Publications by authors named "Marina Borro"

55 Publications

Gastric microbiota composition in patients with corpus atrophic gastritis.

Dig Liver Dis 2021 Jun 8. Epub 2021 Jun 8.

Medical-Surgical Department of Clinical Sciences and Translational Medicine, Sant'Andrea Hospital, University Sapienza, Rome, Italy. Electronic address:

Background: In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate.

Aims: To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG.

Methods: A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene.

Results: Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p < 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p < 0.0001). Streptococcaceae were more abundant in cases (p < 0.0001), Prevotellaceae in controls (p < 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer.

Conclusion: Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.
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http://dx.doi.org/10.1016/j.dld.2021.05.005DOI Listing
June 2021

"Accuracy and Cost-Effectivenss of a Novel Method for Alpha Defensins Measurement in the Diagnosis of Periprosthetic Joint Infections".

J Arthroplasty 2021 May 15. Epub 2021 May 15.

Sant'Andrea Hospital - Sapienza University of Rome, Rome, Italy; Sant'Andrea Hospital - Orthopaedic Unit and Kirk Kilgour Sports Injury Centre, Rome, Italy.

Background: Two methods for detecting synovial fluids alpha defensins are available: the enzyme-linked immunosorbent assay and the lateral flow test. For both, the proper role and accuracy remain uncertain. The purpose of this study was to assess the accuracy of the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) for alpha defensin detection in synovial fluids of patients with total knee arthroplasty/total hip arthroplasty failures. The hypothesis was that the alpha defensin measurement through MALDI-TOF MS assay could be a high sensitive and specific test for periprosthetic joint infections (PJI) diagnosis as compared with Musculoskeletal Infection Society (MSIS) criteria.

Methods: The study included 138 patients. The 2018 MSIS criteria were used to diagnose PJIs. Synovial fluids were assessed for routinely synovial fluid tests and alpha defensin measurement through MALDI-TOF MS. Sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, receiver operator curves, and area under the curve were calculated.

Results: As per the 2018 MSIS criteria, 59 PJIs (43%) and 79 aseptic failures (57%) were diagnosed. The MALDI-TOF MS assay showed an overall accuracy of 94.9%. The sensitivity was 93%, the specificity was 96%, the positive predictive value was 95%, and the negative predictive value was 95%. Receiver operator curves analysis demonstrates an area under the curve of 0.95 (P < .001).

Conclusion: The MALDI-TOF MS assay showed high sensitivity and specificity for alpha defensin detection in case of total knee arthroplasty/total hip arthroplasty failures. The advantages of the technology, such as the few milliliters of sample needed, the rapidity of obtaining results, and the cost-effectiveness of the procedure could make the MALDI-TOF MS alpha defensin assay a useful and widespread test in clinical practice.
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http://dx.doi.org/10.1016/j.arth.2021.05.013DOI Listing
May 2021

PON1 polymorphisms can predict generalized anxiety and depressed mood in patients with multiple chemical sensitivity.

Per Med 2021 May 17;18(3):255-267. Epub 2021 Mar 17.

Department of Neuroscience, Mental Health, & Sensory Organs (NESMOS), Faculty of Medicine & Psychology, Sapienza University, Rome, Italy.

Multiple chemical sensitivity (MCS) is a chronic condition with somatic, cognitive and affective symptoms that follow contact with chemical agents at usually non toxic concentrations. We aimed to assess the role of genetic polymorphisms involved in oxidative stress on anxiety and depression in MCS. Our study investigated the rs1001179, rs2333227, rs662 and rs705379 polymorphisms in MCS. The AG genotype of the rs662 and the TT and CT genotypes of the rs705379 were involved in anxiety and depression. These results are in line with existing evidence of involvement in MCS and suggest a further role of this gene in the exhibition of anxiety and depression in this disease.
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http://dx.doi.org/10.2217/pme-2019-0141DOI Listing
May 2021

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

Biochim Biophys Acta Mol Basis Dis 2021 03 16;1867(3):166042. Epub 2020 Dec 16.

Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Rome, Italy; Laboratory of Clinical Biochemistry, Advanced Molecular Diagnostic Unit, Sant'Andrea University Hospital, Rome, Italy. Electronic address:

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.
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http://dx.doi.org/10.1016/j.bbadis.2020.166042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834629PMC
March 2021

Gut microbiota composition in children with obstructive sleep apnoea syndrome: a pilot study.

Sleep Med 2020 12 17;76:140-147. Epub 2020 Oct 17.

Pediatric Sleep Disease Center, Child Neurology, NESMOS Dept, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Rome, Italy. Electronic address:

Background: Obstructive Sleep Apnoea syndrome (OSAS) is considered a systemic inflammatory disease and is characterized by intermittent hypoxia that can damage the integrity of intestinal barrier and alter gut microbiota composition in adults and animal models. To date there is only one study on snoring children and microbiota but no studies are present on paediatric OSAS related dysbiosis.

Study Objectives: To evaluate gut microbiota composition in OSAS children in respect to healthy subjects and investigate the role of sleep parameters in changing gut microbiome.

Methods: Sixteen children divided in OSAS and healthy groups. Stool samples were collected from both the two groups to assess gut microbiota composition using 16S rRNA sequencing and a nocturnal pulsossimetry and polysomnography were performed in OSAS children.

Results: OSAS children showed a decreased microbial diversity in respect to healthy subjects in terms of number of observed species and Chao1 index (p = 0,01). Firmicutes/Bacteroidetes ratio was directly correlated to Sleep Clinical Record (p = 0,03). The abundance of several inflammation-related strains (Proteobacteria, Clostridiaceae, Oscillospiraceae, Klebsiella) were found significantly modified in relation to sleep parameters. Bacteria implied in the gut barrier integrity (Desulfovibrionaceae, Bacteroides fragilis and Faecalibacterium prausnitzii) were found significantly different in the two study groups and correlated with sleep parameters.

Conclusions: OSAS children showed a lower microbiota diversity in respect to heathy subjects and an increase of inflammation and gut barrier disruptors-related strains probably induced by intermittent hypoxia. Further studies should be conducted to understand the role of gut microbiota in OSAS physiopathology and comorbidities in children.
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http://dx.doi.org/10.1016/j.sleep.2020.10.017DOI Listing
December 2020

Inter-individual variation in CYP2A6 activity and chronic obstructive pulmonary disease in smokers: Perspectives for an early predictive marker.

Biochim Biophys Acta Mol Basis Dis 2021 01 19;1867(1):165990. Epub 2020 Oct 19.

Laboratory of Clinical Biochemistry, Sant'Andrea Hospital, Rome, Italy; Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.bbadis.2020.165990DOI Listing
January 2021

Multiple Chemical Sensitivity Syndrome: A Principal Component Analysis of Symptoms.

Int J Environ Res Public Health 2020 09 9;17(18). Epub 2020 Sep 9.

Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University, 00185 Rome, Italy.

Multiple Chemical Sensitivity (MCS) is a chronic and/or recurrent condition with somatic, cognitive, and affective symptoms following a contact with chemical agents whose concentrations do not correlate with toxicity in the general population. Its prevalence is not well defined; it mainly affects women between 40 and 50 years, without variations in ethnicity, education and economic status. We aimed to assess the core symptoms of this illness in a sample of Italian patients. Two physicians investigated different symptoms with a checklist compilation in 129 patients with MCS (117 women). We conducted a categorical Principal Component Analysis (CATPCA) with Varimax rotation on the checklist dataset. A typical triad was documented: hyperosmia, asthenia, and dyspnoea were the most common symptoms. Patients also frequently showed cough and headache. The CATPCA showed seven main factors: 1, neurocognitive symptoms; 2, physical (objective) symptoms; 3, gastrointestinal symptoms; 4, dermatological symptoms; 5, anxiety-depressive symptoms; 6, respiratory symptoms; 7, hyperosmia and asthenia. Patients showed higher mean prevalence of factors 7 (89.9%), 6 (71.7%), and 1 (62.13%). In conclusion, MCS patients frequently manifest hyperosmia, asthenia, and dyspnoea, which are often concomitant with other respiratory and neurocognitive symptoms. Considering the clinical association that is often made with anxiety, more studies are necessary on the psychosomatic aspects of this syndrome. Further analytical epidemiological studies are needed to support the formulation of aetiological hypotheses of MCS.
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http://dx.doi.org/10.3390/ijerph17186551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558401PMC
September 2020

Evidence-Based Considerations Exploring Relations between SARS-CoV-2 Pandemic and Air Pollution: Involvement of PM2.5-Mediated Up-Regulation of the Viral Receptor ACE-2.

Int J Environ Res Public Health 2020 08 2;17(15). Epub 2020 Aug 2.

Laboratory of Clinical Biochemistry, University Hospital Sant'Andrea, Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University, via di Grottarossa 1035, 00189 Rome, Italy.

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists -coping with the high inter-individual variability of COVID-19, and for policy makers -coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM) concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February-31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM levels and the incidence (r = 0.67, < 0.0001), the mortality rate (r = 0.65, < 0.0001) and the case fatality rate (r = 0.7, < 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.
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http://dx.doi.org/10.3390/ijerph17155573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432777PMC
August 2020

The Exponential Phase of the Covid-19 Pandemic in Central Italy: An Integrated Care Pathway.

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

Medical Direction Sant'Andrea Hospital, University La Sapienza, 00189 Rome, Italy.

The Coronavirus Disease (Covid-19) pandemic is rapidly spreading across the world, representing an unparalleled challenge for health care systems. There are differences in the estimated fatality rates, which cannot be explained easily. In Italy, the estimated case fatality rate was 12.7% in mid-April, while Germany remained at 1.8%. Moreover, it is to be noted that different areas of Italy have very different lethality rates. Due to the complexity of Covid-19 patient management, it is of paramount importance to develop a well-defined clinical workflow in order to avoid the inconsistent management of patients. The Integrated Care Pathway (ICP) represents a multidisciplinary outline of anticipated care to support patient management in the Sant'Andrea Hospital, Rome. The main objective of this pilot study was to develop a new ICP evaluated by care indicators, in order to improve the COVID-19 patient management. The suggested ICP was developed by a multi-professional team composed of different specialists and administrators already involved in clinical and management processes. After a review of current internal practices and published evidences, we identified (1) the activities performed during care delivery, (2) the responsibilities for these activities, (3) hospital structural adaptation needs and potential improvements, and (4) ICP indicators. The process map formed the basis of the final ICP document; 160 COVID-19 inpatients were considered, and the effect of the ICP implementation was evaluated over time during the exponential phase of the COVID-19 pandemic. In conclusion, a rapid adoption of ICP and regular audits of quality indicators for the management of COVID-19 patients might be important tools to improve the quality of care and outcomes.
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http://dx.doi.org/10.3390/ijerph17113792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312393PMC
May 2020

Detection of α-defensin in synovial fluids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as an innovative and cost-effective assay for improved definition of periprosthetic joint infections.

Rapid Commun Mass Spectrom 2020 Jun;34(11):e8791

Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, via di Grottarossa 1035, Rome, 00185, Italy.

Rationale: Detection of α-defensins in synovial fluid is gaining more and more interest in the field of correct diagnosis of periprosthetic joint infections (PJIs). At present, they can be assessed by a quantitative enzyme-linked immunosorbent assay which is expensive and time-consuming and by a qualitative lateral flow immunoassay which is rapid but quite expensive and whose clinical sensitivity is debated. Thus, developing an alternative rapid, accurate, and low-cost assay for α-defensins is important to make α-defensins actionable as novel key clinical markers.

Methods: Synovial fluid (SF) samples were obtained from 18 patients undergoing revision of primary joint arthroplasty. Of these, eight met the 2013 Musculoskeletal Infection Society (MSIS) criteria for PJIs, the remaining were classified as aseptic failure. Microbiological analysis and Synovasure assays were carried out on all samples. Sample preparation and the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) settings were adjusted to detect human neutrophil peptide (HNP)-1, -2 and -3 and to obtain optimal results in term of sensitivity and stability.

Results: MALDI-TOF MS was able to detect HNPs in SF from septic patients. No signals for HNPs were detected in SF from aseptic failure. The limits of detection (LOD) were 2.5 and 1.25 μg/mL for HNP-2 and HNP-1, respectively. The turnaround time of the analysis is 20 min, and SF samples are stable at -20°C for up to 3 days. Assay sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were 100% for all parameters. On the same SF samples, the Synovasure assay showed lower sensitivity specificity, and PPV and NPV of 87.5%, 90%, 87.5% and 90%, respectively. Microbiological analysis of SF confirmed the presence of bacteria only in SF MSIS-positive patients.

Conclusions: The reported MALDI-TOF MS assay was able to detect and differentiate HNPs in SF samples and showed a slightly better diagnostic accuracy than the Synovasure assay.
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http://dx.doi.org/10.1002/rcm.8791DOI Listing
June 2020

Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.

Biol Chem 2020 03;401(4):497-503

Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Via Paolo Gaifami 18, I-95126 Catania, Italy.

Impaired energy metabolism may play a role in the pathogenesis of neurodevelopmental disorders including fragile X syndrome (FXS). We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS. We found that, despite a hyperactivation of MRC complexes, adenosine triphosphate (ATP) production via mitochondrial oxidative phosphorylation (OXPHOS) is compromised, resulting in brain energy impairment in juvenile and late-adult Fmr1 KO mice. Thus, an altered mitochondrial energy metabolism may contribute to neurological impairment in FXS.
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http://dx.doi.org/10.1515/hsz-2019-0221DOI Listing
March 2020

The future of pharmacogenetics in the treatment of migraine.

Pharmacogenomics 2019 11 22;20(16):1159-1173. Epub 2019 Oct 22.

Department of Neurosciences, Mental Health & Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy.

Migraine is considered one of the most disabling neurological disorder with a high socioeconomic burden. Pharmacological management includes many classes of drugs which in the most cases, are administrated in polytherapy. The therapeutic scheme of migraineurs is often affected by comorbidities which need concomitant medications, thus increasing the risk of side effects related to drug-drug interactions. Pharmacogenetics is a promising tool to achieve a personalized cure based on individual genetic profile while the availability of free online knowledge bases allows to check the potential DDIs of selected medications. Combining, these approaches may offer to clinicians a useful tool to improve the appropriateness of migraine polytherapy choice, aiming to increase the efficacy and reduce the toxicity of pharmacological treatments.
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http://dx.doi.org/10.2217/pgs-2019-0069DOI Listing
November 2019

Optimising migraine treatment: from drug-drug interactions to personalized medicine.

J Headache Pain 2019 May 17;20(1):56. Epub 2019 May 17.

Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.

Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale.
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http://dx.doi.org/10.1186/s10194-019-1010-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734220PMC
May 2019

Genetics of Obstructive Sleep Apnea: Vitamin D Receptor Gene Variation Affects Both Vitamin D Serum Concentration and Disease Susceptibility.

OMICS 2019 01 18;23(1):45-53. Epub 2018 Dec 18.

2 MSc Programme in Sleep Medicine, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.

Obstructive sleep apnea syndrome (OSAS) is a multifactorial and common disorder affecting 10-17% of men and 3-9% of women. A low vitamin D serum concentration has been reportedly linked to OSAS susceptibility, but the underlying molecular genetic mechanisms are poorly understood thus far. We report here original findings on the ways in which vitamin D receptor (VDR) gene polymorphic variation (FokI, BsmI, ApaI, and TaqI polymorphisms) impacts serum vitamin D concentration and, additionally, susceptibility to OSAS. In a sample of 176 consecutive subjects (144 patients with OSAS and 32 healthy controls) phenotyped by full polysomnography (PSG), we characterized human genetic variation in VDR using the Sequenom MassARRAY iPLEX platform. A logistic regression analysis was employed to account and correct for covariates such as sex, age, body mass index, and comorbidities. Importantly, we observed that the FokI CC genotype frequency was markedly higher in patients with OSAS compared with controls (50.7% vs. 28.1%; p = 0.027). VDR FokI polymorphism explained 14.5% of vitamin D serum concentration variability. Moreover, the VDR FokI polymorphism was also associated with excessive daytime sleepiness (p = 0.016). To the best of our knowledge, this is the first clinical genetics study examining the role of VDR polymorphic variation on OSAS as phenotyped using full PSG. We call for further studies of vitamin D-related mechanisms that might contribute to OSAS risk in independent populations.
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http://dx.doi.org/10.1089/omi.2018.0184DOI Listing
January 2019

Pharmacogenetic considerations for migraine therapies.

Expert Opin Drug Metab Toxicol 2018 Nov 1;14(11):1161-1167. Epub 2018 Nov 1.

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

Introduction: Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy. Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals. Expert opinion: Pharmacogenetics is based on the identification of polymorphism and promises personalized therapy with efficacy and reduction of adverse events. The association between genotype and an altered metabolizer status could guide clinical decision to evade concomitant treatments and adverse events. The introduction of routine genetic testing could help to choose the efficacy drug on the individual and genetic profile.
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http://dx.doi.org/10.1080/17425255.2018.1541452DOI Listing
November 2018

Tailoring Treatment in Polymorbid Migraine Patients through Personalized Medicine.

CNS Drugs 2018 06;32(6):559-565

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

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http://dx.doi.org/10.1007/s40263-018-0532-6DOI Listing
June 2018

Short-term one-lung ventilation does not influence local inflammatory cytokine response after lung resection.

J Thorac Dis 2018 Mar;10(3):1864-1874

Department of Anesthesiology and Intensive Care, Sapienza University of Rome, Italy.

Background: One-lung ventilation (OLV) is a ventilation procedure used for pulmonary resection which may results in lung injury. The aim of this study was to evaluate the local inflammatory cytokine response from the dependent lung after OLV and its correlation to VT. The secondary aim was to evaluate the clinical outcome of each patient.

Methods: Twenty-eight consecutive patients were enrolled. Ventilation was delivered in volume-controlled mode with a VT based on predicted body weight (PBW). 5 cmHO positive end-expiratory pressure (PEEP) and FiO 0.5 were applied. Bronchoalveolar lavage (BAL) was performed in the dependent lung before and after OLV. The levels of pro-inflammatory interleukins (IL-1α, IL-1β, IL-6, IL-8), tumor necrosis factor alpha (TNFα), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines, such as interleukins (IL-2, IL-4, IL-10) and interferon (IFN-γ), were evaluated. Subgroup analysis: to analyze the VT setting during OLV, all patients were ventilated within a range of 5-10 mL/kg. Thirteen patients, classified as a conventional ventilation (CV) subgroup, received 8-10 mL/kg, while 15 patients, classified as a protective ventilation (PV) subgroup, received 5-7 mL/kg.

Results: Cytokine BAL levels after surgery showed no significant increase after OLV, and no significant differences were recorded between the two subgroups. The mean duration of OLV was 64.44±21.68 minutes. No postoperative respiratory complications were recorded. The mean length of stay was for 4.00±1.41 days in the PV subgroup and 4.45±2.07 days in the CV group; no statistically significant differences were recorded between the two subgroups (P=0.511).

Conclusions: Localized inflammatory cytokine response after OLV was not influenced by the use of different VT. Potentially, the application of PEEP in both ventilation strategies and the short duration of OLV could prevent postoperative complications.
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http://dx.doi.org/10.21037/jtd.2018.03.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906264PMC
March 2018

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient.

Anticancer Drugs 2017 06;28(5):551-556

Departments of aClinical and Molecular Medicine bRadiological Oncological and Pathological Sciences cNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome dDepartment of Medical Oncology, Sant'Andrea Hospital eLaboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute fIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.
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http://dx.doi.org/10.1097/CAD.0000000000000492DOI Listing
June 2017

Clinical Applications of Personalized Medicine: A New Paradigm and Challenge.

Curr Pharm Biotechnol 2017 ;18(3):194-203

Malzoni Clinical-Scientific Institute (MaCSI), Via Carmelo Errico 2, 83100 Avellino, Italy.

The personalized medicine is an emergent and rapidly developing method of clinical practice that uses new technologies to provide decisions in regard to the prediction, prevention, diagnosis and treatment of disease. A continuous evolution of technology and the developments in molecular diagnostics and genomic analysis increased the possibility of an even more understanding and interpretation of the human genome and exome, allowing a "personalized" approach to clinical care, so that the concepts of "Systems Medicine" and "System Biology" are actually increasing. The purpose of this study is to evaluate the personalized medicine about its indications and benefits, actual clinical applications and future perspectives as well as its issues and health care implications. A careful review of the scientific literature on this field that highlighted the applicability and usefulness of this new medical approach as well as the fact that personalized medicine strategy is even more increasing in numerous fields of applications.
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http://dx.doi.org/10.2174/1389201018666170224105600DOI Listing
December 2017

Personalised Healthcare: The DiMA Clinical Model.

Curr Pharm Biotechnol 2017 ;18(3):242-252

DiMA (Advanced Molecular Diagnosis), Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital - Sapienza University of Rome, Via di Grottarossa, 00189 Rome. Italy.

Large-scale application of Personalized Medicine requires a multi-disciplinal environment allowing synergic cooperation among different competences. Strict collaboration between medical and medical sciences, as informatics, ethics, politics, are needed to face the challenges of one-sized healthcare. In spite of the increasing interest, how this system can be globally realized remains tentative. Yet, a relatively small, Personalised Healthcare Service is providing a proof-of principle organizational model to guide implementation into clinical practice.
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http://dx.doi.org/10.2174/1389201018666170208125131DOI Listing
December 2017

Personalized Medicine Applied to Forensic Sciences: New Advances and Perspectives for a Tailored Forensic Approach.

Curr Pharm Biotechnol 2017 ;18(3):263-273

IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli. Italy.

Personalized medicine (PM), included in P5 medicine (Personalized, Predictive, Preventive, Participative and Precision medicine) is an innovative approach to the patient, emerging from the need to tailor and to fit the profile of each individual. PM promises to dramatically impact also on forensic sciences and justice system in ways we are only beginning to understand. The application of omics (genomic, transcriptomics, epigenetics/imprintomics, proteomic and metabolomics) is ever more fundamental in the so called "molecular autopsy". Emerging fields of interest in forensic pathology are represented by diagnosis and detection of predisposing conditions to fatal thromboembolic and hypertensive events, determination of genetic variants related to sudden death, such as congenital long QT syndromes, demonstration of lesions vitality, identification of biological matrices and species diagnosis of a forensic trace on crime scenes without destruction of the DNA. The aim of this paper is to describe the state-of-art in the application of personalized medicine in forensic sciences, to understand the possibilities of integration in routine investigation of these procedures with classical post-mortem studies and to underline the importance of these new updates in medical examiners' armamentarium in determining cause of death or contributing factors to death.
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http://dx.doi.org/10.2174/1389201018666170207141525DOI Listing
December 2017

Integrated OMICS tools for personalised medicine.

J Headache Pain 2015 Dec;16(Suppl 1):A9

Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Sapienza University of Roma, Rome, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715066PMC
December 2015

Lasmiditan for the treatment of migraine.

Expert Opin Investig Drugs 2017 Feb;26(2):227-234

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

Introduction: Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.
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http://dx.doi.org/10.1080/13543784.2017.1280457DOI Listing
February 2017

5-Fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX.

Anticancer Drugs 2017 03;28(3):322-326

Departments of aClinical and Molecular Medicine bNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome Departments of cMedical Oncology dGeneral Surgery, Sant'Andrea Hospital eIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.
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http://dx.doi.org/10.1097/CAD.0000000000000453DOI Listing
March 2017

Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer.

Oncotarget 2017 Feb;8(8):14050-14057

Advanced Molecular Diagnostic, IDI-IRCCS, Rome, Italy.

Background: 5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer, but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity.

Methods: Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Association with toxicities was retrospectively evaluated, using multivariate logistic regression analysis.

Results: 107 gastro-esophageal cancer patients were retrospectively analyzed. No relation between gene polymorphisms and toxicity were detected, while low (< 5th centile) and high (> 95th centile) 5-FUDRs were associated with development of grade 3-4 toxicity (OR 11.14, 95% CI 1.09-113.77 and OR 9.63, 95% CI 1.70-54.55, p = 0.002).

Conclusions: Compared to currently used genetic tests, the pre-treatment 5-FUDR seems useful in identifying patients at risk of developing toxicity.
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http://dx.doi.org/10.18632/oncotarget.12571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355161PMC
February 2017

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

PLoS One 2016;11(9):e0163105. Epub 2016 Sep 22.

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

Background: 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival.

Materials And Methods: Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.

Results: 133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed.

Conclusion: 5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033390PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163105PLOS
September 2016

H2020 and Beyond: Skip Discrepancy between Theory and Practice of Personalized Medicine. A Position Paper by the Italian Society of Personalized Medicine.

Curr Pharm Biotechnol 2016;17(10):926-9

Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00185 Rome, Italy.

Many unsolved practical issues, from technical and scientific to ethical, legal and economic topics, are slowing down the translation of Personalized Medicine principles into medical practice. The Italian Society of Personalized Medicine exposes here its point of view, based on the real-world practice of precision medicine carried-out in Italian healthcare structures.
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http://dx.doi.org/10.2174/1389201017666160519112850DOI Listing
December 2016

CYP19A1 Genetic Polymorphisms rs4646 and Osteoporosis in Patients Treated with Aromatase Inhibitor-Based Adjuvant Therapy.

Eurasian J Med 2016 Feb 7;48(1):10-4. Epub 2015 Jul 7.

Department of Clinical Oncology, Sant'Andrea Hospital, School of Medicine and Psychology, University of Rome La Sapienza, Rome, Italy.

Objective: Third-generation aromatase inhibitors (AI) are potent suppressors of aromatase activity. The aim of this study was to measure the incidence of adverse effects in breast cancer patients treated with AI-based adjuvant therapy and the relationship with the CYP19A1 genotypes.

Materials And Methods: Forty-five postmenopausal breast cancer patients (46-85 yrs) in AI adjuvant treatment were genotyped for the rs4646 polymorphisms of CYP19A1 gene and three variations were identified. Toxicities were registered at each follow-up medical examination, and classified in accord with the Common Terminology Criteria for Adverse Events.

Results: Twenty-four (53.3%) patients presented the GG genotype; 19 (42.2%) the GT, and 2 (4.4%) the TT. The AI treatment was Anastrazole for 35 patients (77.8%) and Letrozole for the others (n=10; 22.2%). Osteoporosis was significantly associated with the GG genotype (p=0.001). Treatment discontinuation (TD) was observed in 6 cases (13.3%). The only parameter able to predict TD was the appearance of severe arthralgia/myalgia (Odds Ratio, OR=23.75; p=0.009), when adjusted for age and AI treatment.

Conclusion: Our results suggest that CYP19A1 polymorphic variants may influence susceptibility to develop AI-related side effects. Further prospective studies are needed to confirm the role of the aromatase gene (CYP19A1) polymorphisms in predicting adverse effects to AI-based therapy.
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http://dx.doi.org/10.5152/eurasianjmed.2015.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792488PMC
February 2016

Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort.

Oncotarget 2016 Apr;7(15):20612-20

Oncology Unit, Sant'Andrea Hospital, Rome, Italy.

Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3-4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A.
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http://dx.doi.org/10.18632/oncotarget.7991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991479PMC
April 2016
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