Study of intracellular signaling pathways in Chronic Myeloproliferative Neoplasms

A gain-of-function mutation in Janus kinase 2 (JAK2V617F) is at the basis of the majority of chronic myeloproliferative neoplasms (MPN). Enhanced activation of other downstream pathways including the PI3K/mTOR pathway has been documented as well. In this study we evaluated the effects of JAK1/2 inhibitors, alone and in combination with mTOR, with a dual mTOR/PI3K inhibitor and with a pan PI3K inhibitor in in-vitro and in-vivo MPN models. Our findings of strong synergy between the JAK2 inhibitors and mTOR/PI3K inhibitor suggested that we might be able to administer these drugs at lower concentrations than when the drugs are used individually. This provides a framework for combination trials using compounds in patients with myeloproliferative neoplasm

Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction

Rationale: Recent evidence indicates that a few human microRNAs (miRNAs), in particular hsa-miR-199a-3p and hsa-miR-590-3p, stimulate proliferation of cardiomyocytes and, once expressed in the mouse heart using viral vectors, induce cardiac regeneration after myocardial infarction. Viral vectors, however, are not devoid of safety issues and, more notably, drive expression of the encoded miRNAs for indefinite periods of time, which might not be desirable in light of human therapeutic application. Objective: As an alternative to the use of viral vectors, we wanted to assess the efficacy of synthetic miRNA mimics in inducing myocardial repair after single intracardiac injection using synthetic lipid formulations. Methods and Results: We comparatively analyzed the efficacy of different lipid formulations in delivering hsa-miR-199a-3p and hsa-miR-590-3p both in primary neonatal mouse cardiomyocytes and in vivo. We established a transfection protocol allowing persistence of these two mimics for at least 12 days after a single intracardiac injection, with minimal dispersion to other organs and long-term preservation of miRNA functional activity, as assessed by monitoring the expression of two direct mRNA targets. Administration of this synthetic formulation immediately after myocardial infarction in mice resulted in marked reduction of infarct size and persistent recovery of cardiac function. Conclusions: A single administration of synthetic miRNA-lipid formulations is sufficient to stimulate cardiac repair and restoration of cardiac function

REDUCTION OF INVASIVE DISEASE IN CHILDREN TWO DECADES AFTER THE INTRODUCTION OF HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINATION IN APULIA REGION, ITALY

Background Haemophilus influenzae type b conjugate (Hib) monovalent vaccination, consisting of 2p+1 doses at 3, 5, and 11 months of age, was introduced in the Italy’s infant immunization schedule in 1999 and included in the DTaP-HBV-IPV/Hib hexavalent vaccine since 2001. The estimated vaccination coverage was 83.4% in 2002, >90% by 2005, and >95% by 2011 [1-4]. In the Apulia region of Italy (about 4,000,000 inhabitants), vaccination coverage for 3 doses reached 75% in 2001, >90% by 2002, and >95% by 2007 (Graph. 1).Methods We considered annual age-specific hospitalization rates in infants <1 year and children 1-4 years as a proxy for incidence in the period 1996-2014. The attributable benefit was calculated as the reduction in incidence of Haemophilus influenzae invasive disease among vaccinated children attributable to the routine use of Hib monovalent vaccine during 1999-2000 (“Hib-monovalent period”) and of the hexavalent DTPa-HBV-IPV/Hib vaccine in the period 2001-2014 (“DTPa-HBV-IPV/Hib period”). The prevented fraction was calculated as the proportion of hypothetical total cases that were prevented by the use of monovalent and hexavalent vaccine, respectively (Panel A) [5]Results The hospitalization rate for Haemophilus influenzae invasive disease among infants decreased from 11.5 (95% CI= 1.4-21.6) per 100,000 in the 1996-1998 pre-vaccination period to 6 (95% CI= -1.4-13.3) per 100,000 in the “Hib-monovalent period”, with an estimated AleB of -5.5 per 100,000 and a PedF of 48.2%. It declined further to 1 (95% CI= -2.2-4.1) per 100,000 in the “DTaP-HBV-IPV/Hib period”, with an AleB of -10.5 per 100,000 and a PedF of 91.6% (Graph. 2). The rate of hospitalization among children aged 1-4 year remained stable at 2.4 per 100.000 from the pre- vaccination period through “Hib-monovalent period” (AleB=0; PedF=2%) and declined to 0.1 (95% CI= - 0.4-0.7) per 100,000 in the “DTaP-HBV-IPV/Hib period”, with an AleB of -2.3 per 100,000 and a PedF of 94.3% (Graph. 3)Conclusions * Hib-monovalent period - ** DTPa-HBV-IPV/Hib period In the Apulia region of Italy, the proportion of Haemophilus influenzae invasive disease requiring hospitalization in children aged <5 years presumably prevented by the introduction of Hib universal vaccination amounted to more than nine in ten cases. These findings are consistent with increased vaccine coverage rates as a result of the wide use of the hexavalent combination vaccines

Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling

Over the last years, a constantly increasing number of genetic diseases associated with epilepsy and movement disorders have been recognized. An emerging group of conditions in this field is represented by genetic disorders affecting G-protein-coupled receptors (GPCRs)-cAMP signaling. This group of postsynaptic disorders includes genes encoding for proteins highly expressed in the central nervous system and involved in GPCR signal transduction and cAMP production (e.g., GNAO1, GNB1, ADCY5, GNAL, PDE2A, PDE10A, and HPCA genes). While the clinical phenotype associated with ADCY5 and GNAL is characterized by movement disorder in the absence of epilepsy, GNAO1, GNB1, PDE2A, PDE10A, and HPCA have a broader clinical phenotype, encompassing movement disorder, epilepsy, and neurodevelopmental disorders. We aimed to provide a comprehensive phenotypical characterization of genetic disorders affecting the cAMP signaling pathway, presenting with both movement disorders and epilepsy. Thus, we reviewed clinical features and genetic data of 203 patients from the literature with GNAO1, GNB1, PDE2A, PDE10A, and HPCA deficiencies. Furthermore, we delineated genotype-phenotype correlation in GNAO1 and GNB1 deficiency. This group of disorders presents with a highly recognizable clinical phenotype combining distinctive motor, epileptic, and neurodevelopmental features. A severe hyperkinetic movement disorder with potential life-threatening exacerbations and high susceptibility to a wide range of triggers is the clinical signature of the whole group of disorders. The existence of a distinctive clinical phenotype prompting diagnostic suspicion and early detection has relevant implications for clinical and therapeutic management. Studies are ongoing to clarify the pathophysiology of these rare postsynaptic disorders and start to design disease-specific treatments

Changes in quality of life and functional capacity after lung transplantation: A single-center experience

Lung transplantation (LT) increases the life expectancy of patients affected by end stage pulmonary disease; specifically, its ultimate aims are to improve survival and health related quality of life (HRQoL). The aim of the present longitudinal study was to determine the HRQoL trajectory and changes in functional capacity from time of entry in the waiting list for LT to 2 year after LT. The study included sixty-nine outpatients enrolled in a single medical center when they entered the waiting list for LT and who subsequently received it. They were then followed up over 2 years after LT. HRQoL was assessed by the physical and mental component summary (PCS and MCS) scores of the 36-item Short Form Health Survey (SF-36) and Saint George's Respiratory Questionnaire (SGRQ). Psychological distress was evaluated with the General Health Questionnaire (GHQ), and functional capacity was investigated using the six-minute walk test (6MWT) and forced expiratory volume (FEV1). Patients showed low SF-36 PCS (30.5±7.8) and SGRQ total (61.8±17.5) scores at entry in the waiting list, but exhibited significant changes over time after LT (p<0.001). Furthermore, patients who showed an increase of at least 50% in SF36 PCS and SGRQ scores at 6 months survived longer. Both FEV1 and 6MWT distance as well as GHQ scores significantly changed over time, with improvements occurring in the first 6 months after LT but no major changes thereafter. Out of the 69 patients enrolled, 32 died over a median follow-up of 51 months. Although mortality tended to be slightly higher for patients with lower HRQoL at the baseline assessment, this difference was not statistically significant. HRQoL evaluations appear critical in the follow-up of LT candidates, in particularly SGRQ, because of its specificity in targeting respiratory symptoms and functional wellbeing

Case report: p.Glu134del SOD1 mutation in two apparently unrelated ALS patients with mirrored phenotype

With upcoming personalized approaches based on genetics, it is important to report new mutations in amyotrophic lateral sclerosis (ALS) genes in order to understand their pathogenicity and possible patient responses to specific therapies. SOD1 mutations are the second most frequent genetic cause of ALS in European populations. Here, we describe two seemingly unrelated Italian patients with ALS carrying the same SOD1 heterozygous c.400_402 deletion (p.Glu134del). Both patients had spinal onset in their lower limbs, progressive muscular weakness with respiratory involvement, and sparing bulbar function. In addition to the clinical picture, we discuss the possible pathogenic role of this unfamiliar SOD1 mutation

Experimental analysis of overcharged Li-polymer batteries

Since safety hazards can occur during the life of a Li-ion battery, understanding its behavior under abusive conditions is important for the development of a safe cell. In this work, overcharge tests on commercial Li-polymer cells were conducted in a climatic chamber, resulting in gas evolution. A comprehensive post-mortem analysis of the abused cells was carried out: the exhaust gases were identified by gas phase chromatography coupled with a thermal conductivity detector (micro-GC/TCD), then flammable and toxic species were detected; the cathode and anode materials were analysed using scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDS), while the electrolyte composition was studied by Fourier-transform infrared spectroscopy (FT-IR). Interestingly, the ambient temperature seemed to affect the degradation of the cell materials and hence the composition of the evolved gas