Genetic and phenotypic attributes of splenic marginal zone lymphoma

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments

Learning of a Sequential Motor Skill Comprises Explicit and Implicit Components That Consolidate Differently

The ability to perform accurate sequential movements is essential to normal motor function. Learning a sequential motor behavior is comprised of two basic components: explicit identification of the order in which the sequence elements should be performed and implicit acquisition of spatial accuracy for each element. Here we investigated the time course of learning of these components for a first sequence (SEQA) and their susceptibility to interference from learning a second sequence (SEQB). We assessed explicit learning with a discrete index, the number of correct anticipatory movements, and implicit learning with a continuous variable, spatial error, which decreased during learning without subject awareness. Spatial accuracy to individual sequence elements reached asymptotic levels only when the whole sequence order was known. Interference with recall of the order of SEQA persisted even when SEQB was learned 24 h after SEQA. However, there was resistance to interference by SEQB with increased initial training with SEQA. For implicit learning of spatial accuracy, SEQB interfered at 5 min but not 24 h after SEQA. As in the case of sequence order, prolonged initial training with SEQA induced resistance to interference by SEQB. We conclude that explicit sequence learning is more susceptible to anterograde interference and implicit sequence learning is more susceptible to retrograde interference. However, both become resistant to interference with saturation training. We propose that an essential feature of motor skill learning is the process by which discrete explicit task elements are combined with continuous implicit features of movement to form flawless sequential actions

Femoral fractures in the extremely elderly

At the Trauma Unit of Pisa we performed an observational study reviewing nineties that about 200 patients were treated and underwent surgery for femoral neck fracture from 1998 to 2005. The clinical and radiographic results obtained were discrete, with a mortality of 42.5%, the survivors are still having a good quality of life

Study of the porcine dermal collagen repair patch in morpho-functional recovery of the rotator cuff after minimum follow-up of 2.5 years

Tendon augmentation grafts have the potential to facilitate the repair of massive or otherwise unrepairable rotator cuff tears. In our clinic, between 2009 and 2013, 25 patients underwent surgery to treat massive symptomatic rotator cuff tears with porcine dermal collagen patch. This study is a clinical and instrumental assessment of 9 patients with the longest follow-up. These patients were evaluated with Constant score, the American Shoulder and Elbow Surgeons Evaluation Form, ultrasound imaging, magnetic resonance imaging, and electromyography. The clinical evaluations have shown good outcomes. The magnetic resonance imaging results were comparable with those of the ultrasound scan. In all cases, we found covering of humeral head, centering of the humeral head, maintenance of the tropism of the supraspinatus, no appearance of fatty degeneration, no worse in cases with fatty degeneration. With the electromyographic examination a complete functional recovery was observed with the possibility of performing maximal contraction against resistance in all cases. We believe that porcine dermal collagen is effective as an augmentation graft in the treatment of chronic extensive rotator cuff tears, providing excellent pain relief with an improvement in active ranges of motion and strength

A predictive model for planning emergency events rescue during COVID-19 in Lombardy, Italy

Forecasting the volume of emergency events is important for resource utilization in emergency medical services (EMS). This became more evident during the COVID-19 outbreak when emergency event forecasts used by various EMS at that time tended to be inaccurate due to fluctuations in the number, type, and geographical distribution of these events. The motivation for this study was to develop a statistical model capable of predicting the volume of emergency events for Lombardy’s regional EMS called AREU at different time horizons. To accomplish this goal, we propose a negative binomial additive autoregressive model with smoothing splines, which can predict over-dispersed counts of emergency events one, two, five, and seven days ahead. In the model development stage, a large set of covariates was considered, and the final model was selected using a cross-validation procedure that takes into account the observations’ temporal dependence. Comparisons of the forecasting performance using the mean absolute percentage error showed that the proposed model outperformed the model used by AREU, as well as other widely used forecasting models. Consequently, AREU decided to adopt the new model for its forecasting purposes

Assessing the heterogeneity of the impact of COVID-19 incidence on all-cause excess mortality among healthcare districts in Lombardy, Italy, to evaluate the local response to the pandemic: an ecological study

Objectives The fragmentation of the response to the COVID-19 pandemic at national, regional and local levels is a possible source of variability in the impact of the pandemic on society. This study aims to assess how much of this variability affected the burden of COVID-19, measured in terms of all-cause 2020 excess mortality.Design Ecological retrospective study.Setting Lombardy region of Italy, 2015–2020.Outcome measures We evaluated the relationship between the intensity of the epidemics and excess mortality, assessing the heterogeneity of this relationship across the 91 districts after adjusting for relevant confounders.Results The epidemic intensity was quantified as the COVID-19 hospitalisations per 1000 inhabitants. Five confounders were identified through a directed acyclic graph: age distribution, population density, pro-capita gross domestic product, restriction policy and population mobility.Analyses were based on a negative binomial regression model with district-specific random effects. We found a strong, positive association between COVID-19 hospitalisations and 2020 excess mortality (p<0.001), estimating that an increase of one hospitalised COVID-19 patient per 1000 inhabitants resulted in a 15.5% increase in excess mortality. After adjusting for confounders, no district differed in terms of COVID-19-unrelated excess mortality from the average district. Minimal heterogeneity emerged in the district-specific relationships between COVID-19 hospitalisations and excess mortality (6 confidence intervals out of 91 did not cover the null value).Conclusions The homogeneous effect of the COVID-19 spread on the excess mortality in the Lombardy districts suggests that, despite the unprecedented conditions, the pandemic reactions did not result in health disparities in the region

Per un’estetica dell’erranza. Marrani, nicodemiti e filosofi in transito nel mondo globalizzato del XVI e XVII Secolo

The Jews of Spain, in 1492, were forced to convert to Christianity or leave the country. But even those who agreed to convert, the Marranos, were always persecuted by the Inquisition and often burned at the stake. The Marranos also therefore sought refuge elsewhere.This exodus took them to Portugal, Italy, the Arab countries and the Ottoman Empire, and then, starting from Holland, also to Asia and the Americas. In this way, the Marranos were among the most important actors in trade and relations on a global scale. Furthermore, forced to continuously change religion, status, nation and ideologies, the Marranos are at the basis of the formation of the new subjectivities of the modern age, represented by artists and writers such as Cervantes and Velázquez, by theologians such as Servetus, by philosophers such as Spinoza, by mystics like Teresa of Avila

Inhibition of SIRT2 Potentiates the Anti-motility Activity of Taxanes: Implications for Antineoplastic Combination Therapies

Taxanes are potent inhibitors of cell motility, a property implicated in their antiangiogenic and antimetastatic activity and unrelated to their antiproliferative effect. The molecular mechanism of this anti-motility activity is poorly understood. In this study, we found that paclitaxel induced tubulin acetylation in endothelial and tumor cells, at concentrations that affected cell motility but not proliferation (10-8 to 10-9 M, for 4 hours). Induction of tubulin acetylation correlated with inhibition of motility but not proliferation based on a comparison of highly and poorly cytotoxic taxanes (paclitaxel and IDN5390) and tumor cell lines sensitive and resistant to paclitaxel (1A9 and 1A9 PTX22). Consistent with the hypothesis that tubulin deacetylase activity might affect cell response to the anti-motility activity of taxanes, we found that overexpression of the tubulin deacetylase SIRT2 increased cell motility and reduced cell response to the anti-motility activity of paclitaxel. Conversely, the SIRT2 inhibitor splitomicin reduced cell motility and potentiated the anti-motility activity of paclitaxel. The inhibitory effect was further potentiated by the addition of the HDAC6 inhibitor trichostatin A. Paclitaxel and splitomicin promoted translocation into the nucleus—and hence activation—of FOXO3a, a negative regulator of cell motility. This study indicates a role for SIRT2 in the regulation of cell motility and suggests that therapies combining sirtuin inhibitors and taxanes could be used to treat cell motility-based pathologic processes such as tumor angiogenesis, invasion, and metastasis