Publications by authors named "Giulia Petroni"

34 Publications

Impact of treatment schedule on the efficacy of cytostatic and immunostimulatory agents.

Oncoimmunology 2021 Feb 19;10(1):1889101. Epub 2021 Feb 19.

Department of Radiation Oncology, Weill Cornell Medical College, New York, USA.

Radiation therapy (RT) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors mediate poorly overlapping cytostatic and immunostimulatory effects, suggesting that combinatorial regimens may enable supra-additive tumor control. Our preclinical findings demonstrate that administration schedule stands out as a major determinant of efficacy when RT and CDK4/6 inhibitors are combined for breast cancer therapy.
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http://dx.doi.org/10.1080/2162402X.2021.1889101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899633PMC
February 2021

Immunogenic Therapies Drive CAR T Cells towards Superior Efficacy.

Trends Cancer 2021 Mar 29;7(3):179-181. Epub 2021 Jan 29.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA; Université de Paris, Paris, France. Electronic address:

Autologous T cells engineered to express a chimeric antigen receptor (CAR) remain poorly effective against solid tumors, partly because solid neoplasms can establish an immunosuppressive microenvironment. Recent findings by Srivastava et al. suggest that immunogenic chemotherapeutics such as oxaliplatin can be harnessed to maximize the capacity of CAR T cells to infiltrate and control solid tumors.
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http://dx.doi.org/10.1016/j.trecan.2021.01.005DOI Listing
March 2021

Extracorporeal membrane oxygenation-assisted emergency percutaneous treatment of left ventricular assist device graft occlusion.

ESC Heart Fail 2021 Jan 26. Epub 2021 Jan 26.

Department of Heart and Vessels, Cardiac Surgery Unit and Heart Transplantation Center, San Camillo Forlanini Hospital, Rome, Italy.

End-stage heart failure is more often treated with Implantable left ventricular assist device (LVAD), even if the prolonged use may increase the risk of complications. In this case, a 51-year-old male patient presented to our emergency department showing acute heart failure signs and symptoms and a dramatic reduction of LVAD flow. Laboratory tests ruled out significant haemolysis, usually associated with pump thrombosis. The echocardiogram and the computed tomography were not able to clarify the correct diagnosis. We immediately placed a veno-arterial extracorporeal membrane oxygenation, followed by a selective retrograde angiography of the pump. The images showed stenosis of the LVAD-outflow graft, suggesting a twist. Through a hand-made J-tip guidewire, we performed multiple dilatations of the occlusion using peripheral balloons. Finally, we implanted an aortic coarctation covered-stent, re-establishing an adequate cardiac output to the patient. Our case indicates that catheter-based approach in extracorporeal membrane oxygenation assistance provides an important therapeutic alternative to treat outflow graft stenosis, especially in the case of acutely unstable patient.
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http://dx.doi.org/10.1002/ehf2.13205DOI Listing
January 2021

Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER Breast Cancer.

Clin Cancer Res 2021 Jan 25. Epub 2021 Jan 25.

Department of Radiation Oncology, Weill Cornell Medical College, New York, New York.

Purpose: Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor-positive (ER) breast cancer to radiotherapy. However, these findings were obtained in human ER breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.

Experimental Design: We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER and ER-negative (ER) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival , as well as tumor growth, overall survival, and metastatic dissemination .

Results: Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects , correlating with suboptimal tumor control . However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested with enhanced cytostasis and loss of clonogenic potential, as well as with improved local and systemic tumor control.

Conclusions: Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3871DOI Listing
January 2021

Immunomodulation by targeted anticancer agents.

Cancer Cell 2020 Dec 17. Epub 2020 Dec 17.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA; Université de Paris, Paris, France. Electronic address:

At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy.
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http://dx.doi.org/10.1016/j.ccell.2020.11.009DOI Listing
December 2020

Telemedicine as a Medical Examination Tool During the Covid-19 Emergency: The Experience of the Onco-Haematology Center of Tor Vergata Hospital in Rome.

Int J Environ Res Public Health 2020 11 27;17(23). Epub 2020 Nov 27.

Department of Biomedicine and Prevention, University Tor Vergata, 00133 Rome, Italy.

Background: Our study analysed the outpatient activity of the onco-hematology Complex Operative Unit (UOC) of Tor Vergata Hospital, Rome coronavirus disease 2019 (Covid-19) center, where, as a result of the sudden and unexpected emergency, healthcare services were provided through telemedicine procedures that can be considered very close to Telehealth.

Aim Of The Study: our retrospective study aimed to assess the widespread use of telemedicine in terms of feasibility and safety related to adverse events, a crucial experience which will make it possible to predict any effective use of such a method in patients with hematological disorders even after the end of the Covid-19 emergency.

Materials And Methods: At the Day Hospital clinic, from 8 March to 31 May 2020, an outpatient group received 3828 medical teleconsultations and 11,484 additional contacts following the first examination; each patient examined through the telematic method required an average of three supplementary contacts via e-mail or telephone.

Results: The follow-up lasted 145 days, and all the events that occurred were monitored. In total, we recorded 16 clinical adverse events, 5 of which classified as major events, and 11 as minor events.

Conclusion: The 3828 telematic clinical examinations and the 11,484 additional contacts following the first examination carried out by the onco-haematology UOC of Tor Vergata Hospital, proved how telemedicine, albeit in its basic form, was a key tool in facing the sanitary emergency caused by the sudden spread of Covid-19. An experience that can be considered reliable enough to be replicated in possible post-Covid-19 emergencies. From a medical forensic point of view, the main issues to consider are informed consent, personal data management and professional responsibility profiles.
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http://dx.doi.org/10.3390/ijerph17238834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729865PMC
November 2020

Detection of immunogenic cell death and its relevance for cancer therapy.

Cell Death Dis 2020 11 26;11(11):1013. Epub 2020 Nov 26.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.
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http://dx.doi.org/10.1038/s41419-020-03221-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691519PMC
November 2020

Senescence Inflames the Pancreatic Tumor Microenvironment.

Cell Rep Med 2020 May 19;1(2):100020. Epub 2020 May 19.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Pancreatic adenocarcinomas (PDACs) are scarcely vascularized and thus virtually insensitive to chemotherapy and immunotherapy. In a recent issue of , Lowe and collaborators have demonstrated that senescence induction by MEK plus CDK4/CDK6 inhibitors favors PDAC revascularization coupled to infiltration by therapeutically actionable CD8 T cells.
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http://dx.doi.org/10.1016/j.xcrm.2020.100020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659541PMC
May 2020

NK cells beat T cells at early breast cancer control.

Oncoimmunology 2020 08 23;9(1):1806010. Epub 2020 Aug 23.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Cancer immunosurveillance generally relies on adaptive immune programs executed by CD8 T cells. Our findings demonstrate that CD8 T cells fail to control early oncogenesis in a mouse model of luminal B breast cancer and suggest that natural killer (NK) cells may instead play a predominant role in this setting.
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http://dx.doi.org/10.1080/2162402X.2020.1806010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458610PMC
August 2020

Caspase 2 and p53 Reunited in Tumor Control.

Trends Cell Biol 2020 12 11;30(12):917-918. Epub 2020 Sep 11.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA; Université de Paris, Paris, France. Electronic address:

Recent findings (Tsabar et al.) demonstrate that human cancer cells that evade the cell cycle blockage normally imposed by DNA damage experience sustained p53 signaling upon MDM2 degradation by caspase 2. Such a response may be connected to the delivery of immunostimulatory signals to ensure the elimination of genetically instable cancer cells.
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http://dx.doi.org/10.1016/j.tcb.2020.09.001DOI Listing
December 2020

Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy.

Nat Immunol 2020 10 3;21(10):1160-1171. Epub 2020 Aug 3.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.
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http://dx.doi.org/10.1038/s41590-020-0751-0DOI Listing
October 2020

Targeting potassium channels and autophagy to defeat chemoresistance.

Authors:
Giulia Petroni

Mol Cell Oncol 2020 30;7(3):1745038. Epub 2020 Mar 30.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Both autophagy and hERG1 potassium channels have been shown to promote tumor progression and resistance to treatment. Our findings indicate that the antibiotic clarithromycin can target hERG1 and modulate autophagy to promote the death of chemoresistant colorectal cancer cells. Thus, clarithromycin stands out as promising combinatorial partner to improve the efficacy of chemotherapy in patients with colorectal cancer.
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http://dx.doi.org/10.1080/23723556.2020.1745038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199737PMC
March 2020

Cancer Immunotherapy with CDK7 Inhibitors.

Trends Cancer 2020 05 28;6(5):361-363. Epub 2020 Feb 28.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA; Université de Paris, Paris, France. Electronic address:

Recent findings demonstrate that pharmacological cyclin-dependent kinase 7 (CDK7) inhibitors can evoke anticancer immunity upon genomic destabilization of neoplastic cells. Besides adding CDK7 to the expanding list of cell cycle proteins that impinge on immune regulation, these results support the value of aggravating genomic instability in cancer cells to enable immunological disease control.
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http://dx.doi.org/10.1016/j.trecan.2020.02.005DOI Listing
May 2020

Immunomodulation by anticancer cell cycle inhibitors.

Nat Rev Immunol 2020 11 28;20(11):669-679. Epub 2020 Apr 28.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Cell cycle proteins that are often dysregulated in malignant cells, such as cyclin-dependent kinase 4 (CDK4) and CDK6, have attracted considerable interest as potential targets for cancer therapy. In this context, multiple inhibitors of CDK4 and CDK6 have been developed, including three small molecules (palbociclib, abemaciclib and ribociclib) that are currently approved for the treatment of patients with breast cancer and are being extensively tested in individuals with other solid and haematological malignancies. Accumulating preclinical and clinical evidence indicates that the anticancer activity of CDK4/CDK6 inhibitors results not only from their ability to block the cell cycle in malignant cells but also from a range of immunostimulatory effects. In this Review, we discuss the ability of anticancer cell cycle inhibitors to modulate various immune functions in support of effective antitumour immunity.
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http://dx.doi.org/10.1038/s41577-020-0300-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584736PMC
November 2020

Noncanonical Cell Fate Regulation by Bcl-2 Proteins.

Trends Cell Biol 2020 07 16;30(7):537-555. Epub 2020 Apr 16.

Université de Paris, Paris, France; Department of Physiology, YLL School of Medicine and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore. Electronic address:

Bcl-2 proteins are widely known as key controllers of mitochondrial outer membrane permeabilization, arguably the most important step of intrinsic apoptosis. Accumulating evidence indicate that most, if not all, members of the Bcl-2 protein family also mediate a number of apoptosis-unrelated functions. Intriguingly, many of these functions ultimately impinge on cell fate decisions via apoptosis-dependent or -independent mechanisms, delineating a complex network through which Bcl-2 family members regulate cell survival and death. Here, we critically discuss the mechanisms through which Bcl-2 proteins influence cell fate as they regulate autophagy, cellular senescence, inflammation, bioenergetic metabolism, Ca fluxes, and redox homeostasis.
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http://dx.doi.org/10.1016/j.tcb.2020.03.004DOI Listing
July 2020

Immunogenicity of cell death driven by immune effectors.

J Immunother Cancer 2020 04;8(1)

Université de Paris, Paris, France

Whether cell death caused by T lymphocytes and natural killer (NK) cells would be immunogenic has been a matter of intense debate. Two back-to-back papers from the Melero's and Pardo's groups have now resolved this conundrum, demonstrating that T and NK cell-mediated cytotoxicity represents indeed a variant of immunogenic cell death.
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http://dx.doi.org/10.1136/jitc-2020-000802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174067PMC
April 2020

Correction: Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K.

Cell Death Dis 2020 Mar 30;11(3):209. Epub 2020 Mar 30.

Department of Experimental and Clinical Medicine, University of Firenze, Viale GB Morgagni 50, 50134, Firenze, Italy.

The financial support for this Article was not fully acknowledged. The acknowledgements should have included the following: We thank M. Lulli (University of Florence, Italy) for acquiring images of immunofluorescence-labeled cells. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (#15627, #21510 and #19766 to A.A.); PAR FAS-Linea di Azione 1.1-Azione 1.1.2-Bando FAS Salute. 2014 (DD 4042/ 2014) Project OMITERC to A.A.; FAR 2018 to A.B.
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http://dx.doi.org/10.1038/s41419-020-2407-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105481PMC
March 2020

Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K.

Cell Death Dis 2020 03 2;11(3):161. Epub 2020 Mar 2.

Department of Experimental and Clinical Medicine, University of Firenze, Viale GB Morgagni 50, 50134, Firenze, Italy.

We have studied how the macrolide antibiotic Clarithromycin (Cla) regulates autophagy, which sustains cell survival and resistance to chemotherapy in cancer. We found Cla to inhibit the growth of human colorectal cancer (CRC) cells, by modulating the autophagic flux and triggering apoptosis. The accumulation of cytosolic autophagosomes accompanied by the modulation of autophagic markers LC3-II and p62/SQSTM1, points to autophagy exhaustion. Because Cla is known to bind human Ether-à-go-go Related Gene 1 (hERG1) K channels, we studied if its effects depended on hERG1 and its conformational states. By availing of hERG1 mutants with different gating properties, we found that fluorescently labelled Cla preferentially bound to the closed channels. Furthermore, by sequestering the channel in the closed conformation, Cla inhibited the formation of a macromolecular complex between hERG1 and the p85 subunit of PI3K. This strongly reduced Akt phosphorylation, and stimulated the p53-dependent cell apoptosis, as witnessed by late caspase activation. Finally, Cla enhanced the cytotoxic effect of 5-fluorouracil (5-FU), the main chemotherapeutic agent in CRC, in vitro and in a xenograft CRC model. We conclude that Cla affects the autophagic flux by impairing the signaling pathway linking hERG1 and PI3K. Combining Cla with 5-FU might be a novel therapeutic option in CRC.
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http://dx.doi.org/10.1038/s41419-020-2349-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052256PMC
March 2020

hERG1 and HIF-2α Behave as Biomarkers of Positive Response to Bevacizumab in Metastatic Colorectal Cancer Patients.

Transl Oncol 2020 Mar 25;13(3):100740. Epub 2020 Feb 25.

Department of Experimental and Clinical Medicine, University of Florence, Italy. Electronic address:

Background: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis.

Methods: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, β1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up.

Results: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, β1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status.

Conclusions: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.
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http://dx.doi.org/10.1016/j.tranon.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044526PMC
March 2020

Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients.

Oncoimmunology 2019;8(11):e1655964. Epub 2019 Aug 26.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Caspase 3 (CASP3) has a key role in the execution of apoptosis, and many cancer cells are believed to disable CASP3 as a mechanism of resistance to cytotoxic therapeutics. Alongside, CASP3 regulates stress-responsive immunomodulatory pathways, including secretion of type I interferon (IFN). Here, we report that mouse mammary carcinoma TSA cells lacking or subjected to chemical caspase inhibition were as sensitive to the cytostatic and cytotoxic effects of radiation therapy (RT) as their control counterparts, yet secreted increased levels of type I IFN. This effect originated from the accrued accumulation of irradiated cells with cytosolic DNA, likely reflecting the delayed breakdown of cells experiencing mitochondrial permeabilization in the absence of CASP3. TSA cells growing in immunocompetent syngeneic mice were more sensitive to RT than their CASP3-proficient counterparts, and superior at generating abscopal responses in the presence of an immune checkpoint blocker. Finally, multiple genetic signatures of apoptotic proficiency were unexpectedly found to have robust negative (rather than positive) prognostic significance in a public cohort of breast cancer patients. However, these latter findings were not consistent with genetic signatures of defective type I IFN signaling, which were rather associated with improved prognosis. Differential gene expression analysis on patient subgroups with divergent prognosis (as stratified by independent signatures of apoptotic proficiency) identified as a new biomarker with independent prognostic value in breast cancer patients. With the caveats associated with the retrospective investigation of heterogeneous, public databases, our data suggest that apoptotic caspases may influence the survival of breast cancer patients (or at least some subsets thereof) via mechanisms not necessarily related to type I IFN signaling as they identify a novel independent prognostic biomarker that awaits prospective validation.
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http://dx.doi.org/10.1080/2162402X.2019.1655964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791460PMC
August 2019

Data describing the effects of the Macrolide Antibiotic Clarithromycin on preclinical mouse models of Colorectal Cancer.

Data Brief 2019 Oct 22;26:104406. Epub 2019 Aug 22.

Department of Experimental and Clinical Medicine, University of Firenze, Viale GB Morgagni 50, 50134 Firenze, Italy.

Macrolide antibiotics, such as Clarithromycin (Cla), have been proven to exert anti-tumour activity in several preclinical models of different types of cancer. Cla can exert its anti-tumour effects through different mechanisms, e.g. by blocking the autophagic flux, inducing apoptosis or inhibiting tumour-induced angiogenesis. The clinical benefit of Cla in treating various tumours in combination with conventional treatment was confirmed in extensive clinical studies in patients suffering from non-small cell lung cancer, breast cancer, multiple myeloma and other haematological malignancies. Data regarding the anti-cancer effect of Cla on Colorectal Cancer (CRC) are still lacking. This article shares data on the efficacy of Cla in two xenograft models of CRC. Our results show that Cla treatment reduces tumour growth and increases the overall survival in CRC mouse xenograft models. Moreover, the Western blot analysis of autophagic and apoptotic markers suggests that the anti-tumour effects of Cla are related to a modulation of both cellular processes. The data suggest that it will worth consider Cla as treatment option for CRC patients.
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http://dx.doi.org/10.1016/j.dib.2019.104406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727004PMC
October 2019

Ion Channel Conformations Regulate Integrin-Dependent Signaling.

Trends Cell Biol 2019 04 8;29(4):298-307. Epub 2019 Jan 8.

Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy.

Cell-matrix adhesion determines the choice between different cell fates and is accompanied by substantial changes in ion transport. The greatest evidence is the bidirectional interplay occurring between integrin receptors and K channels. These proteins can form signaling hubs that regulate cell proliferation, differentiation, and migration in normal and neoplastic tissue. Recent results show that the physical interaction with integrins determines the balance of the open and closed K channel states, and individual channel conformations regulate distinct downstream pathways. We propose a model of how these mechanisms regulate proliferation and metastasis in cancer cells. In particular, we suggest that the neoplastic progression could be modulated by targeting specific ion channel conformations.
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http://dx.doi.org/10.1016/j.tcb.2018.12.005DOI Listing
April 2019

Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias.

Oncol Rep 2019 Jan 18;41(1):312-324. Epub 2018 Oct 18.

Department of Experimental and Clinical Medicine, University of Florence, I‑50134 Florence, Italy.

Notable advances in treatment have been made and increases in the cure rates of pediatric leukemia have been achieved. However, the majority of children with relapsed disease are not expected to survive, with chemotherapy resistance acting as the principal cause of treatment failure. Interaction between leukemic cells and the bone marrow microenvironment is the primary cause of relapse. It was identified that a multi‑protein membrane complex, formed by potassium voltage‑gated channel subfamily H member 2 (hERG1) channels, the β1 integrin subunit and the stromal cell‑derived factor 12 (CXCL12) receptor, C‑X‑C chemokine receptor type 4 (CXCR4), exerts a role in mesenchymal stromal cell (MSC)‑mediated chemoresistance in pediatric leukemias. hERG1 blockade was able to overcome chemoresistance in vitro and in vivo. As an alternative strategy to overcome chemoresistance, the present study evaluated the effects of novel tools targeting the CXCR4/CXCL12 axis. The analysis of CXCL12 structural dynamics was used for the selection of a peptide (4‑1‑17) and a small molecule (8673), which interact with a transient hot spot, identified by a dynamic drug design approach. The present findings indicated that peptide 4‑1‑17 and small molecule 8673 inhibited leukemia cell proliferation and induced a pro‑apoptotic effect, which was not reduced by the presence of MSCs. The combined treatment with 4‑1‑17 and 8673 had a stronger pro‑apoptotic effect, particularly on cells cultured on MSCs in normoxic and hypoxic conditions, and was able to overcome MSC‑induced resistance to cytarabine. Overall, the targeting of CXCL12 and the ensuing inhibition of the CXCR4/CXCL12 axis may be proposed as an alternative strategy to overcome chemoresistance in leukemia.
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http://dx.doi.org/10.3892/or.2018.6808DOI Listing
January 2019

Metal free, full arch, fixed prosthesis for edentulous mandible rehabilitation on four implants.

J Prosthodont Res 2018 Apr 7;62(2):264-267. Epub 2017 Dec 7.

Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy. Electronic address:

Purpose: The goal of this work is to describe an implant-prosthetic protocol for rehabilitation of edentulous mandible, by using a fixed prosthesis made of fiber-reinforced composite material (FRC). The protocol contemplates a minimal invasive surgery and ensures predictable and safe results, with good aesthetic and performance combined to cost savings.

Methods: FRC material is used to build the substructure of a prosthetic framework supported by four short implants (5mm long and 4mm wide). The prosthesis substructure is made of Trinia immersed in a matrix of epoxy resin (FRC). It is supplied in milling blocks (pre-cured) for the CAD/CAM (computer-aided design/computer-aided manufacturing) technique. Implants are placed in lower edentulous jaw in position of first molar and canine, each side. Four month after, a resin bar is build based on a stone model, denture teeth are placed and the occlusion is checked. The resin bar and the stone model with milled abutments are scanned and a FRC bar is achieved with the CAD/CAM technique. The teeth are mounted to the substructure trough denture resin. Temporary cementation of framework is achieved on the abutments connected to the implants.

Conclusion: A protocol for a fixed mandibular implant-prosthetic rehabilitation is described. The protocol contemplates a minimal invasive surgery and ensures predictable and safe results, with good aesthetic and performance combined to cost savings. In addition, this technique allows performing basic surgery also in presence of atrophy.
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http://dx.doi.org/10.1016/j.jpor.2017.10.002DOI Listing
April 2018

The combined activation of K3.1 and inhibition of K11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.

Br J Cancer 2018 01 21;118(2):200-212. Epub 2017 Nov 21.

Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy.

Background: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K channel modulators on colorectal cancer (CRC) cells.

Methods: The functional expression of Ca-activated (K3.1, also known as KCNN4) and voltage-dependent (K11.1, also known as KCNH2 or hERG1) K channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K channel modulators were tested in vitro for their action on K currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance.

Results: Cisplatin-resistant CRC cells expressed higher levels of K3.1 and K11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K3.1 activators (SKA-31) and K11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K3.1 activation and K11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K3.1 and inhibit K11.1. Cisplatin uptake into resistant cells depended on K3.1 channel activity, as it was potentiated by K3.1 activators. K11.1 blockade led to increased K3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K3.1 activator and a K11.1 inhibitor also overcame Cisplatin resistance in vivo.

Conclusions: As Riluzole, an activator of K3.1 and inhibitor of K11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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http://dx.doi.org/10.1038/bjc.2017.392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785745PMC
January 2018

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression.

Sci Signal 2017 Apr 4;10(473). Epub 2017 Apr 4.

Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K flux through the human ether-à-go-go-related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the β integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the β integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with β integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K flow, whereas metastasis of breast cancer cells was reduced when the hERG1/β integrin interaction was disrupted. We conclude that the interaction of β integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression.
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http://dx.doi.org/10.1126/scisignal.aaf3236DOI Listing
April 2017

hERG1 positivity and Glut-1 negativity identifies high-risk TNM stage I and II colorectal cancer patients, regardless of adjuvant chemotherapy.

Onco Targets Ther 2016 14;9:6325-6332. Epub 2016 Oct 14.

Department of Experimental and Clinical Medicine, University of Florence.

Background: The identification of early-stage colorectal cancer (CRC) with high risk of progression is one major clinical challenge, mainly due to lack of validated biomarkers. The aims of the present study were to analyze the prognostic impact of three molecular markers belonging to the ion channels and transporters family: the (hERG1) and the KCa3.1 potassium channels, as well as the (Glut-1); and to define the impact of adjuvant chemotherapy in conjunction with the abovementioned biomarkers, in a cohort of radically resected stage I-III CRC patients.

Patients And Methods: The expressions of hERG1, KCa3.1, and Glut-1 were tested by immunohistochemistry on 162 surgical samples of nonmetastatic, stage I-III CRC patients. The median follow-up was 32 months. The association between biological markers, clinicopathological features, and survival outcomes was investigated by evaluating both disease-free survival and overall survival.

Results: Although no prognostic valence emerged for KCa3.1, evidence of a negative impact of hERG1 expression on survival outcomes was provided. On the contrary, Glut-1 expression had a positive impact. According to the results of the multivariate analysis, patients were stratified in four risk groups, based on TNM stage and hERG1/Glut-1 expression. After adjusting for adjuvant therapy, stage I and II, Glut-1-negative, and hERG1-positive patients showed the worst survival experience.

Conclusion: This study strongly indicates that the combination of hERG1 positivity and Glut-1 negativity behaves as a prognostic biomarker in radically resected CRC patients. This combination identifies a group of stage I and II CRC patients with a bad prognosis, even worse than that of stage III patients, regardless of adjuvant therapy accomplishment.
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http://dx.doi.org/10.2147/OTT.S114090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072508PMC
October 2016

How the immune system responds to therapeutic biological agents.

J Int Med Res 2016 Sep;44(1 suppl):38-42

Department of Biomedicine, Immunoallergology Section, AOU Careggi, University of Florence, Florence, Italy.

Biological agents target disease mechanisms and have modified the natural history of several immune-mediated disorders. Biological agents are structurally immunogenic, and therefore usually elicit a minor, subclinical and transient phenomenon. Occasionally, however, these drugs induce complete cellular and humoral immune responses, with the main clinical consequences being hypersensitivity reactions or loss of treatment response. This article considers the relative pathogenic mechanisms influencing immunogenicity in biological agents and discusses mechanisms of tolerance and adaptive immune response, including adaptive T-regulatory cell induction and immune response induction. Methods of determining cellular and humoral immune response to biological agents are identified and examined. Assays to detect antidrug antibodies and their isotypes can assist in monitoring immunogenicity and in preventing adverse events. Such strategies also enable resource conservation and may provide regulatory authorities with new insights that can be useful during the process of approving new biological or biosimilar agents.
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http://dx.doi.org/10.1177/0300060515593248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536528PMC
September 2016

New gold carbene complexes as candidate anticancer agents.

Biometals 2016 10 6;29(5):905-11. Epub 2016 Aug 6.

(MetMed) Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.

Three structurally related gold(I) carbene complexes with bulky hydrophobic ligands i.e. 1-3 were investigated in solution for further consideration as candidate anticancer agents. Cytotoxic assays were subsequently conducted on bone marrow-derived preosteoclast cell line of human origin (FLG 29.1) and human colon cancer cells (HCT-116). A far greater cytotoxic activity was measured for compound 1 against HCT-116 cells compared to 2 and 3; conversely, all compounds were highly and similarly active against FLG 29.1 cells. Results obtained for the reaction of complexes 1 and 2 with RNase A documented the occurrence of a weak interaction with this model protein and the formation of a tiny amount of the corresponding adduct. Moreover, a certain reactivity of the complex 2 was also detected toward GSH. The general implications of the obtained results are discussed.
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http://dx.doi.org/10.1007/s10534-016-9962-0DOI Listing
October 2016

Treatment with 8-OH-modified adenine (TLR7 ligand)-allergen conjugates decreases T helper type 2-oriented murine airway inflammation.

Immunology 2015 Aug 8;145(4):570-82. Epub 2015 Jun 8.

Immunoallergology Unit, Department of Biomedicine, Careggi Hospital, Florence, Italy.

A strategy to improve allergen-specific immunotherapy is to employ new adjuvants stably linked to allergens. The study is addressed to evaluate the in vivo and in vitro effects of allergens [natural Dermatophagoides pteronyssinus 2 (nDer p 2) and ovalbumin (OVA)] chemically bound to an 8-OH-modified adenine. Humoral and cellular responses were analysed in allergen-sensitized and challenged mice by using conjugates (Conj) in a therapeutic setting. The in vitro activity of the conjugates on cytokine production induced by bone marrow dendritic cells and the co-culture system was also investigated. The nDer p 2-Conj treatment in nDer p 2-primed and challenged BALB/c mice reduced the numbers of eosinophils in bronchoalveolar lavage fluid and lung, airway allergen-driven interleukin-13 (IL-13) production in lung mononuclear cells and IgE, in comparison with nDer p 2-treated mice. The increase of IgG2a paralleled that of interferon-γ (IFN-γ) and IL-10 in allergen-stimulated spleen cells. Similar effects were elicited by treatment with OVA-Conj in an OVA-driven BALB/c model. The nDer p 2-Conj or OVA-Conj redirected memory T helper type 2 cells towards the production of IL-10 and IFN-γ also in C57BL/6 mice and when subcutaneously administered. Interleukin-10, IL-12 and IL-27 were produced in vitro by Conj-stimulated bone marrow dendritic cells, whereas IL-10 and IFN-γ were up-regulated in co-cultures of CD11c(+) and CD4(+) T cells from Conj-treated mice stimulated with allergen. Cytofluorometric analysis indicated that the Conj expanded IFN-γ- and IL-10- producing memory T cells. The Conj effects on IL-10(-/-) and IL-12(-/-) mice confirmed the role of IL-10 and IFN-γ in inducing a protective and balanced redirection the T helper type 2-mediated airway inflammation.
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http://dx.doi.org/10.1111/imm.12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515136PMC
August 2015