Publications by authors named "Andrea Rinaldi"

223 Publications

Exon-Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation.

Noncoding RNA 2021 Apr 16;7(2). Epub 2021 Apr 16.

Institute of Oncology Research, Faculty of Biomedical Sciences, Universita`Svizzera Italiana, 6500 Bellinzona, Switzerland.

Stressful conditions induce the cell to save energy and activate a rescue program modulated by mammalian target of rapamycin (mTOR). Along with transcriptional and translational regulation, the cell relies also on post-transcriptional modulation to quickly adapt the translation of essential proteins. MicroRNAs play an important role in the regulation of protein translation, and their availability is tightly regulated by RNA competing mechanisms often mediated by long noncoding RNAs (lncRNAs). In our paper, we simulated the response to growth adverse condition by bimiralisib, a dual PI3K/mTOR inhibitor, in diffuse large B cell lymphoma cell lines, and we studied post-transcriptional regulation by the differential analysis of exonic and intronic RNA expression. In particular, we observed the upregulation of a lncRNA, lncTNK2-2:1, which correlated with the stabilization of transcripts involved in the regulation of translation and DNA damage after bimiralisib treatment. We identified miR-21-3p as miRNA likely sponged by lncTNK2-2:1, with consequent stabilization of the mRNA of p53, which is a master regulator of cell growth in response to DNA damage.
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http://dx.doi.org/10.3390/ncrna7020026DOI Listing
April 2021

Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.

Nat Commun 2021 02 2;12(1):734. Epub 2021 Feb 2.

Department of Biomedical Research, University of Bern, 3008, Bern, Switzerland.

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.
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http://dx.doi.org/10.1038/s41467-020-20820-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854732PMC
February 2021

The value of ECG changes in risk stratification of COVID-19 patients.

Ann Noninvasive Electrocardiol 2021 Jan 29:e12815. Epub 2021 Jan 29.

Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.

Background: There is growing evidence of cardiac injury in COVID-19. Our purpose was to assess the prognostic value of serial electrocardiograms in COVID-19 patients.

Methods: We evaluated 269 consecutive patients admitted to our center with confirmed SARS-CoV-2 infection. ECGs available at admission and after 1 week from hospitalization were assessed. We evaluated the correlation between ECGs findings and major adverse events (MAE) as the composite of intra-hospital all-cause mortality or need for invasive mechanical ventilation. Abnormal ECGs were defined if primary ST-T segment alterations, left ventricular hypertrophy, tachy or bradyarrhythmias and any new AV, bundle blocks or significant morphology alterations (e.g., new Q pathological waves) were present.

Results: Abnormal ECG at admission (106/216) and elevated baseline troponin values were more common in patients who developed MAE (p = .04 and p = .02, respectively). Concerning ECGs recorded after 7 days (159), abnormal findings were reported in 53.5% of patients and they were more frequent in those with MAE (p = .001). Among abnormal ECGs, ischemic alterations and left ventricular hypertrophy were significantly associated with a higher MAE rate. The multivariable analysis showed that the presence of abnormal ECG at 7 days of hospitalization was an independent predictor of MAE (HR 3.2; 95% CI 1.2-8.7; p = .02). Furthermore, patients with abnormal ECG at 7 days more often required transfer to the intensive care unit (p = .01) or renal replacement therapy (p = .04).

Conclusions: Patients with COVID-19 should receive ECG at admission but also during their hospital stay. Indeed, electrocardiographic alterations during hospitalization are associated with MAE and infection severity.
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http://dx.doi.org/10.1111/anec.12815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994985PMC
January 2021

under the Microscope: Disclosing the Secrets of a Parasitic Plant.

Plants (Basel) 2021 Jan 12;10(1). Epub 2021 Jan 12.

Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.

Well over 1% of all flowering plants are parasites, obtaining all or part of the nutrients they need from other plants. Among this extremely heterogeneous assemblage, the form a small group of holoparasites, with as the main representative genus. Despite the small number of known species and the fact that it doesn't attack crops or plants of economic importance, is paradigmatic among parasitic plants. Recent research has indeed disclosed many aspects of host-parasite interactions and reproductive biology, the latter displaying a vast array of adaptive traits to lure a range of animal pollinators. Furthermore, analysis of biological activities of extracts of the most common species of has provided evidence that this plant could be a valuable source of compounds with high potential in key applicative areas, namely food production (nutraceuticals) and the development of antimicrobial therapeutics. This article offers a complete overview of our current knowledge of .
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http://dx.doi.org/10.3390/plants10010146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828134PMC
January 2021

Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis.

Cancer Cell 2021 Jan 12;39(1):68-82.e9. Epub 2020 Nov 12.

Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland; Department of Medicine, University of Padua, Padua 35128, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich 8093, Switzerland. Electronic address:

Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
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http://dx.doi.org/10.1016/j.ccell.2020.10.012DOI Listing
January 2021

The Anti-Microbial Peptide (Lin-SB056-1)-K Reduces Pro-Inflammatory Cytokine Release through Interaction with Lipopolysaccharide.

Antibiotics (Basel) 2020 Sep 8;9(9). Epub 2020 Sep 8.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56123 Pisa PI, Italy.

The ability of many anti-microbial peptides (AMPs) to modulate the host immune response has highlighted their possible therapeutic use to reduce uncontrolled inflammation during chronic infections. In the present study, we examined the anti-inflammatory potential of the semi-synthetic peptide lin-SB056-1 and its dendrimeric derivative (lin-SB056-1)-K, which were previously found to have anti-microbial activity against in in vivo-like models mimicking the challenging environment of chronically infected lungs (i.e., artificial sputum medium and 3-D lung mucosa model). The dendrimeric derivative exerted a stronger anti-inflammatory activity than its monomeric counterpart towards lung epithelial- and macrophage-cell lines stimulated with lipopolysaccharide (LPS), based on a marked decrease (up to 80%) in the LPS-induced production of different pro-inflammatory cytokines (i.e., IL-1β, IL-6 and IL-8). Accordingly, (lin-SB056-1)-K exhibited a stronger LPS-binding affinity than its monomeric counterpart, thereby suggesting a role of peptide/LPS neutralizing interactions in the observed anti-inflammatory effect. Along with the anti-bacterial and anti-biofilm properties, the anti-inflammatory activity of (lin-SB056-1)-K broadens its therapeutic potential in the context of chronic (biofilm-associated) infections.
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http://dx.doi.org/10.3390/antibiotics9090585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557804PMC
September 2020

Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734.

Blood Adv 2020 09;4(17):4124-4135

Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.

Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.
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http://dx.doi.org/10.1182/bloodadvances.2020001879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479962PMC
September 2020

Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type.

Cancers (Basel) 2020 Jul 15;12(7). Epub 2020 Jul 15.

Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland.

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL.
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http://dx.doi.org/10.3390/cancers12071912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409072PMC
July 2020

RNA to the rescue: RNA is one of the most promising targets for drug development given its wide variety of uses.

Authors:
Andrea Rinaldi

EMBO Rep 2020 07 26;21(7):e51013. Epub 2020 Jun 26.

Cagliari, Italy.

The race for a vaccine against SARS-CoV-2 has accelerated research on RNA-based therapeutics. Beyond vaccines, RNA also shows great potential for cancer therapies.
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http://dx.doi.org/10.15252/embr.202051013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332969PMC
July 2020

Diagnostic Accuracy of Cardiac Computed Tomography and 18-F Fluorodeoxyglucose Positron Emission Tomography in Cardiac Masses.

JACC Cardiovasc Imaging 2020 11 17;13(11):2400-2411. Epub 2020 Jun 17.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Objectives: This study sought to assess the diagnostic accuracy of cardiac computed tomography (CT) and F-fluorodeoxyglucose (F-FDG) with positron emission tomography/computed tomography (PET/CT) in defining the nature of cardiac masses.

Background: The diagnostic accuracy of cardiac CT and F-FDG PET/CT in identifying the nature of cardiac masses has been analyzed to date only in small samples.

Methods: Of 223 patients with echocardiographically diagnosed cardiac masses, a cohort of 60 cases who underwent cardiac CT and F-FDG PET/CT was selected. All masses had histological confirmation, except for a minority of thrombotic formations. For each mass, 8 morphological CT signs, standardized uptake value (SUV, SUV), metabolic tumor volume, and total lesion glycolysis in F-FDG PET were used as diagnostic markers.

Results: Irregular tumor margins, pericardial effusion, invasion, solid nature, mass diameter, CT contrast uptake, and pre-contrast characteristics were strongly associated with the malignant nature of masses. The coexistence of at least 5 CT signs perfectly identified malignant masses, whereas the detection of 3 or 4 CT signs did not accurately discriminate the masses' nature. The mean SUV, SUV, metabolic tumor volume, and total lesion glycolysis values were significantly higher in malignant than in benign masses. The diagnostic accuracy of SUV, metabolic tumor volume, and total lesion glycolysis F-FDG PET/CT parameters was excellent in detecting malignant masses. Among patients with 3 or 4 pathological CT signs, the presence of at least 1 abnormal F-FDG PET/CT parameter significantly increased the identification of malignancies.

Conclusions: Cardiac CT is a powerful tool to diagnose cardiac masses as the number of abnormal signs was found to correlate with the lesions' nature. Similarly, F-FDG PET/CT accurately identified malignant masses and contributed with additional valuable information in diagnostic uncertainties after cardiac CT. These imaging tools should be performed in specific clinical settings such as involvement of great vessels or for disease-staging purposes.
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http://dx.doi.org/10.1016/j.jcmg.2020.03.021DOI Listing
November 2020

Establishment of patient-derived tumor xenograft models of mucinous ovarian cancer.

Am J Cancer Res 2020 1;10(2):572-580. Epub 2020 Feb 1.

Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan 20156, Italy.

Mucinous ovarian carcinoma (mEOC) represents a rare subtype of epithelial ovarian cancer, accounting for 3-4% of all ovarian carcinomas. The rarity of this tumor type renders both the preclinical and clinical research compelling. Very few preclinical and models exist. We here report the molecular, metabolic and pharmacological characterization of two patient derived xenografts (PDXs) from mEOC, recently obtained in our laboratory. These PDXs maintain the histological and molecular characteristics of the patient's tumors they derived from, including a wild type . Gene expression analysis and metabolomics profile suggest that they differ from high grade serous/endometrioid ovarian carcinoma PDXs. The pharmacological characterization was undertaken testing the antitumor activity of both cytotoxic agents (cisplatin, paclitaxel, yondelis, oxaliplatin and 5-fluorouracile) and targeted agents (bevacizumab and lapatinib). These newly established mucinous PDXs do recapitulate mEOC and will be of value in the preclinical development of possible new therapeutic strategies for this tumor type.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061742PMC
February 2020

Copanlisib synergizes with conventional and targeted agents including venetoclax in B- and T-cell lymphoma models.

Blood Adv 2020 03;4(5):819-829

Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Bellinzona, Switzerland.

Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.
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http://dx.doi.org/10.1182/bloodadvances.2019000844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065481PMC
March 2020

Secondary Prevention Medical Therapy and Outcomes in Patients With Myocardial Infarction With Non-Obstructive Coronary Artery Disease.

Front Pharmacol 2019 31;10:1606. Epub 2020 Jan 31.

Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with relevant long-term major cardiovascular events. Several trials have demonstrated that dual antiplatelet therapy (DAPT), β-blocker, renin-angiotensin-aldosterone system (RAAS) inhibitor and statin therapy improve the prognosis in patients with obstructive myocardial infarction (ob-MI). However, evidence on the best medical therapy for secondary prevention in MINOCA patients is lacking.

Purpose: To investigate the effects of secondary prevention treatments at discharge on mid-term outcomes in MINOCA.

Methods: Patients with acute myocardial infarction (MI) undergoing early coronary angiography between 2016 and 2018 were extracted from a clinical database. The diagnosis of MINOCA was made according to 2016 ESC MINOCA Position Paper criteria. Second-level diagnostic work-up including cardiac magnetic resonance was performed to exclude non-ischemic troponin elevation cause. The relationship between treatments and outcomes was evaluated by using Kaplan-Meier survival analysis and Cox regression models. All confirmed MINOCA were followed in our outpatient clinics. The primary end-points were all-cause mortality, re-hospitalization for MI and a composite outcome including all-cause mortality, hospitalization for MI and ischemic stroke (MACE).

Results: Out of 1,141 AMI who underwent coronary angiography, 134 were initially diagnosed as MINOCA. Patients with MINOCA were less likely to receive secondary prevention treatments than patients with obstructive coronary artery disease (CAD) MI (respectively, 42.1% vs 81.8% for DAPT; 75.5% vs 89.6% for β-blockers; 64.7% vs 80.3% for RAAS inhibitor and 63.9% vs 83% for statins). Based on the diagnostic work-up completed during the first month after discharge, a final sample of 88 patients had confirmed MINOCA. During an average follow-up of 19.35 ± 10.65 months, all-cause mortality occurred in 11 (12.5%) patients, recurrence of MI in 4 (4.5%), and MACE in 15 (17.0%) patients. Patients treated with RAAS inhibitors and statins had a significantly longer survival. On the contrary, no increase in survival was found in patients treated with β-blockers or DAPT. Cox multivariable analysis, including all secondary prevention drugs, showed that only RAAS inhibitors were associated with reduced all cause-mortality and MACE.

Conclusion: This prospective study suggests that RAAS inhibitor therapy provides mid-term beneficial effects on outcomes in MINOCA patients; in contrast, dual antiplatelet, β-blocker and statin therapy had no effects on mortality and MACE. These results should be considered preliminary and warrant confirmation from larger studies.
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http://dx.doi.org/10.3389/fphar.2019.01606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005107PMC
January 2020

mutations and disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study.

Haematologica 2020 06 19;105(6):1604-1612. Epub 2019 Sep 19.

Oncology Unit, Humanitas/Gavazzeni Clinic, Bergamo, Italy.

In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of and disruption of by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding mutations and disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring mutations share the same poor outcome as patients harboring disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. ().
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http://dx.doi.org/10.3324/haematol.2018.214056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271566PMC
June 2020

Role of somatic cell sources in the maturation degree of human induced pluripotent stem cell-derived cardiomyocytes.

Biochim Biophys Acta Mol Cell Res 2020 03 28;1867(3):118538. Epub 2019 Aug 28.

Laboratory of Cellular and Molecular Cardiology, Fondazione Cardiocentro Ticino and Foundation for Cardiovascular Research and Education (FCRE), 6900 Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), 6900 Lugano, Switzerland; Center for Molecular Cardiology, University of Zürich, 8001 Zürich, Switzerland. Electronic address:

Background: Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) are a unique source of human cardiomyocytes for cardiac disease modeling. Incomplete functional maturation remains a major limitation, however. One of the determinants of iPSC-CM maturation is somatic cell origin. We therefore compared iPSC-CMs derived from different somatic cell sources.

Methods: Cardiac-derived mesenchymal progenitor cells (CPCs), bone marrow-derived mesenchymal stem cells (BMCs), and human dermal fibroblasts (HDFs) from same patients were reprogrammed into iPSCs and differentiated into iPSC-CMs. Expression of cardiac-specific genes, caffeine-responsive cells, and electrophysiological properties of differentiated cells were analyzed. To assess the contribution of epigenetic memory toward differences in gene expression observed during cardiac differentiation, DNA methylation patterns were determined in the early mesodermal cardiac promoter NKX2-5 and KCNQ1, which encodes for the pore-forming α-subunit of the slow component of delayed-rectifier potassium current (I).

Results: Cardiac genes (MYH6, TNNI3, KCNQ1, KCNE1) were upregulated in CPC-vs. BMC- and HDF-iPSC-CMs. At early differentiation stages, CPC-iPSC-CMs displayed higher numbers of caffeine-responsive cells than BMC- and HDF-iPSC-CMs. The hERG1 (KV11.1) blocker, E4031, followed by the IKs blocker, JNJ303, increased extracellular field potential duration in CPC-iPSC-CMs to a greater extent than in BMC- and HDF-iPSC-CMs. The promoter region of NKX2-5 was more highly methylated in BMCs and HDFs compared to CPCs, and to a lesser extent in BMC-iPSCs compared to CPC-iPSCs.

Conclusions: These results suggest that human iPSCs from cardiac somatic cell sources may display enhanced capacity toward cardiac re-differentiation compared to non-cardiac cell sources, and that epigenetic mechanisms may play a role in this regard.
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http://dx.doi.org/10.1016/j.bbamcr.2019.118538DOI Listing
March 2020

Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer.

Cell Rep 2019 08;28(8):2156-2168.e5

Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Faculty of Medicine, Università della Svizzera Italiana, 1011 Lugano, Switzerland; Department of Medicine, University of Padua, 35131 Padua, Italy; Medical Oncology, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland. Electronic address:

Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Pten; Trp53 mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.
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http://dx.doi.org/10.1016/j.celrep.2019.07.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715643PMC
August 2019

The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents.

Clin Cancer Res 2019 08 10;25(16):5167-5176. Epub 2019 Jun 10.

Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.

Purpose: Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due to their nonenzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 and its clinical derivative, TK-216, targeting ETS factors via blocking the protein-protein interaction with RNA helicases, for their antilymphoma activity.

Experimental Design: The study included preclinical activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on models; and transcriptome and coimmunoprecipitation experiments.

Results: YK-4-279 and TK-216 demonstrated an antitumor activity across several lymphoma cell lines, which we validated . We observed synergistic activity when YK-4-279 and TK-216 were combined with the BCL2 inhibitor venetoclax and with the immunomodulatory drug lenalidomide. YK-4-279 and TK-216 interfere with protein interactions of ETS family members SPIB, in activated B-cell-like type diffuse large B-cell lymphomas, and SPI1, in germinal center B-cell-type diffuse large B-cell lymphomas.

Conclusions: The ETS inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with and antitumor activity in lymphomas. Although their detailed mechanism of action needs to be fully defined, in DLBCL they might act by targeting subtype-specific essential transcription factors.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2718DOI Listing
August 2019

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.

Cell Metab 2019 08 23;30(2):303-318.e6. Epub 2019 May 23.

Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona 6500, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland; Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland. Electronic address:

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here, we uncover a novel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic capability. Depletion of CSCs occurred in multiple prostate cancer models, indicating a common vulnerability and dependency on mitochondrial dynamics. These effects depended on rewiring of the BRD4-driven transcription and repression of mitochondrial fission factor (Mff). Knockdown of Mff reproduced the effects of BRD4 inhibition, whereas ectopic Mff expression rescued prostate CSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigm for developing more effective treatment strategies for prostate cancer.
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http://dx.doi.org/10.1016/j.cmet.2019.05.004DOI Listing
August 2019

Tannin profile, antioxidant properties, and antimicrobial activity of extracts from two Mediterranean species of parasitic plant Cytinus.

BMC Complement Altern Med 2019 Apr 5;19(1):82. Epub 2019 Apr 5.

Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042, Monserrato (CA), Italy.

Background: Cytinus is small genus of endophytic parasitic plants distributed in South Africa, Madagascar, and in the Mediterranean region. In the latter area, two species occur, Cytinus hypocistis and C. ruber, distinguished by both morphological characters and ecological traits. We characterized the ethanolic and aqueous extracts obtained from the inflorescences of C. hypocistis and C. ruber collected in Sardinia, Italy, and explored their tannin content, antioxidant properties and antimicrobial activities.

Methods: Total phenolic contents were determined by Folin-Ciocalteu spectrophotometric method. Tannin content was determined by HPLC. Antioxidant activity of the extracts was tested with both electron transfer-based (FRAP, TEAC, DPPH) and spectrophotometric HAT methods (ORAC-PYR). The antimicrobial activities of extracts/compounds were evaluated using the broth microdilution method. The bactericidal activity was evaluated using the time-kill method. Biofilm formation was evaluated by crystal violet (CV) staining assay.

Results: Characterization of the tannin profile of C. hypocistis and C. ruber revealed a significant amount of gallotannins, in particular 1-O-galloyl-β-D-glucose. In addition, pentagalloyl-O-β-D-glucose was present in all extracts, reaching the concentration of 0.117 g/kg in the ethanolic extract of C. hypocistis. C. hypocistis extracts displayed a strongest antioxidant activity than C. ruber extracts. Three Gram-positive bacterial species tested (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium) resulted sensitive to both Cytinus extracts, with MICs ranging from 125 to 500 μg/ml for aqueous extracts and from 31.25 to 250 μg/ml for ethanolic extracts; on the contrary, Gram-negative strains (Pseudomonas aeruginosa and Klebsiella pneumoniae) were not affected by Cytinus extracts. Intriguingly, we observed the suppressive activity of ethanolic extracts of C. hypocistis and C. ruber on biofilm formation of S. epidermidis. Experiments performed with synthetic compounds indicated that pentagalloyl-O-β-D-glucose is likely to be one of the active antimicrobial components of Cytinus extracts.

Conclusions: These findings show that Cytinus extracts have antimicrobial and antioxidant activities, suggesting a possible application of Cytinus as sources of natural antimicrobials and antioxidants.
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http://dx.doi.org/10.1186/s12906-019-2487-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451225PMC
April 2019

Action Monitoring Through External or Internal Focus of Attention Does Not Impair Endurance Performance.

Front Psychol 2019 13;10:535. Epub 2019 Mar 13.

BIND-Behavioral Imaging and Neural Dynamics Center, Department of Medicine and Aging Sciences, Università degli Studi G. d'Annunzio Chieti e Pescara, Chieti, Italy.

Attentional focus in endurance sports has been found to largely affect performance. To deal with discomfort, fatigue, and pain associated with endurance performance under pressure, athletes tend to direct attention to both internal (e.g., bodily) sensations and external (e.g., environmental) stimuli. The purpose of this study, framed within the multi-action plan (MAP) model, was to examine whether different levels of action monitoring through external or internal focus of attention could influence endurance performance. Action monitoring has been conceptualized as awareness of the current experience without necessarily influencing the course of action or disrupting automated motor processes. Thirty-two male participants ( = 29.12 years, = 6.12 years) were engaged in a treadmill, time-to-exhaustion running task across seven visits to the laboratory (i.e., task familiarization, baseline, four experimental conditions, and follow up). Assessment involved performance (i.e., time to exhaustion), oxygen uptake (O), blood lactate levels, ratings of perceived exertion (RPE), and perceived arousal and hedonic tone. Across four visits, participants were prompted to use the four attentional strategies (one per session) deriving from the interaction of low/high conscious monitoring level by external/internal attention focus in a counterbalanced experimental design. Repeated measures analysis of variance did not yield significant results in any variable of the study, performance included. Consistent with predictions of the MAP model, study findings showed that participants were able to attain same performance levels irrespective of whether they used a high or low level of action monitoring through an external or internal focus of attention. Findings suggest practical indications to help athletes deal with stress in endurance sports.
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http://dx.doi.org/10.3389/fpsyg.2019.00535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425868PMC
March 2019

Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner.

Cell Rep 2019 02;26(9):2307-2315.e5

Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. Electronic address:

The role of natural killer (NK) cells in the immune response against vaccines is not fully understood. Here, we examine the function of infiltrated NK cells in the initiation of the inflammatory response triggered by inactivated influenza virus vaccine in the draining lymph node (LN). We observed that, following vaccination, NK cells are recruited to the interfollicular and medullary areas of the LN and become activated by type I interferons (IFNs) produced by LN macrophages. The activation of NK cells leads to their early production of IFNγ, which in turn regulates the recruitment of IL-6+ CD11b+ dendritic cells. Finally, we demonstrate that the interleukin-6 (IL-6)-mediated inflammation is important for the development of an effective humoral response against influenza virus in the draining LN.
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http://dx.doi.org/10.1016/j.celrep.2019.01.104DOI Listing
February 2019

The Antimicrobial Peptide lin-SB056-1 and Its Dendrimeric Derivative Prevent Biofilm Formation in Physiologically Relevant Models of Chronic Infections.

Front Microbiol 2019 8;10:198. Epub 2019 Feb 8.

Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.

Antimicrobial peptides (AMPs) are promising templates for the development of novel antibiofilm drugs. Despite the large number of studies on screening and optimization of AMPs, only a few of these evaluated the antibiofilm activity in physiologically relevant model systems. Potent activity of AMPs often does not translate into effectiveness due to the interference of the host microenvironment with peptide stability/availability. Hence, mimicking the complex environment found in biofilm-associated infections is essential to predict the clinical potential of novel AMP-based antimicrobials. In the present study, we examined the antibiofilm activity of the semi-synthetic peptide lin-SB056-1 and its dendrimeric derivative (lin-SB056-1)-K against in an -like three-dimensional (3-D) lung epithelial cell model and an wound model (consisting of an artificial dermis and blood components at physiological levels). Although moderately active when tested alone, lin-SB056-1 was effective in reducing biofilm formation in association with 3-D lung epithelial cells in combination with the chelating agent EDTA. The dimeric derivative (lin-SB056-1)-K demonstrated an enhanced biofilm-inhibitory activity as compared to both lin-SB056-1 and the lin-SB056-1/EDTA combination, reducing the number of biofilm-associated bacteria up to 3-Log units at concentrations causing less than 20% cell death. Biofilm inhibition by (lin-SB056-1)-K was reported both for the reference strain PAO1 and cystic fibrosis lung isolates of . In addition, using fluorescence microscopy, a significant decrease in biofilm-like structures associated with 3-D cells was observed after peptide exposure. Interestingly, effectiveness of (lin-SB056-1)-K was also demonstrated in the wound model with a reduction of up to 1-Log unit in biofilm formation by PAO1 and wound isolates. Overall, combination treatment and peptide dendrimerization emerged as promising strategies to improve the efficacy of AMPs, especially under challenging host-mimicking conditions. Furthermore, the results of the present study underlined the importance of evaluating the biological properties of novel AMPs in -like model systems representative of specific infectious sites in order to make a more realistic prediction of their therapeutic success, and avoid the inclusion of unpromising peptides in animal studies and clinical trials.
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http://dx.doi.org/10.3389/fmicb.2019.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376900PMC
February 2019

Genome-wide promoter methylation of hairy cell leukemia.

Blood Adv 2019 02;3(3):384-396

Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton, United Kingdom.

Classic hairy cell leukemia (HCL) is a tumor of mature clonal B cells with unique genetic, morphologic, and phenotypic features. DNA methylation profiling has provided a new tier of investigation to gain insight into the origin and behavior of B-cell malignancies; however, the methylation profile of HCL has not been specifically investigated. DNA methylation profiling was analyzed with the Infinium HumanMethylation27 array in 41 mature B-cell tumors, including 11 HCL, 7 splenic marginal zone lymphomas (SMZLs), and chronic lymphocytic leukemia with an unmutated (n = 7) or mutated (n = 6) immunoglobulin gene heavy chain variable (IGHV) region or using IGHV3-21 (n = 10). Methylation profiles of nontumor B-cell subsets and gene expression profiling data were obtained from public databases. HCL had a methylation signature distinct from each B-cell tumor entity, including the closest entity, SMZL. Comparison with normal B-cell subsets revealed the strongest similarity with postgerminal center (GC) B cells and a clear separation from pre-GC and GC cellular programs. Comparison of the integrated analysis with post-GC B cells revealed significant hypomethylation and overexpression of BCR-TLR-NF-κB and BRAF-MAPK signaling pathways and cell adhesion, as well as hypermethylation and underexpression of cell-differentiation markers and methylated genes in cancer, suggesting regulation of the transformed hairy cells through specific components of the B-cell receptor and the BRAF signaling pathways. Our data identify a specific methylation profile of HCL, which may help to distinguish it from other mature B-cell tumors.
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http://dx.doi.org/10.1182/bloodadvances.2018024059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373742PMC
February 2019

BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance.

ESMO Open 2018 26;3(6):e000387. Epub 2018 Sep 26.

Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.

Background: The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.

Materials And Methods: The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.

Results: Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.

Conclusion: Our data provide the rationale to evaluate birabresib in patients affected by MCL.
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http://dx.doi.org/10.1136/esmoopen-2018-000387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173228PMC
September 2018

Publisher Correction: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.

Nat Genet 2018 09;50(9):1343

Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland.

In the HTML version of this article initially published, the name of author Diletta Di Mitri was miscoded in the XML such that Di was included as part of the given name instead of the family name. The error has been corrected in the HTML version of the article.
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http://dx.doi.org/10.1038/s41588-018-0181-1DOI Listing
September 2018

Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma.

Haematologica 2018 12 3;103(12):2049-2058. Epub 2018 Aug 3.

Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland

Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demonstrated preclinical and clinical activity in hematologic tumors. MicroRNA profiling of diffuse large B-cell lymphoma cells treated with OTX015 revealed changes in the expression levels of a limited number of microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p. Analysis of publicly available chromatin immunoprecipitation sequencing data of diffuse large B-cell lymphoma cells treated with bromodomain and extra-terminal domain (BET) inhibitors showed that the BET family member BRD4 bound to the upstream regulatory regions of multiple microRNA genes and that this binding decreased following BET inhibition. Alignment of our microRNA profiling data with the BRD4 chromatin immunoprecipitation sequencing data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bromodomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 contributes directly to microRNA expression in lymphoma. Treatment with bromodomain and extra-terminal domain inhibitors also decreased the expression of the arginine methyltransferase PRMT5, which plays a crucial role in B-cell transformation and negatively modulates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.
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http://dx.doi.org/10.3324/haematol.2018.191684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269312PMC
December 2018

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.

Nature 2018 07 27;559(7714):363-369. Epub 2018 Jun 27.

Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.

Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.
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http://dx.doi.org/10.1038/s41586-018-0266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461206PMC
July 2018