Publications by authors named "Paolo Rossi"

430 Publications

Humoral and Cellular Response Following Vaccination With the BNT162b2 mRNA COVID-19 Vaccine in Patients Affected by Primary Immunodeficiencies.

Front Immunol 2021 4;12:727850. Epub 2021 Oct 4.

Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

Mass SARS-Cov-2 vaccination campaign represents the only strategy to defeat the global pandemic we are facing. Immunocompromised patients represent a vulnerable population at high risk of developing severe COVID-19 and thus should be prioritized in the vaccination programs and in the study of the vaccine efficacy. Nevertheless, most data on efficacy and safety of the available vaccines derive from trials conducted on healthy individuals; hence, studies on immunogenicity of SARS-CoV2 vaccines in such populations are deeply needed. Here, we perform an observational longitudinal study analyzing the humoral and cellular response following the BNT162b2 mRNA COVID-19 vaccine in a cohort of patients affected by inborn errors of immunity (IEI) compared to healthy controls (HC). We show that both IEI and HC groups experienced a significant increase in anti-SARS-CoV-2 Abs 1 week after the second scheduled dose as well as an overall statistically significant expansion of the Ag-specific CD4+CD40L+ T cells in both HC and IEI. Five IEI patients did not develop any specific CD4+CD40L+ T cellular response, with one of these patients unable to also mount any humoral response. These data raise immunologic concerns about using Ab response as a sole metric of protective immunity following vaccination for SARS-CoV-2. Taken together, these findings suggest that evaluation of vaccine-induced immunity in this subpopulation should also include quantification of Ag-specific T cells.
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http://dx.doi.org/10.3389/fimmu.2021.727850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521226PMC
October 2021

A nationwide study of air pollution from particulate matter and daily hospitalizations for respiratory diseases in Italy.

Sci Total Environ 2021 Oct 16:151034. Epub 2021 Oct 16.

CNR-IFC, Pisa, Italy.

Background/aim: The relationship between air pollution and respiratory morbidity has been widely addressed in urban and metropolitan areas but little is known about the effects in non-urban settings. Our aim was to assess the short-term effects of PM10 and PM2.5 on respiratory admissions in the whole country of Italy during 2006-2015.

Methods: We estimated daily PM concentrations at the municipality level using satellite data and spatiotemporal predictors. We collected daily counts of respiratory hospital admissions for each Italian municipality. We considered five different outcomes: all respiratory diseases, asthma, chronic obstructive pulmonary disease (COPD), lower and upper respiratory tract infections (LRTI and URTI). Meta-analysis of province-specific estimates obtained by time-series models, adjusting for temperature, humidity and other confounders, was applied to extrapolate national estimates for each outcome. At last, we tested for effect modification by sex, age, period, and urbanization score. Analyses for PM were restricted to 2013-2015 cause the goodness of fit of exposure estimation.

Results: A total of 4,154,887 respiratory admission were registered during 2006-2015, of which 29% for LRTI, 12% for COPD, 6% for URTI, and 3% for asthma. Daily mean PM and PM concentrations over the study period were 23.3 and 17 μg/m, respectively. For each 10 μg/m increases in PM and PM at lag 0-5 days, we found excess risks of total respiratory diseases equal to 1.20% (95% confidence intervals, 0.92, 1.49) and 1.22% (0.76, 1.68), respectively. The effects for the specific diseases were similar, with the strongest ones for asthma and COPD. Higher effects were found in the elderly and in less urbanized areas.

Conclusions: Short-term exposure to PM is harmful for the respiratory system throughout an entire country, especially in elderly patients. Strong effects can be found also in less urbanized areas.
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http://dx.doi.org/10.1016/j.scitotenv.2021.151034DOI Listing
October 2021

Clinical, Immunological, and Molecular Variability of RAG Deficiency: A Retrospective Analysis of 22 RAG Patients.

J Clin Immunol 2021 Oct 18. Epub 2021 Oct 18.

Academic Department of Pediatrics (DPUO), Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy.

Purpose: We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data.

Methods: Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate.

Results: Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%).

Conclusion: We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype-phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.
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http://dx.doi.org/10.1007/s10875-021-01130-3DOI Listing
October 2021

Orthostatic hypertension and adverse clinical outcomes in adults and older people.

J Geriatr Cardiol 2021 Sep;18(9):779-782

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

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http://dx.doi.org/10.11909/j.issn.1671-5411.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501383PMC
September 2021

Asymptomatic and Mild SARS-CoV-2 Infections Elicit Lower Immune Activation and Higher Specific Neutralizing Antibodies in Children Than in Adults.

Front Immunol 2021 30;12:741796. Epub 2021 Sep 30.

Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

Background: The immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARSCoV2)-infected adults, but it is still poorly investigated in the pediatric population.

Methods: Of 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1-3.7) and 6.1 (5.3-7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR).

Results: Overall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes.

Conclusions: Adults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.
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http://dx.doi.org/10.3389/fimmu.2021.741796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515185PMC
September 2021

Medially congruent total knee arthroplasty in valgus knee deformities yields satisfactory outcomes: a multicenter, international study.

Knee Surg Sports Traumatol Arthrosc 2021 Oct 1. Epub 2021 Oct 1.

Sezione di Chirurgia Protesica a Indirizzo Robotico, Unità di Traumatologia dello Sport, UOC Ortopedia e Traumatologia e Universita' degli Studi di Pavia, Fondazione Poliambulanza, Brescia, Italy.

Purpose: Postoperative instability represents one of the most common complications following primary total knee arthroplasty (TKA). To prevent this outcome, valgus deformities have been historically treated using more constrained implants. The purpose of this study was to evaluate the outcome of treating a moderate valgus deformity by combining a surgical technique used to release the postero-lateral soft tissue envelope with the use of a medially congruent (MC) TKA design without using classical, semi-constrained inserts.

Methods: Seventy-nine MC TKAs were performed by three surgeons at three institutions between 2016 and 2018 as part of a multicenter, international study. Inclusion criteria were: radiographic late-stage osteoarthritic knees with Ranawat's type 1 or 2 classification of valgus deformity and integrity of the medial capsular-ligament complex (less than 10 mm of medial opening during valgus stress test at 10° of knee flexion). Exclusion criteria were: BMI > 40; neuromuscular, metabolic, or immunologic disorders; or the inability to complete outcome measures or radiographic assessment.

Results: Seventy-seven patients (79 knees), 59 males and 18 females, were evaluated at 2-year minimum follow-up according to the Knee Society Score (KSS) and Forgotten Joint Score (FJS). Mean age at surgery was 70 years (range 48-91). The mean range of motion (ROM) improved from 110° (range 85°-130°) preoperatively to 121° (range 105°-135°) (p < 0.001) at the time of the last follow-up. Preoperative knee extension significantly improved from 3° (range - 15° to 20°) to 1° (range - 5° to 5°) of flexion at the last follow-up in all the patients. KSS and KSS Functional scores were 89 (range 65-100) and 82 points (range 55-100), respectively. The FJS obtained at the last follow-up was 72 (range 49-88). Two patients (2.5%) had major postoperative complications (one periprosthetic joint infection; one postoperative patellar fracture) requiring surgical interventions.

Conclusions: In different surgeon's hands, the use of a modern medially congruent TKA design yielded good clinical outcomes at 2 years in a consecutive series of TKA in valgus arthritic knees. Postoperative instability was not recorded in this series and this finding was related to the high conformity design of the MC polyethylene insert, which significantly differs from classical posterior-stabilized (PS) designs.

Level Of Evidence: IV.
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http://dx.doi.org/10.1007/s00167-021-06754-xDOI Listing
October 2021

Socially desirable responding in geriatric outpatients with and without mild cognitive impairment and its association with the assessment of self-reported mental health.

BMC Geriatr 2021 09 15;21(1):494. Epub 2021 Sep 15.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Socially desirable responding is a potentially relevant issue in older adults and can be evaluated with the Marlowe-Crowne Social Desirability Scale (MCSDS). However, the eight-item MCSDS has never been specifically administered to geriatric subjects, and there is a dearth of literature on the relationship between social desirability and cognitive impairment. Also, the connection between social desirability and subjective measures of psychological well-being is a matter of controversy. This study has three main aims. First, to determine the psychometric properties of the eight-item MCSDS in geriatric outpatients without dementia (i.e. with normal cognition (NC) or mild cognitive impairment (MCI)). Second, to investigate the link between social desirability and cognitive functioning. Third, to determine the association between social desirability and the assessment of self-reported mental health.

Methods: Community-dwelling outpatients (aged ≥ 65) were consecutively recruited and neuropsychologically tested to diagnose NC or MCI (n = 299). Social desirability was assessed with the eight-item MCSDS. Depressive and anxiety symptoms were measured with the short Geriatric Depression (GDS-s) and the State-Trait Personality Inventory Trait Anxiety (STPI-TA) scales.

Results: On principal components analysis, the eight-item MCSDS was found to have a multidimensional structure. Of the initial three-component solution, only two subscales had acceptable internal consistency (Cronbach's alpha > 0.6): "Acceptance of responsibility" and "Integrity". The third subscale ("Kindness towards others") appeared to gauge two distinct constructs of formal (i.e. politeness) versus substantive (i.e. forgiveness) compassion. On binary logistic regression, only higher income was a significant predictor of formal compassion. Test-retest reliability was substantial to excellent (Gwet's AC2 ≥ 0.8). There were no meaningful differences in social desirability between the NC and MCI groups. Likewise, negative Spearman's correlations between social desirability and cognitive Z-scores across the whole sample were weak (r < |0.3|) and confined to one MCSDS item. Although social desirability was an independent predictor of the STPI-TA score in multiple linear regression, it explained only a marginal amount of incremental variance in anxiety symptoms (less than 2%).

Conclusions: Our results suggest that social desirability need not be a major concern when using questionnaires to assess mental health in geriatric outpatients without dementia.
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http://dx.doi.org/10.1186/s12877-021-02435-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442330PMC
September 2021

Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome.

Cancers (Basel) 2021 Aug 29;13(17). Epub 2021 Aug 29.

Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy.

High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of and/or genes correlated with low survival independently of the disease stage. Our data identify the status of the and genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB.
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http://dx.doi.org/10.3390/cancers13174368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430542PMC
August 2021

Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications.

Org Lett 2021 08 11;23(16):6288-6292. Epub 2021 Aug 11.

Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.

Isotopically labeled amino acids are widely used to study the structure and dynamics of proteins by NMR. Herein we describe a facile, gram-scale synthesis of compounds and under standard laboratory conditions from the common intermediate . is obtained via simple deprotection, while is accessed through a reductive deoxygenation/deuteration sequence and deprotection. and provide improved signal intensity using lower amounts of labeled precursor and are alternatives to existing labeling approaches.
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http://dx.doi.org/10.1021/acs.orglett.1c02084DOI Listing
August 2021

Five-year annual incidence and clinico-molecular features of breast cancer after the last negative screening mammography at age 68-69.

Eur Radiol 2021 Aug 6. Epub 2021 Aug 6.

Romagna Cancer Registry, Romagna Cancer Institute (IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"), Meldola, Forlì, Italy.

Objective: The European Commission Initiative on Breast Cancer recommendation for triennial screening of women aged 70-74 is based on very weak evidence. A cohort of Italian women who had their last biennial screening mammography at age 68-69 was followed up for 5 years, assumed to represent the interval to another hypothetical screening mammography, in order to determine the annual proportional incidence of interval breast cancer.

Methods: The cohort included 118,370 women. They had their last mammography between 1997 and 2008. Incident breast cancers were identified by record-linking the cohort with the regional breast cancer registry. The expected incidence in the age range 65-74 was estimated with an age-period-cohort model. The number of interval cancers was divided by the expected number to obtain their proportional incidence.

Results: Overall, there were 298,658 woman-years at risk with 371 interval cancers versus 988.8 expected. In the first, second, third, fourth, and fifth interval year, the proportional incidence was 0.09 (95% confidence interval, 0.06-0.13), 0.32 (0.25-0.39), 0.60 (0.49-0.73), 0.75 (0.60-0.92), and 0.81 (0.60-1.07), respectively. Between the second and the fifth year, tumour stage and molecular subtype did not change significantly.

Conclusion: Though not supported by these findings, the proposal of triennial screening for women aged 70-74 merits further research, because the 95% confidence interval of the third-year proportional incidence of interval cancer included 0.50-the maximum limit considered acceptable for women aged 50-69.

Key Points: • The third-year incidence of breast cancer relative to the expected one was 0.60 (95% confidence interval, 0.49-0.73). • Between the second and the fifth year, tumour stage and molecular subtype did not change significantly (p >0.10). • The proposal of a 3-year screening interval at age 70-74 merits further evaluation.
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http://dx.doi.org/10.1007/s00330-021-08129-9DOI Listing
August 2021

Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF.

Int J Mol Sci 2021 Jul 27;22(15). Epub 2021 Jul 27.

IRCCS Istituto Ortopedico Galeazzi, Via Galeazzi 4, 20161 Milan, Italy.

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer's disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up.
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http://dx.doi.org/10.3390/ijms22158034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347603PMC
July 2021

The Relationship between Practitioners and Caregivers during a Treatment of Palliative Care: A Grounded Theory of a Challenging Collaborative Process.

Int J Environ Res Public Health 2021 07 30;18(15). Epub 2021 Jul 30.

Dipartimento Fragilità Rete Locale Cure Palliative, ASST di Lecco, 23900 Lecco, Italy.

The possibility of coming to a "good death" is a challenging issue that crosses ethical and religious beliefs, cultural assumptions, as well as medical expertise. The provision of palliative care for relieving patients' pain is a practice that reshapes the path to the event of death and gives form to a particular context of awareness, recalling the notion proposed by Glaser and Strauss. This decision redesigns the relationships between patients, practitioners and caregivers and introduces a new pattern of collaboration between them. Our study focuses on the implications of the collaboration between practitioners and caregivers, starting from the assumption that the latter may provide support to their loved ones and to the practitioners, but need to be supported too. We provide a qualitative analysis of this collaboration based on an empirical research that took place in four different settings of provision of palliative care, reporting the contrast between the affective engagement of caregivers and the professional approach of practitioners. We claim that this ambivalent collaboration, while embedded in contingent and incommensurable experiences, brings to the fore the broader understanding of the path to a "good death," outlining its societal representation as a collective challenge.
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http://dx.doi.org/10.3390/ijerph18158081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345580PMC
July 2021

Prioritizing the First Doses of SARS-CoV-2 Vaccine to Save the Elderly: The Case Study of Italy.

Front Public Health 2021 14;9:684760. Epub 2021 Jul 14.

Enrico Fermi Research Center, Rome, Italy.

SARS-CoV-2 is currently causing hundreds of deaths every day in European countries, mostly in not yet vaccinated elderly. Vaccine shortage poses relevant challenges to health authorities, called to act promptly with a scarcity of data. We modeled the mortality reduction of the elderly according to a schedule of mRNA SARS-CoV-2 vaccine that prioritized first dose administration. For the case study of Italy, we show an increase in protected individuals up to 53.4% and a decrease in deaths up to 19.8% in the cohort of over 80's compared with the standard vaccine recalls after 3 or 4 weeks. This model supports the adoption of vaccination campaigns that prioritize the administration of the first doses in the elderly.
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http://dx.doi.org/10.3389/fpubh.2021.684760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318130PMC
August 2021

Cryptococcal Meningitis and Post-Infectious Inflammatory Response Syndrome in a Patient With X-Linked Hyper IgM Syndrome: A Case Report and Review of the Literature.

Front Immunol 2021 15;12:708837. Epub 2021 Jul 15.

Unit of Immune and Infectious Diseases, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy.

The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.
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http://dx.doi.org/10.3389/fimmu.2021.708837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320724PMC
July 2021

"Real world" eligibility for aducanumab.

J Am Geriatr Soc 2021 Oct 31;69(10):2995-2998. Epub 2021 Jul 31.

Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy.

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http://dx.doi.org/10.1111/jgs.17390DOI Listing
October 2021

Altered NK-cell compartment and dysfunctional NKG2D/NKG2D-ligand axis in patients with ataxia-telangiectasia.

Clin Immunol 2021 09 21;230:108802. Epub 2021 Jul 21.

Research Unit of Primary Immunodeficiencies, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Ataxia-telangiectasia (A-T) is a multisystem disorder caused by biallelic pathogenic variants in the gene encoding A-T mutated (ATM) kinase, a master regulator of the DNA damage response (DDR) pathway. Most A-T patients show cellular and/or humoral immunodeficiency that has been associated with cancer risk and reduced survival, but NK cells have not been thoroughly studied. Here we investigated NK cells of A-T patients with a special focus on the NKG2D receptor that triggers cytotoxicity upon engagement by its ligands (NKG2DLs) commonly induced via the DDR pathway on infected, transformed, and variously stressed cells. Using flow cytometry, we examined the phenotype and function of NK cells in 6 A-T patients as compared with healthy individuals. NKG2D expression was evaluated also by western blotting and RT-qPCR; plasma soluble NKG2DLs (sMICA, sMICB, sULBP1, ULBP2) were measured by ELISA. Results showed that A-T NK cells were skewed towards the CD56 anergic phenotype and displayed decreased expression of NKG2D and perforin. NKG2D was reduced at the protein but not at the mRNA level and resulted in impaired NKG2D-mediated cytotoxicity in 4/6 A-T patients. Moreover, in A-T plasma we found 24-fold and 2-fold increase of sMICA and sULBP1, respectively, both inversely correlated with NKG2D expression. Overall, NK cells are disturbed in A-T patients showing reduced NKG2D expression, possibly caused by persistent engagement of its ligands, that may contribute to susceptibility to cancer and infections and represent novel targets for therapeutic interventions.
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http://dx.doi.org/10.1016/j.clim.2021.108802DOI Listing
September 2021

The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Ital J Pediatr 2021 Jul 13;47(1):156. Epub 2021 Jul 13.

Academic Department of Pediatrics (DPUO), Clinical Trial Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.
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http://dx.doi.org/10.1186/s13052-021-01099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276228PMC
July 2021

Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort).

J Int AIDS Soc 2021 07;24(7):e25717

Research Unit of Primary Immunodeficiency, Bambino Gesú Children's Hospital, IRCCS, Rome, Italy.

Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated.

Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), ≤6 months; late treated patients (LT), > 6 months), with at least five years of HIV-1 suppression (<40 HIV copies/mL), were collected between November 2017 and August 2018. NK phenotype and function were analysed by flow cytometry and transcriptional profile of PBMCs by RNA-Seq. HIV-1 DNA was measured by real-time polymerase chain reaction (Data were analysed by Spearman correlation plots and multivariable Poisson regression model (adjusted for baseline %CD4 and RNA HIV viral load and for age at ART start as an interaction term, either ET or LT) to explore the association between NK cell parameters and HIV reservoir modulated by age at ART start.

Results: A significantly higher frequency of CD56 NK cells was found in LT compared with ET. We further found in LT a positive correlation of CD56 NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, CD107a and IFN-γ frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally, RNA-Seq analysis showed in LT an up-regulation of genes related to NK-activating pathways and susceptibility to apoptosis compared with ET.

Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART.
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http://dx.doi.org/10.1002/jia2.25717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264399PMC
July 2021

Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers.

Antioxidants (Basel) 2021 Jun 1;10(6). Epub 2021 Jun 1.

Department of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.

X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the killing of engulfed pathogens. Some XL-CGD carriers suffer from inflammatory and autoimmune manifestations as well as infections, although the skewed-XCI of a mutated allele is reported to be exclusively determinant for infection susceptibility. Indeed, immune dysregulation could be determined by dysfunctional non-phagocytic leukocytes rather than the percentage of functioning neutrophils. Here we investigated in a cohort of 12 X-CGD female carriers at a particular time of their life the gp91phox protein expression/function and how this affects immune cell function. We showed that 50% of carriers have an age-independent skewed-XCI and 65% of them have a misrepresented expression of the wild-type gene. The majority of carriers manifested immune dysregulation and GI manifestations regardless of age and XCI. Immunological investigations revealed an increase in CD19+ B cells, CD56bright-NK cell percentage, a slightly altered CD107a upregulation on CD4+ T cells, and reduced INFγ-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INFγ-expressing T cells, suggesting a role in promoting immune dysregulation in carriers.
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http://dx.doi.org/10.3390/antiox10060891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229314PMC
June 2021

Virological and immunological features of SARS-COV-2 infected children with distinct symptomatology.

Pediatr Allergy Immunol 2021 Jun 26. Epub 2021 Jun 26.

Clinical and Research Unit of Clinical Immunology and Vaccinology, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Although SARS-CoV-2 immunizations have started in most countries, children are not currently included in the vaccination programs; thus, it remains crucial to define their anti-SARS-CoV-2 immune response in order to minimize the risk for other epidemic waves. This study sought to provide a description of the virology ad anti-SARS-CoV-2 immunity in children with distinct symptomatology.

Methods: Between March and July 2020, we recruited 15 SARS-CoV-2 asymptomatic (AS) and 51 symptomatic (SY) children, stratified according to WHO clinical classification. We measured SARS-CoV-2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swab samples. To define anti-SARS-CoV-2 antibodies, we measured neutralization activity and total IgG load (DiaSorin). We also evaluated antigen-specific B and CD8+T cells, using a labeled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink.

Results: Virological profiling showed that AS patients had lower viral load at diagnosis (p = .004) and faster virus clearance (p = .0002) compared with SY patients. Anti-SARS-CoV-2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY patients showed similar titers of SARS-CoV-2 IgG, levels of neutralizing activity, and frequency of Ag-specific B and CD8+ T cells, whereas pro-inflammatory plasma protein profile was found to be associated with symptomatology.

Conclusion: We demonstrated the development of anti-SARS-CoV-2 humoral and cellular response with any regard to symptomatology, suggesting the ability of both SY and AS patients to contribute toward herd immunity. The virological profiling of AS patients suggested that they have lower virus load associated with faster virus clearance.
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http://dx.doi.org/10.1111/pai.13585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420243PMC
June 2021

Incidence and prevalence of large vessel vasculitis (giant cell arteritis and Takayasu arteritis) in northern Italy: A population-based study.

Semin Arthritis Rheum 2021 08 7;51(4):786-792. Epub 2021 Jun 7.

Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Università di Modena e Reggio Emilia, Modena, Italy. Electronic address:

Objectives: To investigate the epidemiology of the entire spectrum of large vessel vasculitis (LVV) in a well-defined population from a Northern Italian area.

Methods: All patients with incident giant cell arteritis (GCA) diagnosed from 2005 to 2016 and all patients with incident Takayasu arteritis (TAK) diagnosed from 1998 to 2016 living in the Reggio Emilia area were identified. Only patients satisfying the modified inclusion criteria of the GiACTA trial, and the 1990 ACR classification criteria for TAK were included. The epidemiology of cranial- and LV-GCA was separately evaluated.

Results: 207 patients were diagnosed with GCA and 5 with TAK. 123 patients had cranial-GCA, 53 patients had LV-GCA, and the remaining 31 patients had overlapping features. The standardized annual incidence rate of GCA was 8.3 (95% CI 7.1, 9.4) per 100,000 population ages ≥50 years. The standardized annual incidence rate of cranial-GCA (6.1 [95% CI 5.1, 7.1] per 100,000 population ages ≥50 years) was double the rate of LV-GCA (3.4 [95% CI 2.7, 4.2]). The age-specific incidence rates were similar in the <70 and >90 years age groups, but they were higher in cranial-GCA than in LV-GCA in the age groups 70-79 and 80-89 years. The age- and sex-adjusted annual incidence rate of TAK was 0.5 (95% CI 0.1, 1.2) per 1,000,000 population.

Conclusion: Incidence of GCA is higher than previously reported by study evaluating only biopsy-proven or ACR classification criteria confirmed cases. Cranial-GCA and LV-GCA have epidemiological differences. TAK is an extremely rare disease also in Italy.
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http://dx.doi.org/10.1016/j.semarthrit.2021.06.001DOI Listing
August 2021

Diagnosis of COVID-19 in children guided by lack of fever and exposure to SARS-CoV-2.

Pediatr Res 2021 Jun 11. Epub 2021 Jun 11.

Department of Emergency, Acceptance and General Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: The objective of this study is to test how certain signs and symptoms related to COVID-19 in children predict the positivity or negativity of the SARS-CoV-2 nasopharyngeal swab in children.

Methods: We review the data of children who were tested for SARS-CoV-2 for a suspected infection. We compared the clinical characteristics of the subjects who tested positive and negative, including the sensibility, positive and negative predictive value of different combination of signs and symptoms.

Results: Of all the suspected infected, 2596 tested negative (96.2%) and 103 tested positive (3.8%). The median age was 7.0 and 5.3 years for the positive and negative ones, respectively. The female to male ratio was ~1:1.3. Fever and respiratory symptoms were mostly reported. Most positive children had a prior exposure to SARS-CoV-2-infected subjects (59.2%). A total of 99.3% of patients without fever nor exposure to the virus proved negative to the SARS-CoV-2 test.

Conclusions: Our study suggests that a child without fever or contact with infected subjects is SARS-CoV-2 negative. If this were to be confirmed, many resources would be spared, with improved care of both COVID-19 and not COVID-19-affected children.

Impact: Key message: lack of fever and exposure to SARS-CoV-2-infected people highly predicts a negative results of the SARS-CoV-2 nasopharyngeal swab in the paediatric population. Added value to the current literature: this is the first article to prove this point.

Impact: reduction of emergency department accesses of children with suspected SARS-CoV-2 infection; increased outpatient management of children with cough or other common respiratory symptoms of infancy; sparing of many human and material health resources.
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http://dx.doi.org/10.1038/s41390-021-01585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193603PMC
June 2021

Post-discharge telephonic follow-up of pediatric patients affected by SARS-CoV2 infection in a single Italianpediatric COVID center: a safe and feasible way to monitor children after hospitalization.

Ital J Pediatr 2021 Jun 2;47(1):119. Epub 2021 Jun 2.

Academic Department of Pediatrics (DPUO), Unit of Perinatal Infection and Congenital Infectious Diseases, Bambino Gesù IRCCS Pediatric Hospital, Rome, Italy.

Background: SARS-CoV-2 infection in children is often non severe and in the majority of cases does not require long term hospitalization, nevertheless it is burdened with social issues and managing difficulties. To our knowledge there is no literature on telephonic follow up in pediatric patients with positive PCR for SARS-CoV-2 on rhino-pharyngeal swab after discharge. The aim of the study is to describe our experience in a telephonic follow up which can allow early and safe discharge from hospital while keeping the patients under close clinical monitoring.

Materials And Methods: Sixty-five children were admitted for SARS-CoV-2 infection at Bambino Gesù Pediatric Hospital COVID Center from 16th March to 3rd July. We monitored through a telephonic follow-up, using a specific survey, the patients discharged still presenting a positive PCR for SARS-CoV-2. We checked if any symptoms occurred at home until recovery, defined as two consecutive negative PCR for SARS-CoV-2 on rhino-pharyngeal swabs.

Results: During the follow up 7 patients had mild and self-limited symptoms related to SARS-CoV-2 infection, while 2 patients were re-hospitalized. One patient had Multisystem Inflammatory Syndrome in Children (MIS-C), the other patient had an increase in troponin and D-dimers. We also monitored the average time of viral shedding, resulting in a median duration of 28 days.

Conclusion: Our experience describes the daily telephonic follow up as safe in pediatric patients discharged with positive PCR. As a matter of fact it could avoid long term hospitalization and allow to promptly re-hospitalize children with major complications such as MIS-C.
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http://dx.doi.org/10.1186/s13052-021-01065-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170435PMC
June 2021

Preoperative breast magnetic resonance imaging in patients with ductal carcinoma in situ: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC).

Eur Radiol 2021 Aug 30;31(8):5880-5893. Epub 2021 May 30.

CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Objective: To evaluate the impact of preoperative MRI in the management of Ductal carcinoma in situ (DCIS).

Methods: We searched the PubMed, EMBASE and Cochrane Library databases to identify randomised clinical trials (RCTs) or cohort studies assessing the impact of preoperative breast MRI in surgical outcomes, treatment change or loco-regional recurrence. We provided pooled estimates for odds ratios (OR), relative risks (RR) and proportions and assessed the certainty of the evidence using the GRADE approach.

Results: We included 3 RCTs and 23 observational cohorts, corresponding to 20,415 patients. For initial breast-conserving surgery (BCS), the RCTs showed that MRI may result in little to no difference (RR 0.95, 95% CI 0.90 to 1.00) (low certainty); observational studies showed that MRI may have no difference in the odds of re-operation after BCS (OR 0.96; 95% CI 0.36 to 2.61) (low certainty); and uncertain evidence from RCTs suggests little to no difference with respect to total mastectomy rate (RR 0.91; 95% CI 0.65 to 1.27) (very low certainty). We also found that MRI may change the initial treatment plans in 17% (95% CI 12 to 24%) of cases, but with little to no effect on locoregional recurrence (aHR = 1.18; 95% CI 0.79 to 1.76) (very low certainty).

Conclusion: We found evidence of low to very low certainty which may suggest there is no improvement of surgical outcomes with pre-operative MRI assessment of women with DCIS lesions. There is a need for large rigorously conducted RCTs to evaluate the role of preoperative MRI in this population.

Key Points: • Evidence of low to very low certainty may suggest there is no improvement in surgical outcomes with pre-operative MRI. • There is a need for large rigorously conducted RCTs evaluating the role of preoperative MRI to improve treatment planning for DCIS.
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http://dx.doi.org/10.1007/s00330-021-07873-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270803PMC
August 2021

The impact of chest CT body composition parameters on clinical outcomes in COVID-19 patients.

PLoS One 2021 14;16(5):e0251768. Epub 2021 May 14.

Epidemiology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

We assessed the impact of chest CT body composition parameters on outcomes and disease severity at hospital presentation of COVID-19 patients, focusing also on the possible mediation of body composition in the relationship between age and death in these patients. Chest CT scans performed at hospital presentation by consecutive COVID-19 patients (02/27/2020-03/13/2020) were retrospectively reviewed to obtain pectoralis muscle density and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, IMAT) at the level of T7-T8 vertebrae. Primary outcomes were: hospitalization, mechanical ventilation (MV) and/or death, death alone. Secondary outcomes were: C-reactive protein (CRP), oxygen saturation (SO2), CT disease extension at hospital presentation. The mediation of body composition in the effect of age on death was explored. Of the 318 patients included in the study (median age 65.7 years, females 37.7%), 205 (64.5%) were hospitalized, 68 (21.4%) needed MV, and 58 (18.2%) died. Increased muscle density was a protective factor while increased TAT, VAT, and IMAT were risk factors for hospitalization and MV/death. All these parameters except TAT had borderline effects on death alone. All parameters were associated with SO2 and extension of lung parenchymal involvement at CT; VAT was associated with CRP. Approximately 3% of the effect of age on death was mediated by decreased muscle density. In conclusion, low muscle quality and ectopic fat accumulation were associated with COVID-19 outcomes, VAT was associated with baseline inflammation. Low muscle quality partly mediated the effect of age on mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121324PMC
May 2021

Colon cancer survival differs from right side to left side and lymph node harvest number matter.

BMC Public Health 2021 05 12;21(1):906. Epub 2021 May 12.

Epidemiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Via Amendola 2, 42122, Reggio Emilia, MD, Italy.

Background: Right-sided colorectal cancer (CRC) has worse survival than does left-sided CRC. The objective of this study was to further assess the impact of right-side location on survival and the role of the extent of lymphadenectomy.

Methods: All CRCs diagnosed between 2000 and 2012 in Emilia-Romagna Region, Italy, were included. Data for stage, grade, histology, screening history, and number of removed lymph nodes (LN) were collected. Multivariable Cox regression models were used to estimate hazard ratios (HR), with relative 95% confidence intervals (95%CI), of right vs. left colon and of removing < 12, 12-21 or > 21 lymph nodes by cancer site.

Results: During the study period, 29,358 patients were registered (8828 right colon, 18,852 left colon, 1678 transverse). Patients with right cancer were more often older, females, with advanced stage and high grade, and higher number of removed LNs. Five-year survival was lower in the right than in the left colon (55.2% vs 59.7%). In multivariable analysis, right colon showed a lower survival when adjusting for age, sex, and screening status (HR 1.12, 95%CI 1.04-1.21). Stratification by number of lymph nodes removed (12-21 or > 21) was associated with better survival in right colon (HR 0.54, 95%CI 0.40-0.72 and HR 0.40, 95%CI 0.30-0.55, respectively) compared to left colon (HR 0.89, 95%CI 0.76-1.06 and HR 0.83, 95%CI 0.69-1.01, respectively).

Conclusions: This study confirms that right CRC has worse survival; the association is not due to screening status. An adequate removal of lymph nodes is associated with better survival, although the direction of the association in terms of causal links is not clear.
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http://dx.doi.org/10.1186/s12889-021-10746-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117551PMC
May 2021

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals.

PLoS Pathog 2021 04 26;17(4):e1009533. Epub 2021 Apr 26.

Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.

The size of the latent HIV reservoir is associated with the timing of therapeutic interventions and overall health of the immune system. Here, we demonstrate that T cell phenotypic signatures associate with viral reservoir size in a cohort of HIV vertically infected children and young adults under durable viral control, and who initiated anti-retroviral therapy (ART) <2 years old. Flow cytometry was used to measure expression of immune activation (IA), immune checkpoint (ICP) markers, and intracellular cytokine production after stimulation with GAG peptides in CD4 and CD8 T cells from cross-sectional peripheral blood samples. We also evaluated the expression of 96 genes in sort-purified total CD4 and CD8 T cells along with HIV-specific CD4 and CD8 T cells using a multiplexed RT-PCR approach. As a measure of HIV reservoir, total HIV-DNA quantification by real-time PCR was performed. Poisson regression modeling for predicting reservoir size using phenotypic markers revealed a signature that featured frequencies of PD-1+CD4 T cells, TIGIT+CD4 T cells and HIV-specific (CD40L+) CD4 T cells as important predictors and it also shows that time of ART initiation strongly affects their association with HIV-DNA. Further, gene expression analysis showed that the frequencies of PD-1+CD4 T cells associated with a CD4 T cell molecular profile skewed toward an exhausted Th1 profile. Our data provide a link between immune checkpoint molecules and HIV persistence in a pediatric cohort as has been demonstrated in adults. Frequencies of PD-1+ and TIGIT+CD4 T cells along with the frequency of HIV-specific CD4 T cells could be associated with the mechanism of viral persistence and may provide insight into potential targets for therapeutic intervention.
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http://dx.doi.org/10.1371/journal.ppat.1009533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112655PMC
April 2021

as an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: A Study with a Review of the Literature.

Diagnostics (Basel) 2021 Mar 28;11(4). Epub 2021 Mar 28.

Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy.

Background: GATA binding protein 3 () expression is positively correlated with estrogen receptor (ER) expression, but its prognostic value as an independent factor remains unclear. Thus, we undertook the current study to evaluate the expression of and its prognostic value in a large series of breast carcinomas (BCs) with long-term follow-up.

Methods: A total of 702 consecutive primary invasive BCs resected between 1989 and 1993 in our institution were arranged in tissue microarrays, immunostained for ER, progesterone receptor (PR), ki-67, HER2, p53, and , and scored. Clinico-pathological data were retrospectively collected.

Results: was evaluable in 608 (87%) of the 702 cases; it was positive in 413 (68%) cases and negative in 195 (32%) cases. positivity was significantly associated with lower grade ( < 0.0001), size ( = 0.0463), stage ( = 0.0049), ER+ ( < 0.0001), PR+ ( < 0.0001), HER2- ( = 0.0175), and p53 wild-type pattern ( < 0.0001). The median follow-up was 183 months, positivity was associated with better overall survival (HR 0.70, = 0.001), and its prognostic value was retained in a multivariate analysis. The association with better overall survival was stronger in patients with grade 1-2, pT1-2, pN0, stage I-II, ER+, PR+, ki-67 < 20%, HER2-, a wild-type p53 immunohistochemical pattern, and in luminal B BC.

Conclusions: Our findings indicate that is a positive prognostic marker in BC patients, especially in patients with biologically less aggressive BC. Incorporating immunohistochemistry into routine practice could help further stratify BC patients for their risk.
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http://dx.doi.org/10.3390/diagnostics11040604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066261PMC
March 2021

Phylogenomics Reveals that Symbionts from Insects Underwent Convergent Genome Reduction, Preserving an Insecticide-Degrading Gene.

mBio 2021 03 30;12(2). Epub 2021 Mar 30.

School of Biosciences & Veterinary Medicine, University of Camerino, Camerino, MC, Italy

The mosquito microbiota is composed of several lineages of microorganisms whose ecological roles and evolutionary histories have yet to be investigated in depth. Among these microorganisms, bacteria play a prominent role, given their abundance in the gut, reproductive organs, and salivary glands of different mosquito species, while their presence has also been reported in several other insects. Notably, has great potential as a tool for the control of mosquito-borne diseases. Here, we present a wide phylogenomic analysis of strains isolated from different species of mosquito vectors and from different populations of the Mediterranean fruit fly (medfly), , an insect pest of worldwide economic importance. We show that phylogenetically distant lineages of experienced independent genome reductions, despite following a common pattern, characterized by the early loss of genes involved in genome stability. This result highlights the role of specific metabolic pathways in the symbiotic relationship between and the insect host. Finally, we discovered that all but one of the strains included in the study possess the pyrethroid hydrolase gene. Phylogenetic analysis revealed that this gene is ancestral in , strongly suggesting that it played a role in the establishment of the symbiotic association between these bacteria and the mosquito hosts. We propose that this gene from the symbiont contributed to initial pyrethroid resistance in insects harboring , also considering the widespread production of pyrethrins by several plants. We have studied genome reduction within several strains of the insect symbiont isolated from different species/strains of mosquito and medfly. Phylogenetically distant strains of , despite following a common pattern involving the loss of genes related to genome stability, have undergone independent genome reductions, highlighting the peculiar role of specific metabolic pathways in the symbiotic relationship between and its host. We also show that the pyrethroid hydrolase gene is present in all the strains isolated except for the South American malaria vector , for which resistance to pyrethroids has never been reported, suggesting a possible involvement of in determining resistance to insecticides.
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http://dx.doi.org/10.1128/mBio.00106-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092202PMC
March 2021
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