Publications by authors named "Andrea Cossarizza"

221 Publications

Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports.

Cells 2021 09 28;10(10). Epub 2021 Sep 28.

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could have multiple effects, also on the mitochondrial DNA (mtDNA) and vice versa; some studies have investigated how mtDNA polymorphisms can affect the performance of general athletes and mtDNA haplogroups seem to be related to the performance of elite endurance athletes. Along with several stimuli, including pathogens, stress, trauma, and reactive oxygen species, acute and intense exercise also seem to be responsible for mtDNA release into the cytoplasm and extracellular space, leading to the activation of the innate immune response. In addition, several sports are characterized by a higher frequency of injuries, including cranial trauma, associated with neurological consequences. However, with regular exercise, circulating cell-free mtDNA levels are kept low, perhaps promoting cf-mtDNA removal, acting as a protective factor against inflammation.
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http://dx.doi.org/10.3390/cells10102575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533813PMC
September 2021

Corrigendum: To Ki or Not to Ki: Re-Evaluating the Use and Potentials of Ki-67 for T Cell Analysis.

Front Immunol 2021 28;12:756641. Epub 2021 Sep 28.

Immunosurveillance Laboratory, The Francis Crick Institute, London, United Kingdom.

[This corrects the article DOI: 10.3389/fimmu.2021.653974.].
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http://dx.doi.org/10.3389/fimmu.2021.756641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507465PMC
September 2021

Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma.

Transl Oncol 2021 Oct 12;15(1):101240. Epub 2021 Oct 12.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy; Rigenerand Srl, Medolla, Modena, Italy. Electronic address:

Background: Ewing's sarcoma (ES) is an aggressive cancer affecting children and young adults. We pre-clinically demonstrated that mesenchymal stromal/stem cells (MSCs) can deliver tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) against primary ES after local injection. However, ES is often metastatic calling for approaches able to support MSC targeting to the ES multiple remote sites. Considering that the disialoganglioside GD2 is expressed by ES and to optimise MSC tumour affinity, bi-functional (BF) MSCs expressing both TRAIL and a truncated anti-GD2 chimeric antigen receptor (GD2 tCAR) were generated and challenged against ES.

Methods: The anti-GD2 BF MSCs delivering a soluble variant of TRAIL (sTRAIL) were tested in several in vitro ES models. Tumour targeting and killing by BF MSCs was further investigated by a novel immunodeficient ES metastatic model characterized by different metastatic sites, including lungs, liver and bone, mimicking the deadly clinical scenario.

Findings: In vitro data revealed both tumour affinity and killing of BF MSCs. In vivo, GD2 tCAR molecule ameliorated the tumour targeting and persistence of BF MSCs counteracting ES in lungs but not in liver.

Interpretation: We here generated data on the potential effects of BF MSCs within a complex ES metastatic in vivo model, exploring also the biodistribution of MSCs. Our BF MSC-based strategy promises to pave the way for potential improvements in the therapeutic delivery of TRAIL for the treatment of metastatic ES and other deadly GD2-positive malignancies.
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http://dx.doi.org/10.1016/j.tranon.2021.101240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517927PMC
October 2021

Sensing Inflammation Biomarkers with Electrolyte-Gated Organic Electronic Transistors.

Adv Healthc Mater 2021 10 22;10(20):e2100955. Epub 2021 Aug 22.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy.

An overview of cytokine biosensing is provided, with a focus on the opportunities provided by organic electronic platforms for monitoring these inflammation biomarkers which manifest at ultralow concentration levels in physiopathological conditions. Specifically, two of the field's state-of-the-art technologies-organic electrochemical transistors (OECTs) and electrolyte gated organic field effect transistors (EGOFETs)-and their use in sensing cytokines and other proteins associated with inflammation are a particular focus. The overview will include an introduction to current clinical and "gold standard" quantification techniques and their limitations in terms of cost, time, and required infrastructure. A critical review of recent progress with OECT- and EGOFET-based protein biosensors is presented, alongside a discussion onthe future of these technologies in the years and decades ahead. This is especially timely as the world grapples with limited healthcare diagnostics during the Coronavirus disease (COVID-19)pandemic where one of the worst-case scenarios for patients is the "cytokine storm." Clearly, low-cost point-of-care technologies provided by OECTs and EGOFETs can ease the global burden on healthcare systems and support professionals by providing unprecedented wealth of data that can help to monitor disease progression in real time.
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http://dx.doi.org/10.1002/adhm.202100955DOI Listing
October 2021

The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study.

PLoS One 2021 12;16(8):e0251378. Epub 2021 Aug 12.

Unit of Statistical and Methodological Support to Clinical Research, Azienda Ospedaliero-Universitaria, Modena, Italy.

Background: The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery.

Methods: In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery.

Results: Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2-5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1-0.7) or in OT (HR = 0.1, 95% CI = 0.0-0.8) treated with tocilizumab.

Conclusion: To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251378PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360516PMC
August 2021

Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection.

Nat Commun 2021 07 29;12(1):4677. Epub 2021 Jul 29.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.

SARS-CoV-2 infection can affect all human beings, including pregnant women. Thus, understanding the immunological changes induced by the virus during pregnancy is nowadays of pivotal importance. Here, using peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection, we investigate cell proliferation and cytokine production, measure plasma levels of 62 cytokines, and perform a 38-parameter mass cytometry analysis. Our results show an increase in low density neutrophils but no lymphopenia or gross alterations of white blood cells, which display normal levels of differentiation, activation or exhaustion markers and show well preserved functionality. Meanwhile, the plasma levels of anti-inflammatory cytokines such as interleukin (IL)-1RA, IL-10 and IL-19 are increased, those of IL-17, PD-L1 and D-dimer are decreased, but IL-6 and other inflammatory molecules remain unchanged. Our profiling of antiviral immune responses may thus help develop therapeutic strategies to avoid virus-induced damages during pregnancy.
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http://dx.doi.org/10.1038/s41467-021-24940-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322155PMC
July 2021

Measles-induced immune amnesia likely recorded in the 18th century.

J Clin Virol 2021 08 1;141:104899. Epub 2021 Jul 1.

University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.1016/j.jcv.2021.104899DOI Listing
August 2021

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19.

Cells 2021 06 23;10(7). Epub 2021 Jun 23.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy.

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.
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http://dx.doi.org/10.3390/cells10071585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306954PMC
June 2021

Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients.

Sci Rep 2021 06 16;11(1):12716. Epub 2021 Jun 16.

Diagnostic Hematology and Clinical Genomics Laboratory, Department of Laboratory Medicine and Pathology, AUSL/AOU Policlinico, Via del Pozzo 71, 41124, Modena, Italy.

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66-0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73-13.96; OR = 7.14, 95% CI: 2.06-24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.
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http://dx.doi.org/10.1038/s41598-021-92236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209163PMC
June 2021

Mitophagy and Oxidative Stress: The Role of Aging.

Antioxidants (Basel) 2021 May 17;10(5). Epub 2021 May 17.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.
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http://dx.doi.org/10.3390/antiox10050794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156559PMC
May 2021

Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: retrospective cohort study.

Multidiscip Respir Med 2021 Jan 17;16(1):737. Epub 2021 May 17.

Intensive Care Unit, University Hospital of Modena.

Background: The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit.

Methods: The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching.

Results: Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in nontreated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission.

Conclusions: Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation.
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http://dx.doi.org/10.4081/mrm.2021.737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139121PMC
January 2021

Identification and characterization of a SARS-CoV-2 specific CD8 T cell response with immunodominant features.

Nat Commun 2021 05 10;12(1):2593. Epub 2021 May 10.

Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, North Holland, The Netherlands.

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8 T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8 T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8 T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8 T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8 T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8 T cells during convalescence.
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http://dx.doi.org/10.1038/s41467-021-22811-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110804PMC
May 2021

COVID-19 in the tonsillectomised population.

Acta Otorhinolaryngol Ital 2021 Jun 6;41(3):197-205. Epub 2021 May 6.

ENT Clinic and Regional Center for Head and Neck Cancer, University of Padova Faculty of Medicine and Surgery, Department of Neurosciences, Treviso Regional Hospital, Treviso, Italy.

Objective: Interactions between SARS-CoV-2 and pharyngeal associated lymphoid tissue are thought to influence the manifestations of COVID-19. We aimed to determine whether a previous history of tonsillectomy, as a surrogate indicator of a dysfunctional pharyngeal associated lymphoid tissue, could predict the presentation and course of COVID-19.

Methods: Multicentric cross-sectional observational study involving seven hospitals in Northern and Central Italy. Data on the clinical course and signs and symptoms of the infection were collected from 779 adults who tested positive for SARS-CoV-2, and analysed in relation to previous tonsillectomy, together with demographic and anamnestic data.

Results: Patients with previous tonsillectomy showed a greater risk of fever, temperature higher than 39°C, chills and malaise. No significant differences in hospital admissions were found.

Conclusions: A previous history of tonsillectomy, as a surrogate indicator of immunological dysfunction of the pharyngeal associated lymphoid tissue, could predict a more intense systemic manifestation of COVID-19. These results could provide a simple clinical marker to discriminate suspected carriers and to delineate more precise prognostic models.
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http://dx.doi.org/10.14639/0392-100X-N1436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283408PMC
June 2021

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

Lancet Respir Med 2021 06 6;9(6):622-642. Epub 2021 May 6.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.
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http://dx.doi.org/10.1016/S2213-2600(21)00218-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102044PMC
June 2021

Gene Expression Analysis of T-Cells by Single-Cell RNA-Seq.

Methods Mol Biol 2021 ;2285:277-296

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

During the last decade, the rapid progress in the development of next-generation sequencing (NGS) technologies has provided relevant insights into complex biological systems, ranging from cancer genomics to microbiology. Among NGS technologies, single-cell RNA sequencing is currently used to decipher the complex heterogeneity of several biological samples, including T cells. Even if this technique requires specialized equipment and expertise, nowadays it is broadly applied in research. In this chapter, we will provide an optimized protocol for the isolation of T cells and the preparation of RNA sequencing libraries by using droplet digital technology (ddSEQ, Bio-Rad Laboratories). We will also illustrate a guide to the main steps of data processing and options for data interpretation. This protocol will support users in building a single-cell experimental framework, from sample preparation to data interpretation.
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http://dx.doi.org/10.1007/978-1-0716-1311-5_22DOI Listing
June 2021

To Ki or Not to Ki: Re-Evaluating the Use and Potentials of Ki-67 for T Cell Analysis.

Front Immunol 2021 9;12:653974. Epub 2021 Apr 9.

Immunosurveillance Laboratory, The Francis Crick Institute, London, United Kingdom.

This study discusses substantive advances in T cell proliferation analysis, with the aim to provoke a re-evaluation of the generally-held view that Ki-67 is a reliable proliferation marker , and to offer a more sensitive and effective method for T cell cycle analysis, with informative examples in mouse and human settings. We summarize recent experimental work from our labs showing that, by Ki-67/DNA dual staining and refined flow cytometric methods, we were able to identify T cells in the S-G/M phases of the cell-cycle in the peripheral blood (collectively termed "T Double S" for T cells in S-phase : in short "T" cells). Without our refinement, such cells may be excluded from conventional lymphocyte analyses. Specifically, we analyzed clonal expansion of antigen-specific CD8 T cells in vaccinated mice, and demonstrated the potential of T cells to reflect immune dynamics in human blood samples from healthy donors, and patients with type 1 diabetes, infectious mononucleosis, and COVID-19. The Ki-67/DNA dual staining, or T assay, provides a reliable approach by which human peripheral blood can be used to reflect the dynamics of human lymphocytes, rather than providing mere steady-state phenotypic snapshots. The method does not require highly sophisticated "-omics" capabilities, so it should be widely-applicable to health care in diverse settings. Furthermore, our results argue that the T assay can provide a window on immune dynamics in extra-lymphoid tissues, a long-sought potential of peripheral blood monitoring, for example in relation to organ-specific autoimmune diseases and infections, and cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.653974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062736PMC
May 2021

Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy.

Nat Commun 2021 03 15;12(1):1669. Epub 2021 Mar 15.

Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8 T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8 T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8 population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.
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http://dx.doi.org/10.1038/s41467-021-21928-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961017PMC
March 2021

Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment.

Cells 2021 02 16;10(2). Epub 2021 Feb 16.

Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.

Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15-17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death.
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http://dx.doi.org/10.3390/cells10020410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920460PMC
February 2021

Methylprednisolone as rescue therapy after tocilizumab failure in patients with severe COVID-19 pneumonia.

Clin Exp Rheumatol 2021 Sep-Oct;39(5):1141. Epub 2021 Mar 3.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

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September 2021

Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.

PLoS One 2021 23;16(2):e0247275. Epub 2021 Feb 23.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria, Policlinico of Modena, Modena, Italy.

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients' profile.

Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day 6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort.

Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively.

Conclusions: Our score could assist clinicians in identifying, early after tocilizumab administration, patients who are likely to progress to mechanical ventilation or death, so that they could be selected for eventual rescue therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901750PMC
March 2021

Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia.

AIDS Res Hum Retroviruses 2021 04;37(4):283-291

Department of Surgical, Medical, Dental, and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch ( > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c,  = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%,  < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%,  = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.
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http://dx.doi.org/10.1089/AID.2020.0305DOI Listing
April 2021

Finding predictive factors for immunotherapy in metastatic renal-cell carcinoma: What are we looking for?

Cancer Treat Rev 2021 Mar 1;94:102157. Epub 2021 Feb 1.

Department of Biomedical Sciences and Human Oncology, University of Bari 'A. Moro', Bari, Italy.

A major breakthrough in cancer immunotherapy was the development of monoclonal antibodies targeting inhibitory immune checkpoint proteins. This approach demonstrated significant antitumor activity and efficacy in different cancer types, including metastatic renal cell carcinoma (mRCC). In the majority of patients, this drug is able to restore the patient's tumour-specific T-cell-mediated response thus improving both overall survival and objective response rate. However, a lack of clinical response occurs in a number of patients, raising questions about how to predict and increase the number of patients who receive long-term clinical benefit from immune checkpoint therapy or not. The aim of this review is to summarize available data about immune biomarkers in patients with mRCC treated with immunotherapy.
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http://dx.doi.org/10.1016/j.ctrv.2021.102157DOI Listing
March 2021

Sex Difference in Access to Sports: A 1-Year Retrospective Study.

Am J Lifestyle Med 2021 Jan-Feb;15(1):108-112. Epub 2020 Dec 29.

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy (MN, AVM).

Regular physical activity is a cornerstone in the prevention and treatment of cardiovascular disease thanks to its anti-inflammatory effects. Thus, favoring the access to sports is of importance for promoting well-being. The aim of the present study was to investigate how the practice of different sports is distributed among different age groups and between men and women, by taking a picture of the medical certificate request in 2017 for sports in the population of the province of Modena, Italy. We analyzed the difference in distribution of requested medical certificate from 18 874 males and 7625 females stratified for age (<18 years, 18-40 years, and >40 years) and for different sporting disciplines (athletics, football, bike, swimming, basketball, volleyball, tennis, other team sports, other individual sports, and disabled sports). Men requested medical certificates more than women (more than 2.5 times). The distribution of requested certificates differs significantly (chi-square test < .0001) at different ages and between males and females of same age. Certificate for men aged less than 18 years were 7550 and for women were 4131 and the difference increase with age. . In order to decrease the imbalance between men and women access to sports, it is mandatory to promote a healthy lifestyle and reduce, as consequence, cardiovascular risks, mostly in women after 40 years.
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http://dx.doi.org/10.1177/1559827620911610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781057PMC
December 2020

Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator.

Clin Microbiol Infect 2021 Aug 20;27(8):1137-1144. Epub 2021 Jan 20.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy; Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy.

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference.

Methods: This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted.

Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO/FiO (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26-0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex.

Discussion: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.
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http://dx.doi.org/10.1016/j.cmi.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816626PMC
August 2021

Anti-drug antibody detection with label-free electrolyte-gated organic field-effect transistors.

Chem Commun (Camb) 2021 Jan;57(3):367-370

Dipartimento di Scienze della Vita - Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

The efficacy of immunotherapy can be undermined by the development of an immune response against a drug/antibody mediated by anti-drug antibodies (ADAs) in treated patients. We present the first label-free EGOFET immunosensor that integrates a biological drug, Nivolumab (Opdivo©), as a specific recognition moiety to quantitatively and selectively detect ADAs against the drug. The limit of detection is 100 fM. This demonstration is a prelude to the detection of ADAs in a clinical setting in the treatment of different pathologies, and it also enables rapid screening of biological drugs for immunogenicity.
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http://dx.doi.org/10.1039/d0cc03399eDOI Listing
January 2021

NLRP3 and IL-1β Gene Expression Is Elevated in Monocytes From HIV-Treated Patients With Neurocognitive Disorders.

J Acquir Immune Defic Syndr 2021 04;86(4):496-499

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

Background: Systemic immune activation and inflammation in chronic HIV infection are driving factors of non-AIDS-related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied, but its association with the extent of neurocognitive dysfunction has been poorly investigated.

Methods: We enrolled 79 HIV-positive patients; 44 with varying levels of HIV-associated neurocognitive disorder (HAND) and 35 without and 8 healthy donors. HAND subtypes included asymptomatic neurocognitive impairment (asymptomatic neurocognitive impairment; n = 19), mild neurocognitive disorder (MND; n = 17), and HIV-associated dementia (n = 8). We quantified plasmatic concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-17A, IL-1β, and IFN-γ) for all HIV patients, and the mRNA expression of genes involved in the inflammasome activity (NLRP3, PYCARD, NAIP, AIM2, IL-1β, and IL-18) in monocytes of a subgroup of 28 HIV patients and 8 healthy donors.

Results: HIV patients' plasma concentrations of IFN-γ, IL-1β, and IL-17A were undetectable. Levels of TNF-α and IL-6 were similar among the HIV patient groups. A trend toward an increased expression of inflammasome genes according to neurocognitive disorder severity was observed. Of note, the NLRP3 mRNA relative expression was higher in MND compared with other groups, and IL-1β was lower in MND than HIV-associated dementia patients.

Conclusions: Changes in inflammasome components in circulating monocytes according to different HAND severity suggest that NLRP3 may be a possible biomarker or target to better understand and treat the link between systemic inflammation and neurocognitive impairment in HIV infection.
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http://dx.doi.org/10.1097/QAI.0000000000002588DOI Listing
April 2021

Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia-Challenges, strengths, and opportunities in a global health emergency.

PLoS One 2020 12;15(11):e0239172. Epub 2020 Nov 12.

Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.

Aims: The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia.

Methods: This was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients' medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome.

Results: A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth "boosted mixed model" included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example.

Conclusion: This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660476PMC
November 2020

Effects of whole-body cryotherapy on the innate and adaptive immune response in cyclists and runners.

Immunol Res 2020 12 7;68(6):422-435. Epub 2020 Nov 7.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The study aimed to identify the effects of whole-body cryotherapy (WBC) on immunological, hormonal, and metabolic responses of non-professional male athletes. Ten cyclists and ten middle-distance runners received 3 once-a-day sessions of WBC. Before initiating and after the final WBC session, a full set of hematologic parameters, serum chemistry profile, hormones, circulating mitochondrial (mt) DNA levels, cytokines, and chemokines concentration were evaluated. The phenotype of monocyte, T cells, and B cells was analyzed. mRNA expression of 6 genes involved in inflammasome activation (NAIP, AIM2, NLRP3, PYCARD, IL-1β, and IL-18) was quantified. WBC reduced glucose and C and S protein and increased HDL, urea, insulin-like growth factor (IGF)-1, follicle-stimulating hormone, IL-18, IL-1RA, CCL2, and CXCL8. Intermediate and non-classical monocyte percentages decreased, and the CD14, CCR5, CCR2, and CXCR4 expressions changed in different subsets. Only IL-1β mRNA increased in monocytes. Finally, a redistribution of B and T cell subsets was observed, suggesting the migration of mature cells to tissue. WBC seems to induce changes in both innate and adaptive branches of the immune system, hormones, and metabolic status in non-professional male athletes, suggesting a beneficial involvement of WBC in tissue repair.
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http://dx.doi.org/10.1007/s12026-020-09165-1DOI Listing
December 2020
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