Catholic University of the Sacred Heart

About: Catholic University of the Sacred Heart is a education organization based out in Milan, Lombardia, Italy. It is known for research contribution in the topics: Population & Medicine. The organization has 13592 authors who have published 31048 publications receiving 853961 citations.

Left atrial appendage: An underrecognized trigger site of atrial fibrillation

Abstract: Background— Together with pulmonary veins, many extrapulmonary vein areas may be the source of initiation and maintenance of atrial fibrillation. The left atrial appendage (LAA) is an underestimated site of initiation of atrial fibrillation. Here, we report the prevalence of triggers from the LAA and the best strategy for successful ablation. Methods and Results— Nine hundred eighty-seven consecutive patients (29% paroxysmal, 71% nonparoxysmal) undergoing redo catheter ablation for atrial fibrillation were enrolled. Two hundred sixty-six patients (27%) showed firing from the LAA and became the study population. In 86 of 987 patients (8.7%; 5 paroxysmal, 81 nonparoxysmal), the LAA was found to be the only source of arrhythmia with no pulmonary veins or other extrapulmonary vein site reconnection. Ablation was performed either with focal lesion (n=56; group 2) or to achieve LAA isolation by placement of the circular catheter at the ostium of the LAA guided by intracardiac echocardiography (167 patients; gro...

MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis

Abstract: MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14+ cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68+ cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14+ cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14+ cells reduced TNF-α production. Finally, miR-155–deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Abstract: Noonan syndrome (NS) is a developmental disordercharacterized by short stature, facial dysmorphia, congenital heartdefects and skeletal anomalies1. Increased RAS-mitogenactivated proteinkinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percentof NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 orKRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutationscluster at residues implicated in the maintenance of SOS1 in itsautoinhibited form and ectopic expression of two NS-associated mutantsinduced enhanced RAS activation. The phenotype associated with SOS1defects is distinctive, although within NS spectrum, with a highprevalence of ectodermal abnormalities but generally normal developmentand linear growth. Our findings implicate for the first timegain-of-function mutations in a RAS GEF in inherited disease and define anew mechanism by which upregulation of the RAS pathway can profoundlychange human development.

Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Abstract: Importance Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non–small cell lung cancer (NSCLC) are unknown. Objectives To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350];P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69];P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Brain generators of laser-evoked potentials: from dipoles to functional significance

Abstract: In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a "lumped" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.