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

Spesolimab in patients with flare of generalized pustular psoriasis: A multicentre case-series

Dear Editor,Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening, chronic inf lammatory disease character-ized by acute f lares of pustular eruptions that can be accom-panied by systemic inf lammation. GPP can be associated with chronic plaque psoriasi

Parathyroidectomy and survival in a cohort of Italian dialysis patients: results of a multicenter, observational, prospective study

Background: Severe secondary hyperparathyroidism (SHPT) is associated with mortality in end stage kidney disease (ESKD). Parathyroidectomy (PTX) becomes necessary when medical therapy fails, thus highlighting the interest to compare biochemical and clinical outcomes of patients receiving either medical treatment or surgery. Methods: We aimed to compare overall survival and biochemical control of hemodialysis patients with severe hyperparathyroidism, treated by surgery or medical therapy followed-up for 36 months. Inclusion criteria were age older than 18 years, renal failure requiring dialysis treatment (hemodialysis or peritoneal dialysis) and ability to sign the consent form. A control group of 418 patients treated in the same centers, who did not undergo parathyroidectomy was selected after matching for age, sex, and dialysis vintage. Results: From 82 Dialysis units in Italy, we prospectively collected data of 257 prevalent patients who underwent parathyroidectomy (age 58.2 ± 12.8 years; M/F: 44%/56%, dialysis vintage: 15.5 ± 8.4 years) and of 418 control patients who did not undergo parathyroidectomy (age 60.3 ± 14.4 years; M/F 44%/56%; dialysis vintage 11.2 ± 7.6 y). The survival rate was higher in the group that underwent parathyroidectomy (Kaplan–Meier log rank test = 0.002). Univariable analysis (HR 0.556, CI: 0.387–0.800, p = 0.002) and multivariable analysis (HR 0.671, CI:0.465–0.970, p = 0.034), identified parathyroidectomy as a protective factor of overall survival. The prevalence of patients at KDOQI targets for PTH was lower in patients who underwent parathyroidectomy compared to controls (PTX vs non-PTX: PTH < 150 pg/ml: 59% vs 21%, p = 0.001; PTH at target: 18% vs 37% p = 0.001; PTH > 300 pg/ml 23% vs 42% p = 0.001). The control group received more intensive medical treatment with higher prevalence of vitamin D (65% vs 41%, p = 0.0001), calcimimetics (34% vs 14%, p = 0.0001) and phosphate binders (77% vs 66%, p = 0.002). Conclusions: Our data suggest that parathyroidectomy is associated with survival rate at 36 months, independently of biochemical control. Lower exposure to high PTH levels could represent an advantage in the long term. Graphical abstract: [Figure not available: see fulltext.]

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