High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by abnormally expanded stretches of CTG DNA triplets in the DMPK gene, leading to mutated-transcript RNA-toxicity. MicroRNAs (miRNAs) are short non-coding RNAs that, after maturation, are loaded onto the RISC effector complex that destabilizes target mRNAs and represses their translation. In DM1 muscle biopsies not only the expression, but also the intracellular localization of specific miRNAs is disrupted, leading to the dysregulation of the relevant mRNA targets. To investigate the functional alterations of the miRNA/target interactions in DM1, we analyzed by RNA-sequencing the RISC-associated RNAs in skeletal muscle biopsies derived from DM1 patients and matched controls. The mRNAs found deregulated in DM1 biopsies were involved in pathways and functions relevant for the disease, such as energetic metabolism, calcium signaling, muscle contraction and p53-dependent apoptosis. Bioinformatic analysis of the miRNA/mRNA interactions based on the RISC enrichment profiles, identified 24 miRNA/mRNA correlations. Following validation in 21 independent samples, we focused on the couple miR-29c/ASB2 because of the role of miR-29c in fibrosis (a feature of late-stage DM1 patients) and of ASB2 in the regulation of muscle mass. Luciferase reporter assay confirmed the direct interaction between miR-29c and ASB2. Moreover, decreased miR-29c and increased ASB2 levels were verified also in immortalized myogenic cells and primary fibroblasts, derived from biopsies of DM1 patients and controls. CRISPR/Cas9-mediated deletion of CTG expansions rescued normal miR-29c and ASB2 levels, indicating a direct link between the mutant repeats and the miRNA/target expression. In conclusion, functionally relevant miRNA/mRNA interactions were identified in skeletal muscles of DM1 patients, highlighting the dysfunction of miR-29c and ASB2

A Retrospective Clinico-Pathologic Study of 35 Dogs with Urethral Transitional Cell Carcinoma Undergoing Treatment

: Chemotherapy and cyclooxygenase inhibitors (COXi) are primary treatments for canine urethral transitional cell carcinoma (uTCC), a tumor known for its aggressiveness and poor prognosis. This retrospective study aimed to evaluate the clinico-pathological characteristics, treatment modalities, and prognostic factors of 35 dogs with confirmed uTCC that received chemotherapy and COXi. Upon admission, urethral obstruction (UO) and urinary tract infection (UTI) were observed in seven (20%) dogs each. Gemcitabine (n = 20; 57.1%) and vinblastine (n = 10; 28.6%) were commonly used as first-line therapies, with four dogs also receiving radiation therapy. Based on RECIST, one (2.9%) dog achieved complete remission, nine (25.7%) partial remission, 20 (57.14%) showed stable disease, and five (14.3%) progressed. Among dogs with UO, six (85.7%) showed resolution or improvement after the first chemotherapy dose. The median time to local progression was 171 days (range: 107-235), and the median survival time was 333 days (range: 158-508). Dogs with UO upon admission had a higher risk of local progression, while both UO and UTI were associated with an increased risk of overall disease progression and tumor-related death. Additionally, gemcitabine significantly improved metastatic control. This study identified UO and UTI as negative prognostic factors, highlighting the importance of a multimodal approach in managing uTCC

Spotlight on capecitabine for the treatment of unresectable or metastatic carcinoma of various origin: A retrospective study of 25 dogs

Capecitabine, the oral prodrug of 5-fluorouracil, is indicated in people to treat various malignant epithelial cancers. In dogs, capecitabine has not been extensively evaluated. The aim of this retrospective study was to investigate toxicity and preliminary efficacy of single agent capecitabine in dogs with advanced malignant epithelial cancers of any site, for which no effective therapy existed, conventional treatment failed or was declined. Capecitabine was administered orally at 750 mg/m2 from day 1 to 14, followed by 1-week rest period, given as 3-week cycles. Safety evaluation was performed after 2 cycles, and every 2-3 cycles thereafter. Tumour response was determined every 2-3 cycles. Twenty-five dogs with hepatocellular carcinoma (n = 6), lung papillary carcinoma (n = 4), anal sac adenocarcinoma (n = 3), colic adenocarcinoma (n = 2), and other individually represented epithelial cancers (n = 10) were included. Dogs received a median of 4 cycles (range, 2-43) for a median of 84 days (range, 42-913). Toxicity occurred in 17 (68.0%) dogs; the most frequent adverse events were gastrointestinal, with the majority being self-resolving and of mild grade. Of the 22 dogs with macroscopic disease, 3 (13.6%) achieved partial remission, 16 (72.7%) were stable and 3 (13.6%) progressed; overall clinical benefit rate was 86.4%. Median progression-free interval was 93 days (95% CI 42-154; range, 1-521) and median tumour-specific survival was 273 days (95% CI 116-482; range 45-913). These findings suggest that capecitabine is an attractive option for the treatment of several types of carcinomas in dogs. Prospective studies are warranted to optimize the scheduling of capecitabine and confirm its efficacy

Cohort study of prevalence and phenomenology of tremor in dementia with Lewy bodies

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p \u3c 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p \u3c 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors. Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-6853-y) contains supplementary material, which is available to authorized users

Multisource Bayesian Probabilistic Tsunami Hazard Analysis for the Gulf of Naples (Italy)

A methodology for a comprehensive probabilistic tsunami hazard analysis is presented for the major sources of tsunamis (seismic events, landslides, and volcanic activity) and preliminarily applied in the Gulf of Naples (Italy). The methodology uses both a modular procedure to evaluate the tsunami hazard and a Bayesian analysis to include the historical information of the past tsunami events. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0001 the submarine earthquakes and the submarine mass failures are initially identified in a gridded domain and defined by a set of parameters, producing the sea floor deformations and the corresponding initial tsunami waves. Differently volcanic tsunamis generate sea surface waves caused by pyroclastic density currents from Somma‐Vesuvius. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0002 the tsunami waves are simulated and propagated in the deep sea by a numerical model that solves the shallow water equations. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0003 the tsunami wave heights are estimated at the coast using the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0004's amplification law. The selected tsunami intensity is the wave height. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0005 the probabilistic tsunami analysis computes the long‐term comprehensive Bayesian probabilistic tsunami hazard analysis. In the prior analysis the probabilities from the scenarios in which the tsunami parameter overcomes the selected threshold levels are combined with the spatial, temporal, and frequency‐size probabilities of occurrence of the tsunamigenic sources. The urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0006 probability density functions are integrated with the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0007 derived from the historical information based on past tsunami data. The urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0008 probability density functions are evaluated to produce the hazard curves in selected sites of the Gulf of Naples. Plain Language Summary Probabilistic analyses are essential to estimate the natural hazards caused by infrequent and devastating events and to elaborate risk assessments aiming to mitigate and reduce the impact of the natural disasters on society. Probabilistic tsunami hazard analyses use procedures that trace and weight the different tsunami sources (submarine earthquakes, aerial/submarine slides, volcanic activity, meteorological events, and asteroid impacts) with varying probability of occurrence. The scope of the present methodology is the reduction of possible biases and underestimations that arise by focusing on a single tunamigenic source. The multisource probabilistic tsunami hazard analysis is applied to a real case study, the Gulf of Naples (Italy), where relevant threats due to natural events exist in a high densely populated district. The probabilistic hazard procedure takes into account multiple tsunamigenic sources in the region and provides a first‐order prioritization of the different sources in a long‐term comprehensive analysis. The methodology is based on a Bayesian approach that merges computational hazard quantification (based on source‐tsunami simulations) and past data, appropriately including in the quantification the epistemic uncertainty. For the first time a probabilistic analysis of the tsunami hazard in the region is presented taking into consideration multiple tsunamigenic sources

Il Centro Allerta Tsunami (CAT) dell’INGV

The Tsunami Alert Centre of the INGV (CAT-INGV) was created with the aim of contributing to the mitigation of the risk due to tsunamis triggered by earthquakes on the Italian and Mediterranean coasts. Tsunamis of seismic origin, in addition to being the most frequent, are those that can be detected more quickly. Seismic waves, in fact, travel in the crust with a much higher speed than that of tsunami waves. With effective seismic networks connected in real time, an "Early Warning" system can be implemented, i.e. a system capable of sending an alert signal before the arrival of the tsunami waves, at least from a certain distance from the source. The CAT-INGV has two main tasks. The first one is to provide alerts to the competent authorities in the event of potential tsunamigenic earthquakes in the Mediterranean, taking into account the criteria defined by the Department of Civil Protection for this purpose. The second one consists in carrying out the necessary studies for the definition of the probabilistic danger of tsunamis for the Italian coasts, starting from those of seismic origin (Seismic Probabili-stic Tsunami Hazard Analysis, SPTHA). In this contribution the first aspect is described, while the realization of the studies on hazard at the Mediterranean scale is the subject of research described in various recent articles (Lorito et al., 2015; Grezio et al., 2017; Selva et al., 2017a; Selva et al., 2017b). The TSUMAPS-NEAM project, funded by the European Commission and concluded at the end of 2017, provided the first hazard map for the Mediterranean region and the north-east Atlantic (Basili et al., 2017).Published91-975T. Modelli di pericolosità sismica e da maremotoN/A or not JC

Biochemical and aggregation analysis of Bence Jones proteins from different light chain diseases

Deposition of immunoglobulin light chains is a result of clonal proliferation of monoclonal plasma cells that secrete free immunoglobulin light chains, also called Bence Jones proteins (Bence Jones proteins). These Bence Jones proteins are present in circulation in large amounts and excreted in urine in various light chain diseases such as light chain amyloidosis (AL), light chain deposition disease (LCDD) and multiple myeloma (MM). BJP from patients with AL, LCDD and MM were purified from their urine and studies were performed to determine their secondary structure, thermodynamic stability and aggregate formation kinetics. Our results show that LCDD and MM proteins have the lowest free energy of folding while all proteins show similar melting temperatures. Incubation of the BJP at their melting temperature produced morphologically different aggregates: amyloid fibrils from the AL proteins, amorphous aggregates from the LCDD proteins and large spherical species from the MM proteins. The aggregates formed under in vitro conditions suggested that the various proteins derived from patients with different light chain diseases might follow different aggregation pathways

Brain connectivity changes in autosomal recessive Parkinson Disease: a model for the sporadic form

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptom

Predictors of single word spelling in English-speaking children: a cross sectional study

Background: The study aimed to explore to what extent variables associated with lexical and sublexical spelling processes predicted single word spelling ability, and whether patterns of lexical and sublexical processes were different across ages. Methods: Beginning (mean age 7-years, N=144) and advanced (mean age 9-years, N=114) English-speaking spellers completed tasks associated with sublexical processing (phonological ability and phonological short-term memory), lexical processing (visual short-term memory, visual attention span), and factors known to predict spelling (e.g., rapid automatised naming). Results: Phonological ability, rapid automatised naming, visual short-term memory and visual attention span were significant predictors of spelling accuracy for beginning spellers, while for more advanced spellers, only visual attention span was a significant predictor. Conclusions: The findings suggested that for beginning spellers, both lexical and sublexical processes are important for single word spelling, but with increasing literacy experience, lexically related variables are more important