Pancreatic cancer molecular classifications: From bulk genomics to single cell analysis

Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, and SMAD4) and a long tail of other mutated genes, with doubtful pathogenic meaning. Even bulk transcriptomic classifications could not resolve this great heterogeneity, as many informations related to small cell populations within cancer tissue could be lost. At the same time, single cell analysis has emerged as a powerful tool to dissect intratumoral heterogeneity like never before, with possibility of generating a new disease taxonomy at unprecedented molecular resolution. In this review, we summarize the most relevant genomic, bulk and single-cell transcriptomic classifications of pancreatic cancer, and try to understand how novel technologies, like single cell analysis, could lead to novel therapeutic strategies for this highly lethal disease

Response to the 2009 influenza A(H1N1) pandemic in Italy

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congenital rubella still a public health problem in italy analysis of national surveillance data from 2005 to 2013

In accordance with the goal of the World Health Organization Regional Office for Europe, the Italian national measles and rubella elimination plan aims to reduce the incidence of congenital rubella cases to?less than?one case per 100,000 live births by the end of 2015. We report national surveillance data for congenital rubella and rubella in pregnancy from 2005 to 2013. A total of 75 congenital rubella infections were reported; the national annual mean incidence was 1.5/100,000 live births, including probable and confirmed cases according to European Union case definition. Two peaks occurred in 2008 and 2012 (5.0 and 3.6/100,000 respectively). Overall, 160 rubella infections in pregnancy were reported; 69/148 women were multiparous and 38/126 had had a rubella antibody test before pregnancy. Among reported cases, there were 62 infected newborns, 31 voluntary abortions, one stillbirth and one spontaneous abortion. A total of 24 newborns were unclassified and 14 women were lost to follow-up, so underestimation is likely. To improve follow-up of cases, systematic procedures for monitoring infected mothers and children were introduced in 2013. To prevent congenital rubella, antibody screening before pregnancy and vaccination of susceptible women, including post-partum and post-abortum vaccination, should be promoted. Population coverage?of two doses of measles-mumps-rubella vaccination of ≥?95% should be maintained and knowledge of health professionals improved

Assessing the experience of using synthetic cannabinoids by means of interpretative phenomenological analysis

BACKGROUND: New psychoactive substances (NPS) have been increasingly consumed by people who use drugs in recent years, which pose a new challenge for treatment services. One of the largest groups of NPS is synthetic cannabinoids (SCs), which are intended as a replacement to cannabis. While there is an increasing body of research on the motivation and the effects associated with SC use, little is known about the subjective interpretation of SC use by the people who use drugs themselves. The aim of this study was to examine the experiences and personal interpretations of SC use of users who were heavily dependent on SC and are in treatment. METHODS: A qualitative research method was applied in order to explore unknown and personal aspects of SC use. Semi-structured interviews were conducted with six participants who had problematic SC use and entered treatment. The research was conducted in Hungary in 2015. We analyzed data using interpretative phenomenological analysis (IPA). RESULTS: Participants perceived SCs to be unpredictable: their initial positive experiences quickly turned negative. They also reported that SCs took over their lives both interpersonally and intrapersonally: the drug took their old friends away, and while initially it gave them new ones, in the end it not only made them asocial but the drug became their only friend, it hijacked their personalities and made them addicted. CONCLUSIONS: Participants experienced rapid development of effects and they had difficulties interpreting or integrating these experiences. The rapid alteration of effects and experiences may explain the severe psychopathological symptoms, which may be important information for harm reduction and treatment services. Since, these experiences are mostly unknown and unpredictable for people who use SCs, a forum where they could share their experiences could have a harm reducing role. For a harm reduction point of view of SCs, which are underrepresented in literature, it is important to emphasize the impossibility of knowing the quantity, purity, or even the number of different SC compounds in a particular SC product. Our study findings suggest that despite the adverse effects, including a rapid turn of experiences to negative, rapid development of addiction and withdrawal symptoms of SCs, participants continued using the drug because this drug was mostly available and cheap. Therefore, a harm reduction approach would be to make available and legal certain drugs that have less adverse effects and could cause less serious dependence and withdrawal symptoms, with controlled production and distribution (similarly to cannabis legalization in the Netherlands)

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects

Nitrate reductase in durum wheat seedlings as affected by nitrate nutrition and salinity

The combined effects of nitrate (0, 0.1, 1, 10 mM) and salt (0, 100 mM NaCl) on nitrogen metabolism in durum wheat seedlings were investigated by analysis of nitrate reductase (NR) expression and activity, and metabolite content. High salinity (100 mM NaCl) reduced shoot growth more than root growth. The effect was independent of nitrate concentration. NR mRNA was present at a low level in both leaves and roots of plants grown in a nitrogen-free medium. NaCl increased NR mRNA at low nitrate, suggesting that chloride can mimic nitrate as a signal molecule to induce transcription in both roots and leaves. However, the level of NR protein remained low in salt-stressed plants, indicating an inhibitory effect of salt on translation of NR mRNA or an increase in protein degradation. The lower activity of nitrate reductase in leaves of high-nitrate treated plants under salinity suggested a restriction of NO3- transport to the shoot under salinity. Salt treatment promoted photorespiration, inhibiting carbohydrate accumulation in plants grown on low nitrate media. Under salinity free amino acids, in particular proline and asparagine, and glycine betaine could function as osmolytes to balance water potential within the cell, especially when nitrogen availability exceeded the need for growth.The combined effects of nitrate (0, 0.1, 1, 10 mM) and salt (0, 100 mM NaCl) on nitrogen metabolism in durum wheat seedlings were investigated by analysis of nitrate reductase (NR) expression and activity, and metabolite content. High salinity (100 mM NaCl) reduced shoot growth more than root growth. The effect was independent of nitrate concentration. NR mRNA was present at a low level in both leaves and roots of plants grown in a nitrogen-free medium. NaCl increased NR mRNA at low nitrate, suggesting that chloride can mimic nitrate as a signal molecule to induce transcription in both roots and leaves. However, the level of NR protein remained low in salt-stressed plants, indicating an inhibitory effect of salt on translation of NR mRNA or an increase in protein degradation. The lower activity of nitrate reductase in leaves of high-nitrate treated plants under salinity suggested a restriction of NO3- transport to the shoot under salinity. Salt treatment promoted photorespiration, inhibiting carbohydrate accumulation in plants grown on low nitrate media. Under salinity free amino acids, in particular proline and asparagine, and glycine betaine could function as osmolytes to balance water potential within the cell, especially when nitrogen availability exceeded the need for growth