma (MB), the most common pediatric brain malignancy. Hh inhibitors acting on GLI1, the final effector of Hh signaling, offer a valuable opportunity to overcome the pitfalls of the existing therapies to treat Hh-driven cancers. In this study, the toxicity, delivery, biodistribution, and anticancer efficacy of Glabrescione B (GlaB), a selective GLI1 inhibitor, were investigated in preclinical models of Hh-dependent MB. To overcome its poor water solubility, GlaB was formulated with a self-assembling amphiphilic polymer forming micelles, called mPEG-cholane. mPEG-cholane/GlaB showed high drug loading and stability, low cytotoxicity, and long permanence in the bloodstream. We found that mPEG-cholane efficiently enhanced the solubility of GlaB, thus avoiding the use of organic solvents. mPEG-cholane/GlaB possesses favorable pharmacokinetics and negligible toxicity. Remarkably, GlaB encapsulated in mPEG-cholane micelles was delivered through the blood-brain barrier and drastically inhibited tumor growth in both allograft and orthotopic models of Hh-dependent MB. Our findings reveal that mPEG-cholane/GlaB is a good candidate for the treatment of Hh-driven tumors and provide relevant implications for the translation of GlaB into clinical practice.
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http://dx.doi.org/10.1016/j.canlet.2020.11.028DOI Listing
February 2021

The RNA-binding protein MEX3A is a prognostic factor and regulator of resistance to gemcitabine in pancreatic ductal adenocarcinoma.

Mol Oncol 2021 02 24;15(2):579-595. Epub 2020 Nov 24.

Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Most patients present with advanced disease at diagnosis, which only permits palliative chemotherapeutic treatments. RNA dysregulation is a hallmark of most human cancers, including PDAC. To test the impact of RNA processing dysregulation on PDAC pathology, we performed a bioinformatics analysis to identify RNA-binding proteins (RBPs) associated with prognosis. Among the 12 RBPs associated with progression-free survival, we focused on MEX3A because it was recently shown to mark an intestinal stem cell population that is refractory to chemotherapeutic treatments, a typical feature of PDAC. Increased expression of MEX3A was correlated with higher disease stage in PDAC patients and with tumor development in a mouse model of PDAC. Depletion of MEX3A in PDAC cells enhanced sensitivity to chemotherapeutic treatment with gemcitabine, whereas its expression was increased in PDAC cells selected upon chronic exposure to the drug. RNA-sequencing analyses highlighted hundreds of genes whose expression is sensitive to MEX3A expression, with significant enrichment in cell cycle genes. MEX3A binds to its target mRNAs, like cyclin-dependent kinase 6 (CDK6), and promotes their stability. Accordingly, knockdown of MEX3A caused a significant reduction in PDAC cell proliferation and in progression to the S phase of the cell cycle. These findings uncover a novel role for MEX3A in the acquisition and maintenance of chemoresistance by PDAC cells, suggesting that it may represent a novel therapeutic target for PDAC.
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http://dx.doi.org/10.1002/1878-0261.12847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858117PMC
February 2021

Uncovering the expression patterns and the clinical significance of miR-182, miR-205, miR-27a and miR-369 in patients with urinary bladder cancer.

Mol Biol Rep 2020 Nov 31;47(11):8819-8830. Epub 2020 Oct 31.

Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia.

Background: Given the high recurrence and progression rates and the absence of reliable markers for early detection and prognosis prediction of patients with urothelial bladder cancer (BCa), the exploration of new biomarkers with high specificity is imperative. Mainly, microRNAs (miRNAs), which are involved in the initiation and the progression of BCa. Herein, the expression patterns of miR-182, miR-205, miR-27a and miR-369 were evaluated in patients with urothelial BCa.

Methods And Results: The expression levels of the miRNAs were investigated in 90 FFPE tissue samples (23 LG NMIBC, 44 HG NMIBC, 23 MIBC) and 10 non tumoral bladder tissues using TaqMan based RT-qPCR. Data analysis was performed using 2 method. Correlation to clinical characteristics of the patients was performed using descriptive statistics and the receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of all miRNAs. MiR-27a, miR-205 and miR-369 were down-regulated whereas miR-182 was up-regulated in patients compared to controls (p < 0.001). MiR-205 and miR-182 positively segregate between NMIBC and MIBC (p = 0.002 and p = 0.000 respectively) whereas the distribution of miR-27a's expression among these tumor groups was almost significant (p = 0.05) and that of miR-369's expression was irrelevant (p = 0.618). Interestingly, miR-182 was discriminative between LG NMIBC and HG NMIBC (p < 0.001) and Ta/T1 tumors (p = 0.000). Furthermore, high levels of miR-182 were potentially predictive of progression in NMIBC patients (p = 0.01).

Conclusion: Collectively, a selection of miRNAs was found to be aberrantly expressed in BCa suggesting a potential diagnostic value in BCa. In addition, the clinical value of miR-182 and miR-205 as potential prognosis biomarkers was highlighted. Indeed, our data provide additional insights into cancer biology. Further functional or target studies are mandatory to strengthen these findings.
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http://dx.doi.org/10.1007/s11033-020-05932-3DOI Listing
November 2020

Diabetes promotes invasive pancreatic cancer by increasing systemic and tumour carbonyl stress in Kras mice.

J Exp Clin Cancer Res 2020 Aug 10;39(1):152. Epub 2020 Aug 10.

Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039 -, 00189, Rome, Italy.

Background: Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved.

Methods: Pdx1-Cre;LSL-Kras mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients.

Results: Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively.

Conclusions: An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).
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http://dx.doi.org/10.1186/s13046-020-01665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418209PMC
August 2020

DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines.

Cells 2020 05 19;9(5). Epub 2020 May 19.

National Research Council of Italy, Institute of Translational Pharmacology (IFT-CNR), 00133 Rome, Italy.

Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.
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http://dx.doi.org/10.3390/cells9051260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290969PMC
May 2020

Urinary expression of let-7c cluster as non-invasive tool to assess the risk of disease progression in patients with high grade non-muscle invasive bladder Cancer: a pilot study.

J Exp Clin Cancer Res 2020 Apr 17;39(1):68. Epub 2020 Apr 17.

Department of Research, Advanced Diagnostics and Technological Innovation, Genomic and Epigenetic Unit, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: High grade non-muscle-invasive bladder cancer (HG-NMIBC) is a heterogeneous disease with variable risk of progression. Urinary microRNAs are promising biomarkers for BC detection and surveillance. Let-7c-5p miRNA, clustered with miR-99a-5p and -125b-5p, is deregulated in cancer, including BC. The aim of this study is to evaluate urinary let-7c cluster expression in Ta/T1 HG-NMIBC patients and its impact on progression-free survival (PFS).

Methods: Quantitative Real-Time-Polymerase-Chain-Reaction (qRT-PCR) was used to analyze the let-7c cluster expression in 57 urine and 49 neoplastic paired tissue samples prospectively collected from transurethral resection (TUR) HG-NMIBC patients. Twenty urine and 10 bladder tissue samples were collected and analyzed as normal controls. QRT-PCR was also used to detect intra-/extra-cellular let-7c cluster in BC cells. Receiver Operating Characteristic (ROC) curves were used to identify urinary miRNAs cut-off values predicting T-stage and PFS. Uni/multivariable Cox regression was performed to identify predictors of PFS. A nomogram predicting progression risk and a decision curve analysis (DCA) were performed.

Results: Urinary let-7c was significantly up-regulated in patients compared with controls, while the whole cluster was down-regulated in tumor tissues. Supporting these findings, in vitro comparison of extra-/intra-cellular ratios of cluster levels between BC cells, showed a higher ratio for let-7c in HG-NMIBC versus low-grade cells. Urinary let-7c cluster expression was increased in higher T-stage and was an independent predictor of progression. Lower EORTC-score and downregulation of urinary cluster were predictors of higher PFS on univariable Cox regression, while on multivariable analysis only cluster expression was an independent progression predictor. On DCA, a benefit was evident for patients with a PFS probability > 20%.

Conclusions: Urinary let-7c cluster evaluation may improve prognosis, identifying patients at risk of progression and addressing early radical treatment.
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http://dx.doi.org/10.1186/s13046-020-01550-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164295PMC
April 2020

Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal-Maternal Interface.

Front Oncol 2020 12;10:156. Epub 2020 Mar 12.

Gynecologic Oncology Unit, Department of Experimental Clinical Oncology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.

The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal-fetal interface. The biological and immunological processes behind the maternal-fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal-fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal-fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific "immune clock" in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.
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http://dx.doi.org/10.3389/fonc.2020.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080858PMC
March 2020

miR-143 expression profiles in urinary bladder cancer: correlation with clinical and epidemiological parameters.

Mol Biol Rep 2020 Feb 20;47(2):1283-1292. Epub 2019 Dec 20.

Laboratory of Proteins Engineering and Bioactive Molecules (LIP-MB), National Institute of Applied Sciences and Technology of Tunis (INSAT), The University of Tunis Carthage, Via Elio Chianesi 53, 00144, Tunis, Tunisia.

Hsa-mir-143 and hsa-let-7c have been reported to be deregulated in multiple neoplasms. The main purpose of this study was to investigate the expression of these miRNAs in bladder cancer (BCa) and to analyze the association between their expression profiles and clinical and epidemiological parameters. Ninety BCa specimens were included. Expression patterns of miR-143 and let-7c were assessed by qRT-PCR using Taqman specific probes. Validated and predicted targets of these miRNA's were identified using CSmiRTar and DAVID tools, respectively. miR-143 was downregulated in tumors compared to controls (mean fold-change (FC) = 0.076). Its expression was significantly higher in MIBC compared to NMIBC (p = 0,001). Its value as a potential biomarker discriminating non invasive tumors from the invasive ones was confirmed by ROC curve (AUC = 0.768; p = 0.0001). Also, this down-regulation positively correlates with frequency of tobacco use (p = 0,04) and chronic alcohol consumption (p = 0,04). Let-7c was overexpressed in BCa samples (mean (FC = 9.92) compared to non tumoral ones but was not associated to clinical and epidemiological parameters. A comprehensive overview of miR-143 targets and pathways implicated in BCa initiation, diagnosis or prognosis using bioinformatical analysis, was conducted. While both deregulated miRNAs may contribute to urothelial tumorigenesis, the deregulation of miR-143 was significantly correlated to epidemiological and clinical parameters.
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http://dx.doi.org/10.1007/s11033-019-05228-1DOI Listing
February 2020

Evaluating prognostic utility of preoperative Neutrophil to Lymphocyte Ratio and hsa-let-7g/c up-regulation in patients with urinary bladder cancer.

Cancer Biomark 2020 ;27(1):63-73

Laboratory of Proteins Engineering and Bioactive Molecules, INSAT, University of Tunis Carthage, Tunis, Tunisia.

Background: Stratification and risk-evaluation of bladder cancer (BCa) patients are far-reached issues, especially for those with non muscle invasive disease. Thus, setting-up biomarkers, especially after resection of the primary tumor, is crucial. Specifically, Neutrophil to lymphocyte ratio NLR and let-7 deregulation which have been preliminarily but not consistently described to be associated to unfavorable prognosis.

Objective: To explore the clinical value of pre-treatment Neutrophil to Lymphocyte Ratio (NLR), let-7c and let-7g's deregulation.

Methods: Data were extracted from ninety BCa samples. Pre-treatment NLR was estimated as the absolute neutrophil count divided by the absolute lymphocyte count. Expression patterns of let-7c and let-7g were assessed by qRT-PCR. Correlation with clinical characteristics was performed by descriptive statistics.

Results: Both let-7 miRs were upregulated. Interestingly, let-7g was associated to pathological stage (p= 0.001) and tumor multiplicity (p= 0.003). NLR was associated to histological grade (p= 0.005) and clinical stage (p= 0.006). They were both associated to more aggressive phenotype and their worth as potential stratification biomarkers was confirmed by ROC curve.

Conclusions: Our data demonstrated the potential clinical value of all markers, especially pretreatment NLR and let-7g. Further studies are recommended to confirm their utility in improving the clinical decision-making regarding treatment and follow-up scheduling.
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http://dx.doi.org/10.3233/CBM-190483DOI Listing
June 2020

The clinical and prognostic value of miR-9 gene expression in Tunisian patients with bladder cancer.

Mol Biol Rep 2019 Oct 18;46(5):4743-4750. Epub 2019 Jun 18.

Laboratory of Proteins Engineering and Bioactive Molecules (LIP-MB), National Institute of Applied Sciences and Technology of Tunis (INSAT), The University of Carthage, Tunis, Tunisia.

There is a major need for the identification of biomarkers, which are able to guide personalized therapy for bladder cancer, in particular after resection of the primary tumor. Specifically, miR-9 upregulation has been preliminarily associated with a more aggressive phenotype of bladder cancer, namely muscle-invasive bladder cancer (MIBC) or high-grade non-muscle-invasive bladder cancer (HG NMIBC). In order to explore the potential utility of miR-9 as a biomarker in bladder cancer, we have investigated its expression pattern in a sample of Tunisian patients who have undergone primary resection. This is a retrospective study performed on BCa samples from 90 patients (44 specimens of HG NMIBC, 23 specimens of LG NMIBC, and 23 specimens of MIBC). Ten samples from the non-tumoral zone of cystectomy specimens were used as controls. For each specimen, we measured miR-9 expression and correlated it with the clinical characteristics of the patients. Overall, miR-9 was overexpressed in MIBC compared to NMIBC specimens (median fold change [FC]: - 8.89 vs 1.41, p = 0.001). Similarly, miR-9 expression was significantly different in LG NMIBC, HG NMIBC and MIBC subgroups (median FC: 0.68, 2.14 and 8.89, respectively; p = 0.001). ROC analysis showed that miR-9 expression pattern could be used as potential biomarker for distinguishing NMIBC subgroups: indeed miR-9 expression is relatively low in LG NMIBC and high in HG NMIBC. The thresholds are estimated at 0.063 and 21.597, respectively. Moreover, miR-9 was associated with a higher risk of progression. This study suggests the clinical value of miR-9 as a prognostic factor in bladder cancer after tumor resection. Should the prognostic ability of miR-9 be confirmed in larger studies, also on different ethnic groups, it would be useful to investigate whether urine sampling-which is easier to perform, less invasive and less costly-can provide the same results as analysis on surgical specimens.
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http://dx.doi.org/10.1007/s11033-019-04920-6DOI Listing
October 2019

Transgenic Animal Models to Visualize Cancer-Related Cellular Processes by Bioluminescence Imaging.

Front Pharmacol 2019 15;10:235. Epub 2019 Mar 15.

UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.

Preclinical animal models are valuable tools to improve treatments of malignant diseases, being an intermediate step of experimentation between cell culture and human clinical trials. Among different animal models frequently used in cancer research are mouse and, more recently, zebrafish models. Indeed, most of the cellular pathways are highly conserved between human, mouse and zebrafish, thus rendering these models very attractive. Recently, several transgenic reporter mice and zebrafishes have been generated in which the luciferase reporter gene are placed under the control of a promoter whose activity is strictly related to specific cancer cellular processes. Other mouse models have been generated by the cDNA luciferase knockin in the locus of a gene whose expression/activity has increased in cancer. Using BioLuminescence Imaging (BLI), we have now the opportunity to spatiotemporal visualize cell behaviors, among which proliferation, apoptosis, migration and immune responses, in any body district in living animal in a time frame process. We provide here a review of the available models to visualized cancer and cancer-associated events in living animals by BLI and as they have been successful in identifying new stages of early tumor progression, new interactions between different tissues and new therapeutic responsiveness.
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http://dx.doi.org/10.3389/fphar.2019.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428995PMC
March 2019

The prognostic significance of positive peritoneal cytology in endometrial cancer and its correlations with L1-CAM biomarker.

Surg Oncol 2019 Mar 5;28:151-157. Epub 2019 Jan 5.

Department of Women and Children Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy. Electronic address:

Background: The aim of this study was to evaluate the prognostic role of positive peritoneal cytology (PPC) in a cohort of patients with endometrial cancer (EC). The secondary objective was to correlate the PPC and the expression of L1CAM in a group of patients with recurrence endometrial disease.

Methods: All women diagnosed with EC and who performed a peritoneal cytology at "Regina Elena" National Cancer Institute of Rome from 2001 to 2013 were included in the study. Patients were divided into two groups according to positivity at peritoneal cytology. Moreover, patients with a recurrence disease and whose a tissue microarray (TMA) tumor sample was available underwent a L1CAM analysis.

Results: Seven hundred sixty six patients underwent to EC staging in our Institute: 696 (90.8%) with negative and 70 (9.2%) with positive cytology. Five-year recurrence rate was higher in women with PPC (46.9% vs 18.4%, p = 0 < 0.0001) and, in particular, distant recurrence (86.7% vs 53.4%, p = 0.03). Moreover, we found an interesting pattern of recurrence disease in the group of early stage of EC with NPC and positive L1CAM.

Conclusions: Our results support the data that PPC may be a potential prognostic factor in early EC, due to its significant association with other risk factors and its significant influence on survival. Our findings confirm the need for large studies that point out the role of PPC and new prognostic factors, including biomarkers as L1CAM.
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http://dx.doi.org/10.1016/j.suronc.2019.01.001DOI Listing
March 2019

Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies.

Cell Death Dis 2018 09 17;9(10):937. Epub 2018 Sep 17.

Cellular Reprogramming Unit, IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013, San Giovanni Rotondo, Foggia, Italy.

Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that match foetal hNSCs and abide by cGMP standards, thus allowing clinical applications, has not been described. We generated hiNSCs by a virus-free technique, whose properties recapitulate those of the clinical-grade hNSCs successfully used in an Amyotrophic Lateral Sclerosis (ALS) phase I clinical trial. Ex vivo, hiNSCs critically depend on exogenous mitogens for stable self-renewal and amplification and spontaneously differentiate into astrocytes, oligodendrocytes and neurons upon their removal. In the brain of immunodeficient mice, hiNSCs engraft and differentiate into neurons and glia, without tumour formation. These findings now warrant the establishment of clinical-grade, autologous and continuous hiNSC lines for clinical trials in neurological diseases such as Huntington's, Parkinson's and Alzheimer's, among others.
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http://dx.doi.org/10.1038/s41419-018-0990-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141489PMC
September 2018

Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS.

Aging Cell 2018 Oct 15;17(5):e12824. Epub 2018 Aug 15.

CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy.

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.
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http://dx.doi.org/10.1111/acel.12824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156291PMC
October 2018

Endometrial cancer prognosis correlates with the expression of L1CAM and miR34a biomarkers.

J Exp Clin Cancer Res 2018 Jul 6;37(1):139. Epub 2018 Jul 6.

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio chianesi, 53 -, 00144, Rome, Italy.

Background: Patients with endometrial cancer (EC) and presumably with good prognosis may develop a recurrence indicating that the classification of this tumor is still not definitive and that new markers are needed to identify a subgroup at risk of relapse. The cell adhesion molecule L1CAM is highly expressed in several human carcinomas and has recently been described as a new marker for endometrial and ovarian carcinomas. The aim of this study was to determine the relevance of L1CAM in recurrent EC.

Methods: In this work we have analyzed, by immunohistochemical and RT-qPCR analysis, the expression of L1CAM in a cohort of 113 endometrial cancers at different stages, which 50% have relapsed. As a predictor of good outcome, the tumors were also analyzed for the expression of miR-34a, a post-transcriptional regulator of L1CAM.

Results: Among metastatic EC, the highest levels (60%) and the median level (24%) of L1CAM in tumors correlate with the progression, suggesting that the expression of this molecule is linked to the tumor component most involved in metastatic processes. We also found an inverse correlation between miR-34a and L1CAM protein expression, suggesting that miR-34a is a positive prognostic marker of EC.

Conclusions: Our results demonstrate the expression of L1CAM and miR-34a in EC as prognostic factors that identify subgroup of patients at high risk of recurrence suggesting for them more aggressive schedules of treatment.
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http://dx.doi.org/10.1186/s13046-018-0816-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035393PMC
July 2018

Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits.

Aging Cell 2018 08 10;17(4):e12730. Epub 2018 Apr 10.

Dipartimento di Biologia e Biotecnologie "C. Darwin", Sapienza Università di Roma, Rome, Italy.

Human AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A- and B-type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 ) mice exhibit telomeric defects and that Ft1 animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 ; p53 and Ft1 ; p53 ) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53-dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.
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http://dx.doi.org/10.1111/acel.12730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052474PMC
August 2018

The advanced glycation end-product N -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention.

J Pathol 2018 06 4;245(2):197-208. Epub 2018 Apr 4.

Department of Clinical and Molecular Medicine, 'La Sapienza' University, Rome, Italy.

Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE N -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for the risk management and prevention of PaC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5072DOI Listing
June 2018

Correction to: Serum DNA integrity index as a potential molecular biomarker in endometrial cancer.

J Exp Clin Cancer Res 2018 02 20;37(1):35. Epub 2018 Feb 20.

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Correction: In the publication of this article [1], there is an error in the first sentence of the Acknowledgements section.
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http://dx.doi.org/10.1186/s13046-018-0708-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820798PMC
February 2018
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