Lung ultrasound supports clinical evaluation of feeding competence development in preterm neonates

IntroductionThe achievement of alimentary competencies is a milestone in the development of preterm neonates. Ten percent of neonates <37 weeks of gestational age and 25% of those VLBW experience swallowing disorders, with an increased risk of problems in the early phase of life (failure to thrive, growth retardation, inhalation, and consequent risk of pulmonary infection) and later in life due to delayed development of oromotor skills.The main diagnostic tools for swallowing disorders are endoscopic (fiber-optic endoscopic examination of swallowing, FEES) or radiographic (videofluoroscopic swallowing study, VFSS) exams. Given the invasiveness of these methods and the bias due to rheologic differences between bolus and contrast medium, FEES and VFSS are poorly reproducible. Moreover, neither of the technique is capable of detecting post-meal inhalations, especially microinhalations or those consequent to a whole meal rather than to a single swallowing.Lung ultrasound (LUS) is a widespread, repeatable, safe, fast point-of-care tool and we reported previous encouraging results in detecting silent and overt inhalation related to the meal in children with dysphagia/gastroesophageal reflux disease (GERD) risk factors.MethodsWe report a pilot study, that investigated LUS approach (performing imaging before and after meals) to assess feeding competence development in a cohort of n. 19 newborns <32 weeks of age.ResultsMeal monitoring by LUS did not show any significant difference in scoring before/after eating. The achievement of full enteral feeding correlates with GA at birth (p < 0.001) but not with LUS scoring. The introduction of the first meal by bottle correlates both with gestational age (p < 0.001) and ultrasound scores (p = 0.004). LUS score at 7 days of life resulted predictive for length of invasive/non-invasive respiratory support (p = 0.002) and length of oxygen supply (p = 0.001), while LUS score at 48 h of life did not (p n.s.).DiscussionOur study suggests that the development of oral feeding skills is not strictly dependent on gestational age. Moreover, our research suggests the predominant role of LUS in predicting the time of readiness to oral feeding, as the LUS score can be a marker of respiratory and lung wellness, and consequently a predictor of neonate stability during deglutitory apnea

Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis

SummaryCopper is an essential yet toxic metal and its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Here, we show that, in response to elevated copper, ATP7B moves from the Golgi to lysosomes and imports metal into their lumen. ATP7B enables lysosomes to undergo exocytosis through the interaction with p62 subunit of dynactin that allows lysosome translocation toward the canalicular pole of hepatocytes. Activation of lysosomal exocytosis stimulates copper clearance from the hepatocytes and rescues the most frequent Wilson-disease-causing ATP7B mutant to the appropriate functional site. Our findings indicate that lysosomes serve as an important intermediate in ATP7B trafficking, whereas lysosomal exocytosis operates as an integral process in copper excretion and hence can be targeted for therapeutic approaches to combat Wilson disease

Identification of p38 MAPK and JNK as New Targets for Correction of Wilson Disease-Causing ATP7B Mutants

Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans-Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum-retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c-Jun N-terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7B(H1069Q) (as well as that of several other WD-causing mutants) from the endoplasmic reticulum to the trans-Golgi network compartment, in recovery of its Cu-dependent trafficking, and in reduction of intracellular Cu levels. Conclusion: Our findings indicate p38 and c-Jun N-terminal kinase as intriguing targets for correction of WD-causing mutants and, hence, as potential candidates, which could be evaluated for the development of novel therapeutic strategies to combat WD

Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials

Proceedings of the Fifth Italian Conference on Computational Linguistics CLiC-it 2018

On behalf of the Program Committee, a very warm welcome to the Fifth Italian Conference on Computational Linguistics (CLiC-­‐it 2018). This edition of the conference is held in Torino. The conference is locally organised by the University of Torino and hosted into its prestigious main lecture hall “Cavallerizza Reale”. The CLiC-­‐it conference series is an initiative of the Italian Association for Computational Linguistics (AILC) which, after five years of activity, has clearly established itself as the premier national forum for research and development in the fields of Computational Linguistics and Natural Language Processing, where leading researchers and practitioners from academia and industry meet to share their research results, experiences, and challenges

Central banks after the crisis: unconventional monetary policies and forward guidance

The core purpose of this dissertation is to highlight the changes in monetary policy, which is conducted by central banks, in the very recent times. In particular, the focus is on the actions of the Federal Reserve, the Bank of England, the Bank of Japan, and the European Central Bank, whose development is, generally speaking, similar. However, many differences are still in place in the implementation of monetary policy, and the fact they have all engaged in unconventional measures does not entail that the obtain the same results