Publications by authors named "Caterina Mammi"

38 Publications

Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi.

J Clin Oncol 2021 Apr 12;39(11):1214-1222. Epub 2021 Feb 12.

Division of Medical Oncology and Immune-related Tumors, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN), Italy.

Purpose: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL).

Methods: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050).

Results: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases.

Conclusion: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
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http://dx.doi.org/10.1200/JCO.20.02465DOI Listing
April 2021

Tyrosol May Prevent Obesity by Inhibiting Adipogenesis in 3T3-L1 Preadipocytes.

Oxid Med Cell Longev 2020 9;2020:4794780. Epub 2020 Dec 9.

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

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500 M), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBP, PPAR, SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500 M TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment ( < 0.05). Mature adipocytes treated with TR at 300 and 500 M showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity.
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http://dx.doi.org/10.1155/2020/4794780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746459PMC
December 2020

The novel non-steroidal MR antagonist finerenone improves metabolic parameters in high-fat diet-fed mice and activates brown adipose tissue via AMPK-ATGL pathway.

FASEB J 2020 09 30;34(9):12450-12465. Epub 2020 Jul 30.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN-mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN-treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT-specific effect of FIN. Mechanistically, FIN increased activation of AMP-activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein-1 in brown adipocytes.
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http://dx.doi.org/10.1096/fj.202000164RDOI Listing
September 2020

Altered Tregs Differentiation and Impaired Autophagy Correlate to Atherosclerotic Disease.

Front Immunol 2020 13;11:350. Epub 2020 Mar 13.

Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy.

Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy-a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress-may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategies.
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http://dx.doi.org/10.3389/fimmu.2020.00350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082762PMC
March 2021

Role of Aldosterone and Mineralocorticoid Receptor in Cardiovascular Aging.

Front Endocrinol (Lausanne) 2019 23;10:584. Epub 2019 Aug 23.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.
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http://dx.doi.org/10.3389/fendo.2019.00584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716354PMC
August 2019

Obinutuzumab and miniCHOP for unfit patients with diffuse large B-cell lymphoma. A phase II study by Fondazione Italiana Linfomi.

J Geriatr Oncol 2020 01 8;11(1):37-40. Epub 2019 Jul 8.

Hematology Unit, Arcispedale S.Maria Nuova, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy; Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa, University of Modena and Reggio Emilia, Reggio Emilia, Italy.

Objective: To evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy.

Materials And Methods: We conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA).

Results: Overall, 34 patients were enrolled (median age 82 years; range 68-89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3-4 adverse event was neutropenia in thirteen patients (26%).

Conclusions: Based on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL.
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http://dx.doi.org/10.1016/j.jgo.2019.06.020DOI Listing
January 2020

Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice.

J Vis Exp 2018 09 26(139). Epub 2018 Sep 26.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy;

Atherosclerosis is due to a chronic inflammatory response affecting vascular endothelium and is promoted by several factors such as hypertension, dyslipidemia, and diabetes. To date, there is evidence to support a role for circulating aldosterone as a risk factor for the development of cardiovascular disease. Transgenic mouse models have been generated to study cellular and molecular processes leading to atherosclerosis. In this manuscript, we describe a protocol that takes advantage of continuous infusion of aldosterone in ApoE mice and generates atherosclerotic plaques in the aortic root after 4 weeks of treatment. We, therefore, illustrate a method for quantification and characterization of atherosclerotic lesions at the aortic root level. The added value of aldosterone infusion is represented by the generation of atherosclerotic lesions rich in lipid and inflammatory cells after 4 weeks of treatment. We describe in detail the staining procedures to quantify lipid and macrophage content within the plaque. Notably, in this protocol, we perform heart tissue-embedding in OCT in order to preserve the antigenicity of cardiac tissue and facilitate detectability of antigens of interest. Analysis of the plaque phenotype represents a valid approach to study the pathophysiology of atherosclerosis development and to identify novel pharmacological targets for the development of anti-atherogenic drugs.
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http://dx.doi.org/10.3791/58303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235332PMC
September 2018

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease.

Biomolecules 2018 09 18;8(3). Epub 2018 Sep 18.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy.

The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.
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http://dx.doi.org/10.3390/biom8030096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165349PMC
September 2018

Impact of Adrenal Steroids on Regulation of Adipose Tissue.

Compr Physiol 2017 09 12;7(4):1425-1447. Epub 2017 Sep 12.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11β-HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. © 2017 American Physiological Society. Compr Physiol 7:1425-1447, 2017.
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http://dx.doi.org/10.1002/cphy.c160037DOI Listing
September 2017

Essential role of ICAM-1 in aldosterone-induced atherosclerosis.

Int J Cardiol 2017 Apr 5;232:233-242. Epub 2017 Jan 5.

Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy. Electronic address:

Objective: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression.

Methods And Results: Apolipoprotein-E (ApoE) mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE/ICAM-1) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1.

Conclusions: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
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http://dx.doi.org/10.1016/j.ijcard.2017.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890338PMC
April 2017

Effect of hormone replacement therapy with the anti-mineralocorticoid progestin Drospirenone compared to tibolone on endothelial function and central haemodynamics in post-menopausal women.

Int J Cardiol 2017 Jan 9;227:217-221. Epub 2016 Nov 9.

Department of Medical Sciences, IRCCS San Raffaele, Roma, Italy; Cardiovascular & Cell Sciences Institute, St Georges Hospital Medical School, London, UK.

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70±5,6% vs HFD-E 41±4,5%, p<0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone.
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http://dx.doi.org/10.1016/j.ijcard.2016.11.149DOI Listing
January 2017

Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects.

Eat Weight Disord 2017 Mar 23;22(1):27-41. Epub 2016 Aug 23.

Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University Tor Vergata, Rome, Italy.

Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.
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http://dx.doi.org/10.1007/s40519-016-0312-6DOI Listing
March 2017

Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi.

J Clin Oncol 2016 Apr 28;34(11):1175-81. Epub 2015 Dec 28.

Francesco Merli, Caterina Mammi, Fiorella Ilariucci, and Angela Ferrari, Azienda Ospedaliera Arcispedale S. Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS); Reggio Emilia; Stefano Luminari, Luigi Marcheselli, and Massimo Federico, University of Modena and Reggio Emilia, Modena; Paolo G. Gobbi, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia; Nicola Cascavilla and Potito Rosario Scalzulli, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo; Caterina Stelitano, A.O. Bianchi Melacrino Morelli, Reggio Calabria; Maurizio Musso, Ospedale La Maddalena, Palermo; Luca Baldini, Fondazione IRCCS Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano; Sara Galimberti, University of Pisa, Pisa; Francesco Angrilli, Ospedale Santo Spirito, Pescara; and Giuseppe Polimeno, Ospedale "Miulli," Acquaviva delle Fonti, Bari, Italy.

Purpose: The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years.

Patients And Methods: Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months).

Results: The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively).

Conclusion: With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.
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http://dx.doi.org/10.1200/JCO.2015.62.4817DOI Listing
April 2016

Integrating oncogeriatric tools into the management of chronic lymphocytic leukemia: current state of the art and challenges for the future.

Curr Oncol Rep 2015 Jul;17(7):31

Hematology, Arcispedale S. Maria Nuova-IRCCS, Viale Risorgimento 80, 42123, Reggio Emilia, Italy,

Although the achievement of deep and long lasting remissions is a realistic goal of therapy in the fit patient with chronic lymphocytic leukemia (CLL), this disease typically affects elderly patients who also show one or more concomitant pathological conditions or functional limitations that have an additive effects on the reduction of patient's life expectancy and represent major limitations in the adoption of standard therapies. In these unfit but typical patients with CLL, the goals of treatment may vary from achieving good remissions without severe toxicity to simple palliation. Differently from the past when the definition of patient medical status was mainly based on age and was left to the subjective assessment of the physician, today there are several tools to define in a standardized, reproducible, and multidimensional way the initial patient assessment and to plan treatment goals in an objective way. In this review, an overview of the current approaches to the definition of the medical fitness of the patient is provided along with some practical suggestions to integrate these tools in the clinical approach to elderly patients with CLL.
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http://dx.doi.org/10.1007/s11912-015-0454-0DOI Listing
July 2015

Hsp90 blockers inhibit adipocyte differentiation and fat mass accumulation.

PLoS One 2014 4;9(4):e94127. Epub 2014 Apr 4.

University of Zurich, Zurich, Switzerland.

Geldanamycin derivatives are benzoquinone ansamycin antibiotics that bind to Hsp90 and alter its function. The alteration of Hsp90 activity limits some cellular hormonal responses by inhibiting nuclear receptors activation. The nuclear receptors activity, such as PPARγ, the mineralocorticoid and glucocorticoid receptors (MR and GR) play a critical role in the conversion of preadipocytes to mature adipocytes. Given the importance of these nuclear receptors for adipogenesis, we investigated the effects of geldanamycin analogues (GA) on adipocyte differentiation and function. We found that early exposure of preadipocyte cells to GA inhibited their conversion into mature adipocytes by inhibiting the adipogenic transcriptional program and lipid droplets accumulation. Furthermore, GA altered the adipokines secretion profile of mature adipocyte. The anti-adipogenic effect of GA was also confirmed in mice fed a high fat diet. Biochemical analysis revealed that anti-adipogenic effects of geldanamycin analogues may result from the simultaneous inhibition of MR, GR and PPARγ activity. Taken together, our observations lead us to propose Hsp90 as a potent target for drug development in the control of obesity and its related metabolic complications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094127PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976389PMC
December 2014

Outcome of frail elderly patients with diffuse large B-cell lymphoma prospectively identified by Comprehensive Geriatric Assessment: results from a study of the Fondazione Italiana Linfomi.

Leuk Lymphoma 2014 Jan 30;55(1):38-43. Epub 2013 Apr 30.

Hematology Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico , Reggio Emilia , Italy.

In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diffuse large B-cell lymphoma (DLBCL) identified by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classified as frail. Frail patients had a median age of 78 years, stage III-IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2-3 in 53%. Treatment consisted of several different regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2-3 (p = 0.005) and the presence of respiratory comorbidity (p = 0.044) were the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fit patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confidence interval 1.48-3.78; p < 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL.
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http://dx.doi.org/10.3109/10428194.2013.788176DOI Listing
January 2014

Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity.

J Steroid Biochem Mol Biol 2013 Sep 28;137:99-106. Epub 2013 Feb 28.

San Raffaele Sulmona, Sulmona (AQ), Italy.

The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'.
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http://dx.doi.org/10.1016/j.jsbmb.2013.02.012DOI Listing
September 2013

Vitamin D: a novel player in endothelial function and dysfunction.

Arch Med Sci 2012 Feb;8(1):4-5

Centre for Clinical and Basic Research, Department of Medical Sciences, Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.

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http://dx.doi.org/10.5114/aoms.2012.27271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309427PMC
February 2012

Androgens and adipose tissue in males: a complex and reciprocal interplay.

Int J Endocrinol 2012 22;2012:789653. Epub 2011 Dec 22.

Centre of Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, 235 00163 Rome, Italy.

Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a "hallmark" of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost.
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http://dx.doi.org/10.1155/2012/789653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253446PMC
August 2012

The role of the mineralocorticoid receptor in adipocyte biology and fat metabolism.

Mol Cell Endocrinol 2012 Mar 10;350(2):281-8. Epub 2011 Sep 10.

San Raffaele Sulmona, Sulmona (AQ), Italy.

Aldosterone controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor which regulates critical genes controlling salt and water homeostasis in the kidney. In recent years, inappropriate MR activation has been shown to trigger deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction, and oxidative stress. Moreover, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. In particular, recent work has revealed functional MRs in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity. This recent evidence finally moved MR out of the shadow of the glucocorticoid receptor (GR), which had previously been considered the only player mediating corticosteroid action in adipose tissue. This has opened a new era of research focusing on the complexity and selectivity of MR function in adipocyte biology. The aim of this review is to summarize the latest concepts on the role of MR in white and brown adipocytes, and to discuss the potential benefits of tissue-selective MR blockade in the treatment of obesity and metabolic syndrome.
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http://dx.doi.org/10.1016/j.mce.2011.09.011DOI Listing
March 2012

Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi.

Leuk Lymphoma 2012 Apr 15;53(4):581-8. Epub 2011 Nov 15.

Oncology Department, Azienda Ospedaliera Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Argentina.

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of "fit" elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive six courses of R-miniCEOP (n = 114) or R-CHOP (n = 110). Overall, the rate of complete remission was 70% (p = 0.466). After a median follow-up of 42 months, 5-year event-free survival (EFS) rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (p = 0.538). Patients older than 72 years and with low-risk disease had a better outcome when treated with R-miniCEOP (p = 0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly "fit" patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.
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http://dx.doi.org/10.3109/10428194.2011.621565DOI Listing
April 2012

Exercise training reduces serum capacity to induce endothelial cell death in patients with chronic heart failure.

Eur J Heart Fail 2011 Jun;13(6):642-50

Department of Medical Sciences, Centre of Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy.

Aims: Physical training improves endothelial function and exercise capacity in patients with heart failure (HF). Serum from patients with cardiovascular diseases increases apoptosis of human endothelial cells suggesting the importance of humoral factors in the progression of the disease. We evaluated whether exercise training influences the apoptotic capacity of serum from patients with chronic HF (CHF).

Methods And Results: The study included 39 patients with HF (NYHA II) and 10 age-matched healthy controls. Patients were allocated to either a structured programme of exercise training (24 patients) or standard care (15 patients). Human umbilical vein endothelial cells (HUVECs) were incubated with a medium containing 20% serum obtained before and after either a 3-week exercise training programme or standard care. At baseline, serum from patients with CHF induced a higher degree of lactate dehydrogenase (LDH) release and apoptosis in HUVECs compared with healthy controls (43 ± 1.5 vs. 16 ± 1.1%, P< 0.001 and 67 ± 5.4 vs. 23 ± 5.8%, P< 0.001, respectively). Exercise training significantly increased performance in the 6 min walking test (+34.7%) and reduced the ability of serum to induce LDH release and apoptosis of HUVECs. The reduction of apoptosis after exercise training correlated with the improvement in functional capacity. The expression of the apoptosis markers Bax and Caspase-3 was significantly reduced in HUVECs exposed to serum collected after exercise training. Circulating tumour necrosis factor-alpha, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were significantly reduced by exercise training and the MMP-9/TIMP-1 ratio increased.

Conclusion: A short term in-hospital structured cardiovascular training programme reduces the ability of serum-derived factors to induce endothelial cell death in patients with CHF.
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http://dx.doi.org/10.1093/eurjhf/hfr026DOI Listing
June 2011

Sildenafil reduces insulin-resistance in human endothelial cells.

PLoS One 2011 Jan 28;6(1):e14542. Epub 2011 Jan 28.

Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy.

Background: The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro.

Methodology/principal Findings: Human umbilical vein endothelial cells (HUVECs) were treated with insulin in presence of glucose 30 mM (HG) and glucosamine 10 mM (Gluc-N) with or without sildenafil. Insulin increased the expression of PDE5 and eNOS mRNA assayed by Real time-PCR. Cytofluorimetric analysis showed that sildenafil significantly increased NO production in basal condition. This effect was partially inhibited by the PI3K inhibitor LY 294002 and completely inhibited by the NOS inhibitor L-NAME. Akt-1 and eNOS activation was reduced in conditions mimicking insulin resistance and completely restored by sildenafil treatment. Conversely sildenafil treatment can counteract this noxious effect by increasing NO production through eNOS activation and reducing oxidative stress induced by hyperglycaemia and glucosamine.

Conclusions/significance: These data indicate that sildenafil might improve NOS activity of endothelial cells in insulin resistance conditions and suggest the potential therapeutic use of sildenafil for improving vascular function in diabetic patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030559PMC
January 2011

Increase in clusterin forms part of the stress response in Hodgkin's lymphoma.

Int J Oncol 2011 Mar 14;38(3):677-84. Epub 2011 Jan 14.

Hematology Division, Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy.

Clusterin (also called APOJ, SGP-2, XIP8) has thus far been only partially characterized in lymphomas contrary to other types of cancer. Its expression has been reported only for anaplastic large cell lymphomas and, more recently, in mycosis fungoides. Here, we demonstrate an up-regulation of intracellular clusterin in Hodgkin's lymphoma (HL)-derived cell lines L-428, KM-H2 and L-540, caused by different stimuli such as IFN-γ, doxorubicin and X-rays. These stimuli are relevant for the pathophysiology and therapy of HL and represent a first step in the characterisation of this glycoprotein known to have a role in drug chemoresistance. p53 up-regulation accompanies increases in clusterin levels accordingly with the onset of apoptosis. We also show that the cells secrete more clusterin after treatment with doxorubicin, which is consistent with the observed intracellular increase. These observations suggested that the levels of circulating clusterin should also be measured in the peripheral blood from HL patients both at the time of diagnosis and after two cycles of chemotherapy. In a preliminary study on patient sera we observed that an increase in clusterin is correlated with positron emission tomography (PET) positivity after two cycles of chemotherapy.
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http://dx.doi.org/10.3892/ijo.2011.907DOI Listing
March 2011

Antiadipogenic effects of the mineralocorticoid receptor antagonist drospirenone: potential implications for the treatment of metabolic syndrome.

Endocrinology 2011 Jan 17;152(1):113-25. Epub 2010 Nov 17.

Centre for Clinical and Basic Research, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, 81-00163 Rome, Italy.

The mineralocorticoid receptor (MR) mediates aldosterone- and glucocorticoid-induced adipocyte differentiation. Drospirenone (DRSP) is a potent synthetic antimineralocorticoid with progestogenic and antiandrogenic properties, which is widely used for contraception and hormone replacement therapy. We investigated its potential role on adipocyte differentiation. The effects of DRSP were studied in murine preadipocyte cell lines and primary cultures of human preadipocytes. Differentiation markers and mechanisms underlying phenotypic variations in response to DRSP were explored. Early exposure to DRSP during differentiation led to a marked dose-dependent inhibition of adipose differentiation and triglyceride accumulation in 3T3-L1 and 3T3-F442A cells. DRSP also markedly inhibited adipose conversion of human primary preadipocytes derived from visceral (mesenteric and epicardial) and subcutaneous fat. This effect was MR-dependent and did not involve the glucocorticoid, androgen, or progesterone receptors. DRSP inhibited clonal expansion of preadipocytes and decreased expression of PPARγ, a key transcriptional mediator of adipogenesis, but had no effect on lipolysis, glucose uptake, and PPARγ binding to its ligands. DRSP exerts a potent antiadipogenic effect that is related to an alteration of the transcriptional control of adipogenesis via an antagonistic effect on the MR. Selective MR blockade therefore has promise as a novel therapeutic option for the control of excessive adipose tissue deposition and its related metabolic complications.
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http://dx.doi.org/10.1210/en.2010-0674DOI Listing
January 2011

ATP secreted by endothelial cells blocks CX₃CL 1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y₁₁ receptor activation.

Blood 2010 Nov 28;116(22):4492-500. Epub 2010 Jul 28.

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Pisana, Rome, Italy.

Endothelial cells (ECs) represent a major source of actively secreted adenosine triphosphate (ATP). Natural killer (NK) cells can mediate vascular injury in several pathologic conditions, including cytomegalovirus infection and vascular leak syndrome. We studied NK-cell expression of P2 receptors and the role of these nucleotide receptors in the regulation of endothelial-NK cell cross-talk. NK cells from healthy subjects expressed P2Y(₁,₂,₄,₆,₁₁,₁₂,₁₃,₁₄) and P2X(₁,₄,₅,₆,₇) receptors. NK cells stimulated with ATP, but not uridine triphosphate, increased intracellular Ca²(+) and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX₃CL1, whereas chemotaxis to CXCL12 was increased. CX₃CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX₃CL1 failed to stimulate killing of ECs. Such inhibitory effect was lost on exogenous addition of the ATP-hydrolyzing enzyme apyrase or by pharmacologic inhibition of the P2Y₁₁R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y₁₁R agonists, including NAD(+). Extracellular ATP regulates NK-cell cytotoxicity via P2Y₁₁R activation, protecting ECs from CX₃CL1-elicited NK cell-mediated killing. These findings point out the P2Y₁₁R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury.
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http://dx.doi.org/10.1182/blood-2009-12-260828DOI Listing
November 2010

Cellular models for understanding adipogenesis, adipose dysfunction, and obesity.

J Cell Biochem 2010 Jun;110(3):564-72

Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy.

White adipose tissue (WAT) is no longer considered a depot for energy storage in the form of triglycerides, but is a secretory organ that releases factors, known as adipokines, capable of regulating several physiological processes. Alteration of WAT function with subsequent dysfunctional expression and secretion of adipokines plays a key role in the pathogenesis of obesity, diabetes, and other metabolic diseases. For this reason, a deeper understanding of the molecular mechanisms regulating adipocyte function is deemed necessary for planning strategies to treat and prevent obesity and its metabolic complications. This review examines cell culture models currently available for studying adipocyte biology. We focus on advantages, disadvantages and main differences between established preadipocyte cell lines and primary preadipocyte cultures. We revise protocols used to promote adipocyte differentiation and mature adipocytes dedifferentiation into preadipocytes. Finally, we briefly describe co-cultures of adipocytes with other cell types and three-dimensional adipocyte culture systems. These models allow investigation of cell-cell interactions with the cross-talk physiologically occurring between adipocytes and other cell types residing within or outside adipose tissue.
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http://dx.doi.org/10.1002/jcb.22598DOI Listing
June 2010

Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study.

J Am Coll Cardiol 2009 Sep;54(10):919-27

Centre for Clinical and Basic Research, Cardiovascular Research Unit, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy.

Objectives: This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF).

Background: CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure.

Methods: Seventy elderly patients with stable CHF-median age 70 years, ejection fraction 31.8 +/- 7%-were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique).

Results: Baseline peak oxygen consumption (VO(2)) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO(2) significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO(2) and MVC. There were no significant changes in left ventricular function either in testosterone or placebo.

Conclusions: These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects.
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http://dx.doi.org/10.1016/j.jacc.2009.04.078DOI Listing
September 2009

Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs.

Neurosci Lett 2009 Mar 7;453(1):36-40. Epub 2009 Feb 7.

IRCCS San Raffaele Pisana, Via dei Bonacolsi 81, Rome, Italy.

Elevated oxidative stress-induced apoptosis has been found in peripheral cells from patients with Alzheimer's disease (AD). Furthermore, treatment of lymphocytes from AD patients, with Abeta(1-42) and H(2)O(2) results in enhanced apoptosis. Mild cognitive impairment (MCI), a clinical condition between normal aging and AD, shares with AD a similar pattern of peripheral markers of oxidative stress. In this study we investigated spontaneous and H(2)O(2)-induced oxidative stress and apoptosis levels in peripheral blood mononuclear cells (PBMCs) from MCI and AD patients, as well as from Parkinson's disease (PD) patients without cognitive impairment or age-matched healthy control. Sod1 mRNA levels were studied to analyse the anti-oxidative pathway, while Bax and Bcl-2 mRNAs levels and PARP protein cleavage were monitored to study apoptosis. We found that the expression of Sod1 and Bax mRNAs was statistically higher in both MCI and AD patients compared to controls or PD subjects. Since Bcl-2 mRNA level was not different among groups, the Bax/Bcl-2 ratio was statistically higher in AD and MCI patients. PARP cleavage was also enhanced in PBMCs from MCI and AD individuals and this finding was associated with a higher level of spontaneous apoptosis. Interestingly, exposure to H(2)O(2) induced a significant decrease of Bcl-2 mRNA transcript, while Sod1 and Bax mRNAs levels were unchanged in PBMCs derived from MCI and AD patients. In conclusion, our results show that Bax and Sod1 mRNA levels are altered in PBMCs from both MCI and AD patients and indicate these changes as potential biomarkers in the early diagnosis of AD.
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http://dx.doi.org/10.1016/j.neulet.2009.02.003DOI Listing
March 2009

Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma.

Oncol Rep 2009 Apr;21(4):1029-35

Clinica Medica I, Università di Pavia, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.

The aim of this study was to evaluate the apoptotic damage to bone marrow cells caused by three chemotherapy regimens for advanced Hodgkin's lymphoma, ABVD, COPPEBVCAD and BEACOPP, which were randomly administered in the HD 2000 GISL trial. Bone marrow mononuclear cells (BMMCs) stained with anti-CD34 antibody and Annexin V, were evaluated by flow cytometry before starting chemotherapy, 30 days after completing chemotherapy and after 6 months. Results are expressed as the percentages of BMMCs positive to anti-CD34, to Annexin V or to both. Fourteen patients treated with ABVD, 11 with COPPEBVCAD and 13 with BEACOPP were evaluated before and 30 days after treatment. Late assessments were made in 6, 7 and 8 of them, respectively. No differences were found among the pretherapeutic flow cytometry findings in relation to the staging characteristics (marrow involvement included). All the regimens increased the apoptotic fraction of the whole mononuclear bone marrow cells (COPPEBVCAD did so significantly) and increased the CD34+ compartment (with significant early differences after ABVD and BEACOPP, tending to late persistence for ABVD, only). All the regimens increased the apoptotic CD34+ cells within the whole BMMC population (significantly after BEACOPP), although with a general trend to decrease in their percentage within the CD34+ compartment over time, even after the most dose-dense regimens. Based on the variations induced in the apoptotic fraction of all mononuclear and CD34+ cells, ABVD was the least toxic regimen and COPPEBVCAD the most toxic one.
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http://dx.doi.org/10.3892/or_00000320DOI Listing
April 2009