Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

The RNA-Binding Protein SMN as a Novel Player in Laryngeal Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium in the oral cavity, pharynx, sino-nasal region, and larynx. Laryngeal squamous cell carcinoma (LSCC) represents one-third of all head and neck cancers. Dysregulated RNA-related pathways define an important molecular signature in this aggressive carcinoma. The Survival Motor Neuron (SMN) protein regulates fundamental aspects of the RNA metabolism but, curiously, its role in cancer is virtually unknown. For the first time, here, we focus on the SMN in the cancer context. We conducted a pilot study in a total of 20 patients with LSCC where the SMN was found overexpressed at both the protein and transcript levels. By a cellular model of human laryngeal carcinoma, we demonstrated that the SMN impacts cancer-relevant behaviors and perturbs key players of cell migration, invasion, and adhesion. Furthermore, in LSCC we showed a physical interaction between the SMN and the epidermal growth factor receptor (EGFR), whose overexpression is an important feature in these tumors. This study proposes the SMN protein as a novel therapeutic target in LSSC and likely in the whole spectrum of HNSCC. Overall, we provide the first analysis of the SMN in human cancer.

An immunometabolic pathomechanism for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with abnormal immune responses, leading to airflow obstruction. Lungs of COPD subjects show accumulation of proinflammatory T helper (Th) 1 and Th17 cells resembling that of autoreactive immune responses. As regulatory T (Treg) cells play a central role in the control of autoimmune responses and their generation and function are controlled by the adipocytokine leptin, we herein investigated the association among systemic leptin overproduction, reduced engagement of glycolysis in T cells, and reduced peripheral frequency of Treg cells in different COPD stages. These phenomena were also associated with an impaired capacity to generate inducible Treg (iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited the expression of forkhead-boxP3 (FoxP3) and its splicing variants containing the exon 2 (FoxP3-E2) that correlated inversely with inflammation and weakened lung function during COPD progression. Our data reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a decline in the expression of FoxP3 splicing forms, and an impairment in Treg cell generation and function. These results have potential implications for better understanding the autoimmune-like nature of COPD and the pathogenic events leading to lung damage.

Reduced Annexin A1 Expression Associates with Disease Severity and Inflammation in Multiple Sclerosis Patients.

Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4+CD25- conventional T and CD4+RORγt+ T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.

Multidisciplinary Approach to the Diagnosis and Therapy of Mycosis Fungoides.

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, characterized by skin-homing CD4+ T cells derivation, indolent course, and low-grade of malignancy. Mycosis fungoides's classic type typically onsets with cutaneous erythematous patches, plaque, and tumor. In WHO-EORTC classification, folliculotropic mycosis fungoides, pagetoid reticulosis, and granulomatous slack skin are recognized as distinct variants of mycosis fungoides, because of their clinical and histological features, behavior, and /or prognosis. Mycosis fungoides often shows diagnostic difficulties, due to its absence of specific features and lesional polymorphism. A patient's treatment requires staging. In about 10% of cases, mycosis fungoides can progress to lymph nodes and internal organs. Prognosis is poor at advanced stage and management needs a multidisciplinary team approach. Advanced stage disease including tumors, erythroderma, and nodal, visceral, or blood involvement needs skin directed therapy associated with systemic drugs. Skin directed therapy includes steroids, nitrogen mustard, bexarotene gel, phototherapy UVB, and photochemiotherapy, i.e., total skin electron radiotherapy. Systemic therapies include retinoids, bexarotene, interferon, histone deacetylase inhibitors, photopheresis, targeted immunotherapy, and cytotoxic chemotherapy. Complexity of mycosis fungoides associated with long-term chronic evolution and multiple therapy based on disease stage need a multidisciplinary team approach to be treated.

Clinical evaluation of a ridge augmentation procedure for the severely resorbed alveolar socket: multicenter randomized controlled trial, preliminary results.

OBJECTIVE: To radiographically analyze extraction sites left untreated or treated using a socket preservation technique. MATERIALS AND METHODS: A total of 20 patients scheduled for single extraction in the maxilla from second to second premolar were enrolled in this study. All sites showed a bone defect >5 mm at the buccal wall and no soft tissue recession. At baseline (T0), tooth extraction was performed; subsequently, sites were randomly allocated to the control (CG: left to heal without grafting) or test group (TG: grafted using hydroxyapatite). Two months later (T1), implants were inserted and eventual GBR procedure was performed. Three months later, the definitive crown was placed. Follow up was 24 months (T2). A cone-beam computed tomographic examination (CT) was performed at each time point. At each radiographic analysis, horizontal and vertical widths of the sockets were measured. Comparisons between CG and TG were performed by a Wilcoxon non-parametric test. RESULTS: At the end of the study, no patient dropped out and all implants inserted (10 in each group) resulted integrated. GBR procedures were performed at T1 only in the CG. In the CG, the mean value of the horizontal width in the coronal CT slices was 0.98 mm (± 0.37), 7.70 mm (± 0.92), 7.45 mm (± 0.69) at T0, T1 (after bone regeneration) and T2, respectively. In the TG, the mean value of the horizontal width in the coronal CT slices was 0.96 mm (± 0.41), 8.97 mm (± 1.91), 9.48 mm (± 1.56); at T2, it was 9.52 mm (± 1.87) at T0 (pre- and post-socket preservation) T1 and T2, respectively. At each follow up, the mean horizontal bone width in TG was statistically significantly greater than in the control group (P < 0.05). At T0, mean value of the vertical bone defect length (BDL) was 6.93 mm for TG, 6.5 mm for CG. At T1 and T2, mean BDL value was 0 for both groups. Statistically significant difference was not found between TC and CG at any time point (P > 0.05). CONCLUSIONS: This randomized controlled trial suggested that in sites with buccal bone defects >5 mm, the application of HA can minimize alveolar crest resorption following tooth extraction. Furthermore, compared with traditional regenerative procedure carried out following socket healing, this preservation technique seems to result in better horizontal regeneration of the buccal bone wall.

Heparin versus bivalirudin for carotid artery stenting using proximal endovascular clamping for neuroprotection: results from a prospective randomized study.

BACKGROUND: General recommendations indicate that, during a carotid artery stenting (CAS), sufficient unfractionated heparin (UFH) has to be given to maintain the activated clotting time between 250 to 300 seconds. Bivalirudin use is able to reduce postprocedural bleedings in percutaneous interventions when compared with UFH. The study purpose was to evaluate, in a randomized study, the safety and efficacy of bivalirudin versus heparin during CAS, using proximal endovascular occlusion (PEO) as a distal protection device. METHODS: From January 2006 to December 2009, 220 patients undergoing CAS using PEO have been randomly assigned to one of the study arms (control arm: 100 UI/kg UFH or bivalirudin arm: 0.75 mg/kg intravenous bolus and intraprocedural infusion at 1.75 mg/kg/h). RESULTS: Procedural success was achieved in all the patients. No episodes of intraprocedural thrombosis occurred. One major stroke occurred in the bivalirudin arm, and two minor strokes occurred, one in each group. A significant difference in the incidence of postprocedural bleedings was observed between the study groups; bivalirudin use was associated with reduced number of bleedings according to Thrombolysis In Myocardial Infarction criteria. CONCLUSIONS: The use of bivalirudin should be considered a safe and effective anticoagulation regimen during CAS, using PEO as a distal protection device. Bivalirudin use is associated with a reduced incidence of bleedings.

Use of Rituximab in NHL Malt Type Pregnant in I° Trimester for Two Times.

Administration of rituximab, one of the basic drugs for the therapy of B-cell lymphoproliferative diseases, during pregnancy has been suspected to cause developmental fetal events, particularly if given during the first trimester of pregnancy. Therefore, use in pregnancy is not permitted. Howe ver, several cases of pregnant women being treated with rituximab are reported herein; an exception is often made in cases with grave illness. We describe an exceptional case of a woman with non-Hodgkin lymphoma of the mucosa-associated lymphoid tissue type where rituximab was given as a single agent without interruption during two consecutive pregnancies. This case can certainly supply important indications on the safety of rituximab.

Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: responders vs. non-responders.

AIMS: MicroRNAs (miRNAs) play an important role in the pathogenesis of structural alterations of the failing heart through their ability to regulate negatively the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodelling. We studied whether LV reverse remodelling after CRT was associated with changes of circulating miRNAs in patients with heart failure (HF) and dyssynchrony. METHODS AND RESULTS: A prospective, non-randomized self-control trial was performed in 81 patients with HF eligible for CRT. At baseline, to select the HF miRNA profile, we evaluated the expression of 84 miRNAs (implicated in the pathogenesis of structural alterations of the failing heart) in three groups of patients: healthy subjects (healthy group, n = 15); patients with HF (HF group, n = 81); and patients without HF matched for age, sex, and concomitant disease with HF patients (control group, n = 60). At 12 months, the selected miRNA profile was evaluated in plasma from responder (n = 55) and non-responder HF patients (n = 26) to CRT. In the test cohort, the HF patients were characterized by lower expression of 48 miRNAs (all P < 0.04) as compared with healthy subjects. In the validation cohort, the HF patients were characterized by lower expression of 24 miRNAs (all P < 0.03) as compared with control patients. At 12 months, 55 patients (68%) were considered responders and 26 non-responders to CRT (32%). Responders showed an increase in expression of 19 miRNAs (all P < 0.03) compared with baseline expression, whereas in the non-responders we observed an increase of six miRNAs (all P < 0.05) compared with baseline expression. At follow-up, miRNAs were differentially expressed between responders and non-responders. The responders were characterized by higher expression of five miRNAs (miRNA-26b-5p, miRNA-145-5p, miRNA-92a-3p, miRNA-30e-5p, and miRNA-29a-3p; P < 0.01 for all) as compared with non-responders. CONCLUSIONS: In responders, reverse remodelling is associated with favourable changes in miRNAs that regulate cardiac fibrosis, apoptosis, and hypertrophy.

Crestal minimally-invasive sinus lift on severely resorbed maxillary crest: prospective study.

OBJECTIVES: This case series aimed to explore the clinical outcome of sinus floor elevation surgery using a crestal approach technique in case of severely resorbed maxillae. MATERIAL AND METHODS: Seventeen edentulous patients received 20 implants and sinus floor elevation in posterior maxillae with residual crestal height of 1.2-5.0 mm and >7 mm. Drilling perforation was performed until the sinus floor was felt; the sinus mucosa was then lifted and magnesium-enriched hydroxyapatite granules (Mg-e HAP) were placed; and implants were immediately inserted. Four months later, definitive crowns were cemented, and patients were followed up for 24 months. Implant failures and complications 24 months after prosthetic loading were noted, and radiographic regenerated bone height was measured. RESULTS: No patient dropped out, and all implants were successfully osseointegrated. There was minimal postoperative patient discomfort, and the only complication was a minimal perforation of the sinus membrane with no negative consequences. At the time of implant insertion, the residual crestal height mean value was 4.12 mm. After surgery and at the last follow-up, the mean heights of bone were 13.51 and 12.98 mm, respectively. CONCLUSION: The procedure was able to obtain sinus elevation and implant osseointegration.

A case series on crestal sinus elevation with rotary instruments.

PURPOSE: This case series aimed to evaluate the clinical outcome of a crestal approach technique in sinus floor elevation surgery with insertion of an alloplastic material. MATERIAL AND METHODS: A total of 50 edentulous patients received 64 implants and sinus floor elevation in posterior maxillae with residual crestal height 1.2 to 9.8 mm, and larger than 7 mm in width. Drilling perforation was performed until the sinus floor was felt. The sinus mucosa was then lifted. Hydroxyapatite granules were placed and implants were immediately inserted. Three months later, definitive crowns were cemented and patients were followed up for 18 months. Outcome measures were implant failures, complications and radiographic bone height gain measured 18 months after prosthetic loading. RESULTS: No patient dropped out and all implants were successfully osseointegrated. Only minimal postoperative patient discomfort was reported. Only one complication occurred: a minor perforation of the sinus membrane with no negative consequences. At the time of implant insertion, the residual bone height mean value was 6.20 mm (±2.22). After surgery and at the last follow-up, the mean height of bone was 15.26 (±3.19) and 15.40 mm (±4.21), respectively. CONCLUSION: The procedure was able to obtain sinus elevation and implant osseointegration.