32 results on '"Picconi O"'
Search Results
2. High HIV-1 diversity in immigrants resident in Italy (2008–2017)
- Author
-
Maggiorella M. T., Sanarico N., Brindicci G., Monno L., Santoro C. R., Coppola N., Cuomo N., Azzurri A., Cesario F., Luciani F., El-Hamad I., D'Ettorre G., Turriziani O., Mazzuti L., Poggi A., Vichi F., Mariabelli E., Surace L., Berardelli G., Picconi O., Cenci A., Sernicola L., Rovetto C., Fulgenzi D., Belli R., Salvi E., Zeo P. D., Borsetti A., Ridolfi B., Losappio R., Zoboli F., Schietroma I., Cella E., Angeletti S., Ciccozzi M., D'Amato S., Ensoli B., Butto S., Angarano G., Babudieri S., Scheri G. C., Lichtner M., Martini S., Mazzella A., Romano N., Pansera A., Pontali E., Raddi A., Starnini G., Dell'Isola S., Maggiorella, M. T., Sanarico, N., Brindicci, G., Monno, L., Santoro, C. R., Coppola, N., Cuomo, N., Azzurri, A., Cesario, F., Luciani, F., El-Hamad, I., D'Ettorre, G., Turriziani, O., Mazzuti, L., Poggi, A., Vichi, F., Mariabelli, E., Surace, L., Berardelli, G., Picconi, O., Cenci, A., Sernicola, L., Rovetto, C., Fulgenzi, D., Belli, R., Salvi, E., Zeo, P. D., Borsetti, A., Ridolfi, B., Losappio, R., Zoboli, F., Schietroma, I., Cella, E., Angeletti, S., Ciccozzi, M., D'Amato, S., Ensoli, B., Butto, S., Angarano, G., Babudieri, S., Scheri, G. C., Lichtner, M., Martini, S., Mazzella, A., Romano, N., Pansera, A., Pontali, E., Raddi, A., Starnini, G., and Dell'Isola, S.
- Subjects
0301 basic medicine ,Male ,Latin Americans ,Immigration ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,HIV Infections ,Drug resistance ,medicine.disease_cause ,Antiretroviral Therapy, Highly Active ,Cluster Analysis ,HIV Infection ,lcsh:Science ,Phylogeny ,media_common ,Recombination, Genetic ,Multidisciplinary ,Geography ,virus diseases ,High HIV-1 diversity in immigrants ,Middle Aged ,Italy ,Medicine ,Infectious diseases ,Female ,Human ,Adult ,Tuberculosis ,media_common.quotation_subject ,Science ,030106 microbiology ,Emigrants and Immigrants ,Article ,03 medical and health sciences ,Population screening ,Drug Resistance, Viral ,medicine ,Humans ,Hepatitis ,Cluster Analysi ,lcsh:R ,Genetic Variation ,Emigrants and Immigrant ,medicine.disease ,Antiretroviral therapy ,030104 developmental biology ,Mutation ,HIV-1 ,lcsh:Q ,Demography ,Diversity (politics) - Abstract
The proportion of new diagnoses of HIV infection in immigrants residing in Italy raised from 11% in 1992 to 29.7% in 2018. To investigate the HIV clades circulating in this community a retrospective study was performed in 557 HIV-infected immigrants living in 12 Italian cities. Immigrants originated from East-Europe and Central-Asia (11.7%), North Africa and Middle East (7.3%), South and South-East Asia (7.2%), Latin America and the Caribbean (14.4%), and sub-Saharan Africa (59.4%). More than 87% of immigrants were on antiretroviral therapy (ART), although 26.6% of them were viremic. A 22.0% of immigrants had hepatitis (HBV and/or HCV) and/or tuberculosis. HIV phylogenetic analysis on sequences from 192 immigrants showed the presence of clades B (23.4%), G (16.1%), C (10.4%), A1 (9.4%), F1 (5.2%), D (1.6%) and Circulating Recombinant Forms (CRFs) (33.9%). CRF02_AG represented 72.3% of the total CRFs. Clusters between immigrants and Italian natives were also present. Drug resistance mutations to NRTI, NNRTI, and PI drug classes occurred in 29.1% of ART-treated and in 12.9% of ART-naïve individuals. These data highlight the need for tailored public health interventions in immigrants to avoid spreading in Italy of HIV genetic forms and ART-resistant variants, as well as HIV co-morbidities.
- Published
- 2020
3. Clinical and Functional Comparison between Anatomical and Non-Anatomical Acute Repair of Tears of the Distal Tendon of Biceps Brachii
- Author
-
De Carli, A., primary, Gaj, E., additional, Pagnotta, S.M., additional, Picconi, O., additional, and Ferretti, A., additional
- Published
- 2021
- Full Text
- View/download PDF
4. Characterization of variable regions of the Gp120 protein from HIV-1 subtype C virus variants obtained from individuals at different disease stages in Sub-Saharan Africa
- Author
-
Cenci, A., Tavoschi, L., D'Avenio, G., Narino, P., Becattini, S., Bernasconi, D., Chiappi, M., La Torre, L., Sukati, H., Vardas, E., Lo Presti, A., Cella, E., Ciccozzi, M., Picconi, O., Monini, P., Ensoli, B., and Buttò, S.
- Subjects
virus diseases - Abstract
Background: The development of a vaccine against HIV/AIDS capable of preventing virus infection has been hampered by the HIV envelope (Env) heterogeneity that makes it difficult to induce neutralizing antibodies against Env proteins from different HIV clades. Several studies have indicated that gp120 Env protein sequence tends to change considerably during the course of HIV disease which allows the virus to escape the immune responses. In order to define gp120 sequence changes, we have characterized the V1, V2, V4 and V5 variable regions of gp120 variants from 72 HIV-1-clade-C-infected subjects from South Africa and Swaziland, which were naïve to antiretroviral (ARV) therapy and at different disease stages. Sequence characteristics, such as aminoacid sequence length, presence of Putative N- Glycosylation Sites (PNGSs) and electric charge were investigated. Methods: According to the Avidity Index value and CD4+ T cell count, patients were classified for disease stage in three groups: recent, chronic and late stage, each one comprised of 24 patients. The V1 to V5 Env variable regions were directly PCR amplified from plasma virus RNA and sequenced. Results: A significant increase in the amino acid sequence length of V1 and V4 domains, and a corresponding increase of the “shifting” PNGSs were observed in the HIV variants obtained from individuals at chronic stage of disease, as compared to the recent infection group. Finally, a significant increase of the net electric positive charge of the V5 loop was found in the HIV variants from the group of subjects with late disease, as compared to the chronic disease group. Conclusion: We conclude that changes in sequence length, glycosylation pattern and net electrical charge in the variable V1, V4 and V5 regions of gp120 occur in the course of HIV infection, possibly in response to the pressure of the host immune response.
- Published
- 2019
5. A multicenter clinical study with myo-inositol and alpha-lactalbumin in Mexican and Italian PCOS patients.
- Author
-
HERNANDEZ MARIN, I., PICCONI, O., LAGANÀ, A. S., COSTABILE, L., and UNFER, V.
- Abstract
OBJECTIVE: This open-label non-randomized clinical study aimed at evaluating the effects of myo-inositol plus alpha-lactalbumin in two groups of PCOS women, treated in Mexico and Italy. Alpha-lactalbumin was used being effective in increasing myo-inositol intestinal absorption. This effect is very useful in greatly reducing the therapeutic failure of myo-inositol in some patients (inositol resistant subjects). PATIENTS AND METHODS: The study involved 34 normal weight or overweight patients (14 in Mexico and 20 in Italy), aged 18 to 40 years, with anovulation and infertility > 1 year and insulin resistance diagnosed by HOMA-Index. Patients were administered orally with 2 g myo-inositol, 50 mg alpha-lactalbumin, and 200 μg of folic acid twice a day for 6 months. Controls were the same patients at t0 (baseline). The primary outcome was HOMA-index decrease after 3 and 6 months of treatment. Other parameters monitored were BMI, progesterone, LH, FSH, total testosterone, free testosterone, androstenedione, total cholesterol, HDL, LDL, triglycerides. RESULTS: Recovery was general, and its relevance was higher when the starting point was further away from the normal range. The most important results were obtained with insulin, HOMA-index, LH, and androstenedione. No significant adverse effects were detected in both groups of patients. CONCLUSIONS: This clinical trial demonstrated for the first time that myo-inositol and alpha- lactalbumin improve important parameters in PCOS patients characterized by different metabolic profiles. [ABSTRACT FROM AUTHOR]
- Published
- 2021
6. Safety of oral alpha-lipoic acid treatment in pregnant women: a retrospective observational study.
- Author
-
PARENTE, E., COLANNINO, G., PICCONI, O., and MONASTRA, G.
- Abstract
OBJECTIVE: Alpha-lipoic acid is a natural molecule, which directly or by means of its reduced form, dihydrolipoic acid, exerts antioxidant, anti-inflammatory and immunomodulatory activities, very helpful also in preventing miscarriage and preterm delivery. Used as dietary supplement alpha-lipoic acid was demonstrated to be safe for living organisms even when administered at high doses. However, no study was made so far to verify the safety of its continuous administration on a substantial number of pregnant women. The present investigation was performed to answer this issue. PATIENTS AND METHODS: An observational retrospective study was carried out analyzing 610 expectant mothers. They had been treated daily by oral route with 600 mg alpha-lipoic acid, for at least 7 weeks during gestation. The primary outcome was to verify alpha-lipoic acid safety in the mother and infant. Maternal safety was assessed by monitoring for adverse reactions, physical and clinical examination, including a morbidity assessment. Laboratory and clinical examinations were performed monthly. Neonatal safety was assessed by the evaluation of birth weight, gestational age, Apgar scores, neonatal death with the related cause of death. Data collected from the Birth Registry of Campania Region were used as control. RESULTS: This study provided a very clear and reassuring picture about the safety of alpha-lipoic acid oral treatment during pregnancy. No adverse effect was noticed in mothers or newborns. The two sets of monitored data, from treated and controls, were completely superimposable or, in some cases, better in alpha-lipoic acid group. CONCLUSIONS: Our results open a reassuring scenario regarding the administration of alpha-lipoic acid during pregnancy. [ABSTRACT FROM AUTHOR]
- Published
- 2017
7. Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors
- Author
-
Orietta Picconi, Anna Rita Migliaccio, Gabriella Girelli, Emanuel F. Petricoin, Agostino Tafuri, Federica Francescangeli, Mario Falchi, Maria Mazzarini, Lilian Varricchio, Paola Contavalli, Fabrizio Martelli, Giulia Federici, Ann Zeuner, Federici G., Varricchio L., Martelli F., Falchi M., Picconi O., Francescangeli F., Contavalli P., Girelli G., Tafuri A., Petricoin E.F., Mazzarini M., Zeuner A., and Franco Migliaccio Anna Rita
- Subjects
0301 basic medicine ,Cancer Research ,Stem cell factor ,Stimulation ,erythroid progenitors ,ckit ,erythropoiesis ,polycythemia vera ,stem cell factor ,Biology ,DEPTOR ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,Tetraspanin ,erythroid progenitor ,medicine ,erythropoiesi ,PI3K/AKT/mTOR pathway ,Original Research ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cord blood ,Erythropoiesis ,cKIT - Abstract
Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.
- Published
- 2019
8. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial
- Author
-
Laura Sighinolfi, Guido Palamara, Massimo Di Pietro, Barbara Ensoli, Angela Arancio, Sonia Moretti, Mauro Magnani, Stefania Bellino, Fabrizio Ensoli, Vito S. Mercurio, Francesco Castelli, Leonardo Sernicola, Enrico Garaci, Maria Teresa Maggiorella, Andrea Gori, Giovanni Di Perri, Cecilia Sgadari, Massimo Galli, Vittorio Francavilla, Orietta Picconi, Anna Casabianca, Olimpia Longo, Chiara Orlandi, Aurelio Cafaro, Adriano Lazzarin, Antonella Tripiciano, Cristina Mussini, Maria Rosaria Pavone Cossut, Giovanni Paniccia, Gioacchino Angarano, Paolo Monini, Ensoli, F, Cafaro, A, Casabianca, A, Tripiciano, A, Bellino, S, Longo, O, Francavilla, V, Picconi, O, Sgadari, C, Moretti, S, Cossut, M, Arancio, A, Orlandi, C, Sernicola, L, Maggiorella, M, Paniccia, G, Mussini, C, Lazzarin, A, Sighinolfi, L, Palamara, G, Gori, A, Angarano, G, Di Pietro, M, Galli, M, Mercurio, V, Castelli, F, Di Perri, G, Monini, P, Magnani, M, Garaci, E, and Ensoli, B
- Subjects
Male ,HAART ,Antibodie ,HIV Antibodies ,CD38 ,Antibodies ,CD38+HLA-DR+/CD8+ T cells ,HIV-1 ,Neutralization ,Proviral DNA ,Tat protein ,Vaccine ,AIDS Vaccines ,Acquired Immunodeficiency Syndrome ,Adult ,Antibodies, Neutralizing ,Antiretroviral Therapy, Highly Active ,CD4 Lymphocyte Count ,Female ,Follow-Up Studies ,Humans ,Immunoglobulin G ,Immunoglobulin M ,Italy ,Leukocytes ,Middle Aged ,Treatment Outcome ,Young Adult ,tat Gene Products, Human Immunodeficiency Virus ,Viral Load ,Virology ,Infectious Diseases ,Medicine ,+ ,HLA-DR ,CD8 ,T cells ,Neutralizing ,biology ,Immunogenicity ,Vaccination ,CD38+HLA-DR+/CD8+ T cell ,Antibody ,tat Gene Products ,Viral load ,Human Immunodeficiency Virus ,Antiretroviral Therapy ,Viremia ,Immune system ,Highly Active ,business.industry ,Research ,medicine.disease ,Immunization ,Immunology ,biology.protein ,business - Abstract
Background The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia
- Published
- 2015
9. Clinical Efficacy of the HIV Protease Inhibitor Indinavir in Combination with Chemotherapy for Advanced Classic Kaposi Sarcoma Treatment: A Single-Arm, Phase II Trial in the Elderly.
- Author
-
Sgadari C, Scoppio B, Picconi O, Tripiciano A, Gaiani FM, Francavilla V, Arancio A, Campagna M, Palladino C, Moretti S, Monini P, Brambilla L, and Ensoli B
- Subjects
- Humans, Male, Female, Aged, Aged, 80 and over, Treatment Outcome, Herpesvirus 8, Human, Sarcoma, Kaposi drug therapy, Indinavir therapeutic use, Indinavir administration & dosage, Indinavir adverse effects, HIV Protease Inhibitors therapeutic use, HIV Protease Inhibitors administration & dosage, HIV Protease Inhibitors adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use
- Abstract
Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients., Significance: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
10. Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.
- Author
-
Molfino A, Anastasi E, Assanto E, Toccini L, Imbimbo G, Gigante A, Viggiani V, Farina A, Picconi O, Angeloni A, and Muscaritoli M
- Abstract
To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRP were measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
11. Muscularity and adiposity are differently associated with inflammatory and nutritional biomarkers among patients on hemodialysis and peritoneal dialysis.
- Author
-
Molfino A, Imbimbo G, Picconi O, Tartaglione L, Amabile MI, and Lai S
- Subjects
- Humans, Renal Dialysis, Obesity, Body Composition, Biomarkers, C-Reactive Protein, Water, Adiposity, Peritoneal Dialysis
- Abstract
Purpose: Nutritional alterations are prevalent in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD). We aimed at evaluating whether body composition parameters in HD vs PD are differently associated with nutritional and inflammatory biomarkers., Methods: Body composition was assessed by bioimpedance analysis. Neutrophil to lymphocyte ratio (NLR), serum albumin and C-reactive protein were used as nutritional and inflammatory biomarkers. Multivariable linear regression analysis was used to determine association(s) of body composition parameters with biomarkers., Results: We enrolled a total of 108 patients, 58 on HD and 50 on PD. Fat free mass percent was higher in HD patients than PD (p = 0.006) and higher extracellular water (ECW)/intracellular water (ICW) in HD compared to PD patients (p = 0.023), as well as fat mass index was greater in PD than HD (p = 0.004). In HD patients, albumin positively correlated with fat free mass (r = 0.42; p = 0.001) and ICW/h
2 (r = 0.31; p = 0.02). In PD, NLR positively correlated with fat mass (r = 0.36; p = 0.01), fat mass index (r = 0.37; p = 0.01) and ECW (r = 0.41; p = 0.005), and negatively correlated with fat free mass percent (r = -0.30; p = 0.04) and ICW percent (r = -0.34; p = 0.02). By linear regression analysis, in HD fat free mass index was associated with albumin and the absence of diabetes. In PD, the association of fat free mass index was present with NLR. Regarding adiposity, in HD we found no association of ECW/ICW with NLR and CRP, whereas in PD the ECW/ICW was associated with NLR., Conclusion: Inflammation drives body composition changes with differences according to the type of dialysis, as expressed by the modulation of some circulating biomarkers., Competing Interests: Declaration of Competing Interest The authors declare that they do not have relevant financial or non- financial interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
12. Intraoperative navigation system use increases accuracy of glenoid component inclination but not functional outcomes in reverse total shoulder arthroplasty: a prospective comparative study.
- Author
-
Gaj E, Pagnotta SM, Berlinberg EJ, Patel HH, Picconi O, Redler A, and De Carli A
- Subjects
- Humans, Male, Female, Aged, Aged, 80 and over, Prospective Studies, Treatment Outcome, Scapula surgery, Retrospective Studies, Range of Motion, Articular, Arthroplasty, Replacement, Shoulder methods, Shoulder Joint surgery
- Abstract
Background: While the use of computer-assisted navigation systems in prosthetic implantation is steadily increasing, its utility in reverse shoulder arthroplasty (RSA) remains unclear. The purpose of this study was to evaluate the clinical utility of an intraoperative navigation system in patients undergoing RSA., Materials and Methods: Patients undergoing navigated or standard RSA at a single institution between September 2020 and December 2021 were prospectively enrolled. Exclusion criteria included noncompliance with study procedures or humeral fracture. Outcome measures included postoperative version and inclination, range of motion (ROM), complications, and patient-reported outcome measurements (PROMs: American Shoulder and Elbow Surgeons score [ASES], Disabilities of the Arm, Shoulder, and Hand score [DASH], Simple Shoulder Test [SST], and Visual Analog Scale [VAS]) at final follow-up., Results: The final cohort contained 16 patients with navigation and 17 with standard RSA at a mean follow-up of 16 months (range 12-18 months). Average age was 72 years (range 66-80 years), 8 male (24%) and 25 female (76%). There were no differences in demographics between groups (p > 0.05). At baseline, the navigated group had a greater proportion of Walch B1 and B2 glenoids (p = 0.04). There were no differences between groups regarding baseplate type and native/planned/postoperative glenoid version and inclination. In both groups, planned and postoperative versions were not significantly different (p = 0.76). Patients who did not have navigation demonstrated significant differences between planned and postoperative inclination (p = 0.04), while those with navigation did not (p = 0.09). PROM scores did not differ between groups at final follow-up for SST (p = 0.64), DASH (p = 0.38), ASES (p = 0.77), or VAS (p = 0.1). No difference in final ROM was found between groups (p > 0.05). Over 50% of all screws in both groups were positioned outside the second cortex (p = 0.37), albeit with no complications., Conclusions: There were no statistically significant differences in ROM, PROMs, and satisfaction between patients receiving computer-navigated and standard RSA at a short-term follow-up. Despite more severe preoperative glenoid erosion in the navigated group, all patients were able to achieve an appropriate neutral axis postoperatively. The cost effectiveness and appropriate use of computer-navigated RSA warrant specific investigation in future studies., Level of Evidence: II, prospective cohort study., Trial Registration: 9/1/2020 to 12/31/2021., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
13. Single cell analysis of the localization of the hematopoietic stem cells within the bone marrow architecture identifies niche-specific proliferation dynamics.
- Author
-
Mazzarini M, Arciprete F, Picconi O, Valeri M, Verachi P, Martelli F, Migliaccio AR, Falchi M, and Zingariello M
- Abstract
Introduction: Hematopoietic stem cells (HSC) reside in the bone marrow (BM) in specialized niches which provide support for their self-replication and differentiation into the blood cells. Recently, numerous studies using sophisticated molecular and microscopic technology have provided snap-shots information on the identity of the BM niches in mice. In adults, HSC are localized around arterioles and sinusoids/venules whereas in juvenile mice they are in close to the osteoblasts. However, although it is well recognized that in mice the nature of the hematopoietic niche change with age or after exposure to inflammatory insults, much work remains to be done to identify changes occurring under these conditions. The dynamic changes occurring in niche/HSC interactions as HSC enter into cycle are also poorly defined., Methods: We exploit mice harboring the hCD34tTA/Tet-O-H2BGFP transgene to establish the feasibility to assess interactions of the HSC with their niche as they cycle. In this model, H2BGFP expression is driven by the TET trans-activator under the control of the human CD34 promoter which in mice is active only in the HSC. Since Doxycycline inhibits TET, HSC exposed to this drug no longer express H2BGFP and loose half of their label every division allowing establishing the dynamics of their first 1-3 divisions. To this aim, we first validated user-friendly confocal microscopy methods to determine HSC divisions by hemi-decrement changes in levels of GFP expression. We then tracked the interaction occurring in old mice between the HSC and their niche during the first HSC divisions., Results: We determined that in old mice, most of the HSC are located around vessels, both arterioles which sustain quiescence and self-replication, and venules/sinusoids, which sustain differentiation. After just 1 week of exposure to Doxycycline, great numbers of the HSC around the venules lost most of their GFP label, indicating that they had cycled. By contrast, the few HSC surrounding the arterioles retained maximal levels of GFP expression, indicating that they are either dormant or cycle at very low rates., Conclusion: These results reveal that in old mice, HSC cycle very dynamically and are biased toward interactions with the niche that instructs them to differentiate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mazzarini, Arciprete, Picconi, Valeri, Verachi, Martelli, Migliaccio, Falchi and Zingariello.)
- Published
- 2023
- Full Text
- View/download PDF
14. The challenge of complexity in the Big Data era: how to ride the wave of high-dimensional data revolution. Editorial.
- Author
-
Bossa C, Branchi I, Caccia B, Cisbani E, Daniele C, D'Avenio G, Esposito G, Facchiano F, Frustagli G, Gagliardi RV, Galluzzi A, Giansanti D, Gigante G, Giuliani A, Le Pera L, Mattia M, Morelli S, Moro O, Palma A, Pazienti A, Picconi O, Pizzi E, Poli C, Ruspantini I, Tait S, and Tcheremenskaia O
- Published
- 2022
- Full Text
- View/download PDF
15. Kaposi's Sarcoma Lesion Progression in BKV-Tat Transgenic Mice Is Increased by Inflammatory Cytokines and Blocked by Treatment with Anti-Tat Antibodies.
- Author
-
Brocca-Cofano E, Sgadari C, Picconi O, Palladino C, Caputo A, and Ensoli B
- Subjects
- Angiogenesis Inducing Agents metabolism, Animals, Anti-Retroviral Agents pharmacology, Disease Models, Animal, HIV-1 drug effects, Male, Mice, Mice, Transgenic, Sarcoma, Kaposi metabolism, Antibodies pharmacology, Cytokines metabolism, Sarcoma, Kaposi drug therapy, Sarcoma, Kaposi pathology, tat Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
Kaposi's sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved AIDS-KS incidence and course, it continues to be an incurable disease and the development of new rational targeted therapies is warranted. We used the BKV/Tat transgenic mouse model to evaluate the effects of IC and anti-Tat antibodies (Abs) treatment on KS-like lesions arising in BKV/Tat mice. We demonstrated here that IC-treatment increases the severity and delays the regression of KS-like lesions. Further, anti-Tat Abs reduced KS-like lesion severity developing in IC-treated mice when anti-Tat Abs were administered at an early-stage of lesion development as compared to more advanced lesions. Early anti-Tat Abs treatment also accelerated KS-like lesion regression and reduced the rate of severe-grade lesions. This effect was more evident in the first weeks after Ab treatment, suggesting that a longer treatment with anti-Tat Abs might be even more effective, particularly if administered just after lesion development. Although preliminary, these results are encouraging, and the approach deserves further studies for the development of anti-Tat Ab-based therapies for AIDS-KS. Clinical studies specifically addressing the effect of anti-Tat antibodies in treating AIDS-KS are not yet available. Nevertheless, the effectiveness of anti-Tat antibodies in controlling HIV/AIDS progression, likely due to the neutralization of extracellular Tat activities, is suggested by several cross-sectional and longitudinal clinical studies, indicating that anti-Tat Ab treatment or Tat-based vaccines may be effective to treat AIDS-KS patients or prevent the tumor in individuals at risk.
- Published
- 2022
- Full Text
- View/download PDF
16. Short- and Long-Term Immunological Responses in Chronic HCV/HIV Co-Infected Compared to HCV Mono-Infected Patients after DAA Therapy.
- Author
-
Farcomeni S, Moretti S, Fimiani C, Sulekova LF, Vescio F, Sernicola L, Maggiorella MT, Remoli AL, Picconi O, Mosca L, Esvan R, Biliotti E, Ciccozzi M, Sgarbanti M, Taliani G, and Borsetti A
- Abstract
Background: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV., Objectives: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed., Materials and Methods: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT)., Results: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-β, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed., Conclusions: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.
- Published
- 2021
- Full Text
- View/download PDF
17. New insights into pathogenesis point to HIV-1 Tat as a key vaccine target.
- Author
-
Ensoli B, Moretti S, Borsetti A, Maggiorella MT, Buttò S, Picconi O, Tripiciano A, Sgadari C, Monini P, and Cafaro A
- Subjects
- AIDS Vaccines immunology, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Comorbidity, HIV Infections epidemiology, HIV Infections virology, HIV-1 physiology, Humans, tat Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines pharmacology, HIV Infections transmission, HIV-1 pathogenicity, tat Gene Products, Human Immunodeficiency Virus physiology
- Abstract
Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)
- Published
- 2021
- Full Text
- View/download PDF
18. Effects of Inositol Hexaphosphate and Myo-Inositol Administration in Breast Cancer Patients during Adjuvant Chemotherapy.
- Author
-
Amabile MI, De Luca A, Tripodi D, D'Alberti E, Melcarne R, Imbimbo G, Picconi O, D'Andrea V, Vergine M, Sorrenti S, and Molfino A
- Abstract
Background: Treatment of breast cancer (BC) includes locoregional and systemic therapies depending on tumor and patient's characteristics. Inositol hexaphosphate (IP6) is known as a strong antioxidant agent, able to improve local (i.e., breast region) side effects, functional status and quality-of-life. We investigated some potential beneficial effects, including hematological and local, of the combined therapy with oral myo-inositol administration and topical IP6 application in patients undergoing surgery for BC and eligible to adjuvant chemotherapy., Methods: We considered BC patients randomly assigned to the Inositol Group (oral myo-inositol + IP6 local application for the entire neoadjuvant treatment period) and to the Control Group (standard of care). The EORTC QLQ-BR23 and QLQ-C30 questionnaires were administered to both groups and blood parameters were assessed as per clinical routine practice at baseline (before starting adjuvant chemotherapy), T1 (after the first two doses of epirubicin-cyclophosphamide regimen), T2 (at the end of epirubicin-cyclophosphamide regimen), T3 (after the first six doses of paclitaxel regimen), and T4 (at the end of the paclitaxel treatment)., Results: A total of 36 BC patients were considered, 18 in the Inositol Group and 18 in the Control Group. The Inositol Group showed a lower decrease in red blood cells, hemoglobin levels and white blood cells with respect to controls ( p ≤ 0.02), as well as amelioration in scores related to breast and arm local symptoms ( p ≤ 0.02), body image ( p = 0.04) and quality-of-life related symptoms ( p ≤ 0.04)., Conclusions: In our cohort of BC patients, a combined treatment with oral myo-inositol + IP6 local application was able to improve local symptoms and quality-of-life related symptoms which represent clinically relevant aspects associated with patient's prognosis.
- Published
- 2021
- Full Text
- View/download PDF
19. Anti-Tat immunity defines CD4 + T-cell dynamics in people living with HIV on long-term cART.
- Author
-
Tripiciano A, Picconi O, Moretti S, Sgadari C, Cafaro A, Francavilla V, Arancio A, Paniccia G, Campagna M, Pavone-Cossut MR, Sighinolfi L, Latini A, Mercurio VS, Pietro MD, Castelli F, Saracino A, Mussini C, Perri GD, Galli M, Nozza S, Ensoli F, Monini P, and Ensoli B
- Subjects
- Antiretroviral Therapy, Highly Active, B-Lymphocytes immunology, B-Lymphocytes metabolism, Biomarkers, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, HIV Antibodies immunology, HIV Infections drug therapy, Humans, Immunophenotyping, Lymphocyte Activation, Viral Load, CD4-Positive T-Lymphocytes immunology, HIV Infections immunology, HIV Infections virology, HIV-1 immunology, Host-Pathogen Interactions immunology, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Background: Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4
+ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4+ T-cell dynamics has not yet been defined., Methods: Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4+ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations., Findings: Anti-Tat immunity is significantly associated with higher nadir CD4+ T-cell numbers, control of low-level viremia and long-lasting CD4+ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4+ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8+ T cells and B cells. Anti-Env immunity was not related to CD4+ T-cell recovery., Interpretation: Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART., Trial Registration: ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 FUNDING: Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020., Competing Interests: Declaration of Competing Interest M. Di Pietro reports grants received from the Azienda Sanitaria of Florence during the conduct of the study. The other authors declares no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
20. HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication.
- Author
-
Cafaro A, Barillari G, Moretti S, Palladino C, Tripiciano A, Falchi M, Picconi O, Pavone Cossut MR, Campagna M, Arancio A, Sgadari C, Andreini C, Banci L, Monini P, and Ensoli B
- Subjects
- Alkynes pharmacology, Benzoxazines pharmacology, Biomarkers, Cell Adhesion, Cell-Penetrating Peptides metabolism, Cyclopropanes pharmacology, Cytokines metabolism, Fibronectins metabolism, HIV-1 drug effects, Host-Pathogen Interactions, Humans, Inflammation Mediators metabolism, Integrins chemistry, Models, Molecular, Oxidation-Reduction, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Structure-Activity Relationship, Temperature, Vitronectin metabolism, tat Gene Products, Human Immunodeficiency Virus chemistry, Endothelial Cells metabolism, Endothelial Cells virology, HIV Infections metabolism, HIV Infections virology, HIV-1 physiology, Integrins metabolism, Virus Replication, tat Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling-docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection.
- Published
- 2020
- Full Text
- View/download PDF
21. HIV Protease Inhibitors Block HPV16-Induced Murine Cervical Carcinoma and Promote Vessel Normalization in Association with MMP-9 Inhibition and TIMP-3 Induction.
- Author
-
Qiu Y, Maione F, Capano S, Meda C, Picconi O, Brundu S, Pisacane A, Sapino A, Palladino C, Barillari G, Monini P, Bussolino F, Ensoli B, Sgadari C, and Giraudo E
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Female, Human papillomavirus 16, Humans, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Transgenic, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms etiology, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms pathology, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, HIV Protease Inhibitors pharmacology, Matrix Metalloproteinase Inhibitors pharmacology, Tissue Inhibitor of Metalloproteinase-3 agonists
- Abstract
Antiretrovirals belonging to the human immunodeficiency virus (HIV) protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and HIV; of note, combined antiretroviral therapy has reduced cervical carcinoma onset and progression in HIV-infected women. We evaluated the effectiveness and mechanism(s) of action of HIV-PI against cervical carcinoma using a transgenic model of HR-HPV-induced estrogen-promoted cervical carcinoma (HPV16/E2) and found that treatment of mice with ritonavir-boosted HIV-PI, including indinavir, saquinavir, and lopinavir, blocked the growth and promoted the regression of murine cervical carcinoma. This was associated with inhibition of tumor angiogenesis, coupled to downregulation of matrix metalloproteinase (MMP)-9, reduction of VEGF/VEGFR2 complex, and concomitant upregulation of tissue inhibitor of metalloproteinase-3 (TIMP-3). HIV-PI also promoted deposition of collagen IV at the epithelial and vascular basement membrane and normalization of both vessel architecture and functionality. In agreement with this, HIV-PI reduced tumor hypoxia and enhanced the delivery and antitumor activity of conventional chemotherapy. Remarkably, TIMP-3 expression gradually decreased during progression of human dysplastic lesions into cervical carcinoma. This study identified the MMP-9/VEGF proangiogenic axis and its modulation by TIMP-3 as novel HIV-PI targets for the blockade of cervical intraepithelial neoplasia/cervical carcinoma development and invasiveness and the normalization of tumor vessel functions. These findings may lead to new therapeutic indications of HIV-PI to treat cervical carcinoma and other tumors in either HIV-infected or uninfected patients., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
22. HIV therapeutic vaccines aimed at intensifying combination antiretroviral therapy.
- Author
-
Moretti S, Cafaro A, Tripiciano A, Picconi O, Buttò S, Ensoli F, Sgadari C, Monini P, and Ensoli B
- Subjects
- AIDS Vaccines immunology, Animals, Anti-HIV Agents administration & dosage, CD4-Positive T-Lymphocytes immunology, Drug Therapy, Combination, HIV Infections immunology, HIV Infections virology, Humans, Virus Replication drug effects, AIDS Vaccines administration & dosage, Anti-HIV Agents pharmacology, HIV Infections prevention & control
- Abstract
Introduction : Although successful at suppressing HIV replication, combination antiretroviral therapy (cART) only partially restores immune functions and fails to reduce the latent HIV reservoir, thus requiring novel interventions for its intensification. Areas covered : Here are reviewed therapeutic vaccine candidates that are being developed to this goal. Among them, the Tat vaccine has been shown to promote immune restoration, including CD4+ T-cell recovery in low immunological responders, and to reduce the virus reservoirs well beyond what achieved with long-term suppressive cART. Expert opinion : The authors propose the Tat vaccine as a promising vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies, suggesting that targeting a key protein in the virus life cycle is pivotal to success.
- Published
- 2020
- Full Text
- View/download PDF
23. Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors.
- Author
-
Federici G, Varricchio L, Martelli F, Falchi M, Picconi O, Francescangeli F, Contavalli P, Girelli G, Tafuri A, Petricoin EF 3rd, Mazzarini M, Zeuner A, and Migliaccio AR
- Abstract
Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV., (Copyright © 2019 Federici, Varricchio, Martelli, Falchi, Picconi, Francescangeli, Contavalli, Girelli, Tafuri, Petricoin, Mazzarini, Zeuner and Migliaccio.)
- Published
- 2019
- Full Text
- View/download PDF
24. Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease.
- Author
-
Cafaro A, Tripiciano A, Picconi O, Sgadari C, Moretti S, Buttò S, Monini P, and Ensoli B
- Abstract
HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies.
- Published
- 2019
- Full Text
- View/download PDF
25. Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study.
- Author
-
Sgadari C, Monini P, Tripiciano A, Picconi O, Casabianca A, Orlandi C, Moretti S, Francavilla V, Arancio A, Paniccia G, Campagna M, Bellino S, Meschiari M, Nozza S, Sighinolfi L, Latini A, Muscatello A, Saracino A, Di Pietro M, Galli M, Cafaro A, Magnani M, Ensoli F, and Ensoli B
- Subjects
- Anti-Retroviral Agents therapeutic use, Antibodies, Viral metabolism, Follow-Up Studies, HIV Infections therapy, Humans, Viral Load, AIDS Vaccines immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, DNA, Viral genetics, HIV Infections immunology, HIV-1 physiology, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy ( ISS T-002 ) and South Africa ( ISS T-003 ) indicated that Tat vaccination promotes increases of CD4
+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168 ). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/ u L and in poor immunological responders and was associated with a concomitant increase of the CD4+ /CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+ /CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.- Published
- 2019
- Full Text
- View/download PDF
26. "cART intensification by the HIV-1 Tat B clade vaccine: progress to phase III efficacy studies".
- Author
-
Cafaro A, Sgadari C, Picconi O, Tripiciano A, Moretti S, Francavilla V, Pavone Cossut MR, Buttò S, Cozzone G, Ensoli F, Monini P, and Ensoli B
- Subjects
- AIDS Vaccines administration & dosage, Adult, Animals, Anti-HIV Agents pharmacology, Antibodies, Neutralizing immunology, Child, Drug Therapy, Combination, HIV Infections immunology, HIV-1 drug effects, HIV-1 immunology, Humans, Virus Replication drug effects, Anti-HIV Agents administration & dosage, HIV Infections therapy
- Abstract
Introduction: In spite of its success at suppressing HIV replication, combination antiretroviral therapy (cART) only partially reduces immune dysregulation and loss of immune functions. These cART-unmet needs appear to be due to persistent virus replication and cell-to-cell transmission in reservoirs, and are causes of increased patients' morbidity and mortality. Up to now, therapeutic interventions aimed at cART-intensification by attacking the virus reservoir have failed., Areas Covered: We briefly review the rationale and clinical development of Tat therapeutic vaccine in cART-treated subjects in Italy and South Africa (SA). Vaccination with clade-B Tat induced cross-clade neutralizing antibodies, immune restoration, including CD4
+ T cell increase particularly in low immunological responders, and reduction of proviral DNA. Phase III efficacy trials in SA are planned both in adult and pediatric populations., Expert Commentary: We propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and may lead to a functional cure and provide new perspectives for prevention and virus eradication strategies.- Published
- 2018
- Full Text
- View/download PDF
27. The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera.
- Author
-
Falchi M, Varricchio L, Martelli F, Marra M, Picconi O, Tafuri A, Girelli G, Uversky VN, and Migliaccio AR
- Subjects
- Amino Acid Substitution, Calcium metabolism, Calreticulin chemistry, Calreticulin genetics, Cell Differentiation genetics, Cell Line, Codon, Erythroblasts metabolism, Erythroid Cells cytology, Erythroid Cells metabolism, Humans, Immunophenotyping, Janus Kinase 2 metabolism, Polycythemia Vera metabolism, Protein Transport, Receptors, Glucocorticoid metabolism, Signal Transduction, Calreticulin metabolism, Erythropoiesis genetics, Janus Kinase 2 genetics, Mutation, Polycythemia Vera genetics
- Abstract
Calreticulin (CALR) is a Ca
2+ -binding protein that shuttles among cellular compartments with proteins bound to its N/P domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+ fluxes prompted us to investigate the role of CALR in human erythropoiesis. As shown by Western blot analysis, erythroblasts generated in vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of CALR. However, Ca2+ regulated CALR conformation only in normal cells. Normal erythroblasts expressed mostly the N-terminal domain of CALR (N-CALR) on their cell surface (as shown by flow cytometry) and C-terminal domain (C-CALR) in their cytoplasm (as shown by confocal microscopy) and expression of both epitopes decreased with maturation. In the proerythroblast (proEry) cytoplasm, C-CALR was associated with the glucocorticoid receptor (GR), which initiated the stress response. In these cells, Ca2+ deprivation and inhibition of nuclear export increased GR nuclear localization while decreasing cytoplasmic detection of C-CALR and C-CALR/GR association and proliferation in response to the GR agonist dexamethasone (Dex). C-CALR/GR association and Dex responsiveness were instead increased by Ca2+ and erythropoietin. In contrast, JAK2V617F proErys expressed normal cell-surface levels of N-CALR but barely detectable cytoplasmic levels of C-CALR. These cells contained GR mainly in the nucleus and were Dex unresponsive. Ruxolitinib rescued cytoplasmic detection of C-CALR, C-CALR/GR association, and Dex responsiveness in JAK2V617F proErys and its effects were antagonized by nuclear export and Ca2+ flux inhibitors. These results indicates that Ca2+ -induced conformational changes of CALR regulate nuclear export of GR in normal erythroblasts and that JAK2V617F deregulates this function in PV., (Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
28. Retrospective analysis of the effectiveness and costs of traditional treatments for moderate-to-severe psoriasis: A single-center, Italian study.
- Author
-
Carpentieri A, Pacello L, De Marco IM, Loiacono A, Picconi O, and Loconsole F
- Subjects
- Acitretin economics, Acitretin therapeutic use, Adult, Cyclosporine therapeutic use, Female, Humans, Italy, Male, Methotrexate economics, Methotrexate therapeutic use, Middle Aged, Phototherapy methods, Retrospective Studies, Treatment Outcome, Dermatologic Agents economics, Dermatologic Agents therapeutic use, Phototherapy economics, Psoriasis therapy
- Abstract
Background: Current guidelines recommend the use of systemic therapy and phototherapy for the treatment of moderate-to-severe plaque psoriasis., Objectives: To evaluate the effectiveness, impact on health status perception, and costs of traditional systemic therapies and phototherapy in real-life patients with moderate-to-severe psoriasis., Methods: Retrospective analysis of data from 100 psoriatic patients referring to a dermatology clinic in Italy and treated with traditional therapies., Results: Patients were predominantly treated with cyclosporine (72%). Cyclosporine was associated with fewer treatment discontinuations due to lack of efficacy (37%) compared with methotrexate (65%), acitretin (67%) and phototherapy (50%). Rates of treatment discontinuation due to adverse events were: cyclosporine (24%), methotrexate (9%), acitretin (25%) and phototherapy (0%). Improvements in PASI scores were comparable between treatments. The need for topical therapy was reduced with cyclosporine versus other therapies (35% vs 71%, p = 0.0009); respectively, 33% of patients treated with cyclosporine versus 14% of patients receiving other therapies perceived an improvement in their health status (p = 0.0018). Mean total per-patient direct costs of the first treatment cycle were higher with cyclosporine than with other therapies (€1812.85 vs €648.90, p < 0.0001)., Conclusions: Cyclosporine was effective even if more expensive than other traditional therapies. Nevertheless patients' perception of improvement was quite low.
- Published
- 2016
- Full Text
- View/download PDF
29. HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial.
- Author
-
Ensoli B, Nchabeleng M, Ensoli F, Tripiciano A, Bellino S, Picconi O, Sgadari C, Longo O, Tavoschi L, Joffe D, Cafaro A, Francavilla V, Moretti S, Pavone Cossut MR, Collacchi B, Arancio A, Paniccia G, Casabianca A, Magnani M, Buttò S, Levendal E, Ndimande JV, Asia B, Pillay Y, Garaci E, and Monini P
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines adverse effects, Adolescent, Adult, Antiretroviral Therapy, Highly Active, Cross Reactions, Female, HIV Infections virology, Humans, Immunization Schedule, Immunogenicity, Vaccine, Male, Middle Aged, South Africa, Vaccination, Viral Load, Young Adult, AIDS Vaccines immunology, Antibodies, Neutralizing blood, CD4-Positive T-Lymphocytes immunology, HIV Antibodies blood, HIV Infections immunology, HIV Infections therapy, HIV-1 immunology, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Background: Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa., Methods: The ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 μg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4(+) T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4(+) T-cell counts and therapy compliance., Results: Immunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4(+) T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4(+) T-cell numbers over study entry levels as compared to placebo., Conclusions: The data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa. Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012.
- Published
- 2016
- Full Text
- View/download PDF
30. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial.
- Author
-
Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, Francavilla V, Picconi O, Sgadari C, Moretti S, Cossut MR, Arancio A, Orlandi C, Sernicola L, Maggiorella MT, Paniccia G, Mussini C, Lazzarin A, Sighinolfi L, Palamara G, Gori A, Angarano G, Di Pietro M, Galli M, Mercurio VS, Castelli F, Di Perri G, Monini P, Magnani M, Garaci E, and Ensoli B
- Subjects
- AIDS Vaccines adverse effects, Acquired Immunodeficiency Syndrome immunology, Adult, Antibodies, Neutralizing blood, CD4 Lymphocyte Count, Female, Follow-Up Studies, Humans, Immunoglobulin G blood, Immunoglobulin M blood, Italy, Leukocytes immunology, Male, Middle Aged, Treatment Outcome, Young Adult, AIDS Vaccines administration & dosage, AIDS Vaccines immunology, Acquired Immunodeficiency Syndrome therapy, Antiretroviral Therapy, Highly Active methods, HIV Antibodies blood, Viral Load, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Background: The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia <50 copies/mL in the last 6 months prior to enrollment, and CD4(+) T-cell number ≥200 cells/μL. Subjects from a parallel observational study (ISS OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the same criteria constituted an external reference group to explore biomarkers of disease., Results: The vaccine was safe and well tolerated and induced anti-Tat Abs in most patients (79%), with the highest frequency and durability in the Tat 30 μg groups (89%) particularly when given 3 times (92%). Vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4(+) and CD8(+) central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 μg given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant increases of NK cells and CD38(+)HLA-DR(+)/CD8(+) T cells, a phenotype associated with increased killing activity in elite controllers., Conclusions: Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir. Thus, Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy.
- Published
- 2015
- Full Text
- View/download PDF
31. Development of a novel AIDS vaccine: the HIV-1 transactivator of transcription protein vaccine.
- Author
-
Cafaro A, Tripiciano A, Sgadari C, Bellino S, Picconi O, Longo O, Francavilla V, Buttò S, Titti F, Monini P, Ensoli F, and Ensoli B
- Subjects
- AIDS Vaccines immunology, Animals, Antiretroviral Therapy, Highly Active methods, Clinical Trials as Topic methods, Disease Progression, HIV Infections immunology, Humans, tat Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines therapeutic use, HIV Infections prevention & control, HIV-1 immunology, tat Gene Products, Human Immunodeficiency Virus therapeutic use
- Abstract
Introduction: Classical approaches aimed at targeting the HIV-1 envelope as well as other structural viral proteins have largely failed. The HIV-1 transactivator of transcription (Tat) is a key HIV virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. Notably, anti-Tat Abs are uncommon in natural infection and, when present, correlate with the asymptomatic state and lead to lower or no disease progression. Hence, targeting Tat represents a pathogenesis-driven intervention., Areas Covered: Here, we review the rationale and the translational development of a therapeutic vaccine targeting the Tat protein. Preclinical and Phase I studies, Phase II trials with Tat in anti-Tat Ab-negative, virologically suppressed highly active antiretroviral therapy-treated subjects in Italy and South Africa were conducted. The results indicate that Tat-induced immune responses are necessary to restore immune homeostasis, to block the replenishment and to reduce the size of the viral reservoir. Additionally, they may help in establishing key parameters for highly active antiretroviral therapy intensification and a functional cure., Expert Opinion: We propose the therapeutic setting as the most feasible to speed up the testing and comparison of preventative vaccine candidates, as the distinction lies in the use of the vaccine in uninfected versus infected subjects and not in the vaccine formulation.
- Published
- 2015
- Full Text
- View/download PDF
32. Building up a collaborative network for the surveillance of HIV genetic diversity in Italy. A pilot study.
- Author
-
Sanarico N, D'Amato S, Picconi O, Ensoli B, and Buttò S
- Subjects
- Adult, Female, HIV Infections epidemiology, Humans, Italy epidemiology, Male, Middle Aged, Pilot Projects, Prevalence, Public Health Surveillance, Transients and Migrants, Genetic Variation, HIV Infections virology, HIV-1 genetics
- Abstract
Introduction: Prevalence of infection with HIV-1 non-B subtypes in Italy has been reported to raise, due to increased migration flows and travels. HIV-1 variants show different biological and immunological properties that impact on disease progression rate, response to antiretroviral therapy (ART) and sensitivity of diagnostic tests with important implications for public health. Therefore, a constant surveillance of the dynamics of HIV variants in Italy should be a high public health priority. Organization of surveillance studies requires building up a platform constituted of a network of clinical centers, laboratories and institutional agencies, able to properly collect samples for the investigation of HIV subtypes heterogeneity and to provide a database with reliable demographic, clinical, immunological and virological data., Aim: We here report our experience in building up such a platform, co-ordinated by the National AIDS Center of the Istituto Superiore di Sanità, taking advantage of a pilot study aimed at evaluating HIV subtypes diversity in populations of HIV-infected migrant people in Italy., Materials and Methods: Four hundred and thirty four HIV-infected migrants were enrolled in 9 Italian clinical centers located throughout the Italian territory. Standard Operating Procedures (SOPs) for sample collection were provided by the National AIDS Center to each clinical center. In addition, clinical centers were required to fill up a case report form (crf) for each patient, which included demographic, clinical, immunological and virological information., Results: All centers properly collected and stored samples from each enrolled individual. Overall, the required information was correctly provided for more than 90% of the patients. However, some fields of the crf, particularly those including information on the last HIV-negative antibody test and presence of co-infections, were properly filled up in less than 80% of the enrolled migrants. Centers from Northern and Central Italy showed a better tendency to report correct information in the crf than centers from the South. These results provide evidence that procedures for establishing a platform for the surveillance of HIV subtype heterogeneity are affordable by all the components of the network and lay the ground for the organization of a broader HIV subtypes surveillance in Italy.
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.