The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase.

The receptor for hepatocyte growth factor, also known as scatter factor (HGF/SF), has recently been identified as the 190-kDa heterodimeric tyrosine kinase encoded by the MET proto-oncogene (p190MET). The signaling pathway(s) triggered by HGF/SF are unknown. In A549 cells, a lung epithelial cell line, nanomolar concentrations of HGF/SF induced tyrosine phosphorylation of the p190MET receptor. The autophosphorylated receptor coprecipitated with phosphatidylinositol 3-kinase (PI 3-kinase) activity. In GTL16 cells, a cell line derived from a gastric carcinoma, the p190MET receptor, overexpressed and constitutively phosphorylated on tyrosine, coprecipitated with PI 3-kinase activity and with the 85-kDa PI 3-kinase subunit. In these cells activation of protein kinase C or the increase of intracellular [Ca2+] inhibits tyrosine phosphorylation of the p190MET receptor as well as the association with both PI 3-kinase activity and the 85-kDa subunit of the enzyme. In an in vitro assay, tyrosine phosphorylation of the immobilized p190MET receptor was required for binding of PI 3-kinase from cell lysates. These data strongly suggest that the signaling pathway activated by the HGF/SF receptor includes generation of D-3-phosphorylated inositol phospholipids

Hepatocyte growth factor/scatter factor stimulates the Ras-guanine nucleotide exchanger

Hepatocyte growth factor/scatter factor (HGF/SF) induces mitogenesis and cell dissociation upon binding to the protein-tyrosine kinase receptor encoded by the MET proto-oncogene (p190MET). The signal transduction pathways downstream from the receptor activation are largely unknown. We show that HGF/SF activates Ras protein. HGF/SF stimulation of metabolically labeled A549 cells raised the amount of Ras-bound radiolabeled guanine nucleotides by over 5-fold. Furthermore, following HGF/SF stimulation of these cells, 50% of Ras was in the GTP-bound active state. The uptake by Ras of radiolabeled GTP was also increased by 5-fold following HGF/SF stimulation in digitonin-permeabilized A549 cells. Moreover, HGF/SF treatment of A549 cells leads to stimulation of the cytosolic Ras-guanine nucleotide exchange activity, measured as accelerated release of [3H]GDP from purified recombinant Ras protein in vitro, in a dose- and time-dependent manner. Likewise, treatment with the protein-tyrosine kinase inhibitor 3-(1',4'-dihydroxytetralyl)methylene-2-oxindole of GTL-16 cells (featuring a p190MET receptor constitutively active) significantly decreased the cytosolic Ras-guanine nucleotide exchange activity. These data demonstrate that HGF/SF activates Ras protein by shifting the equilibrium toward the GTP-bound state and increases the uptake of guanine nucleotides by Ras, through mechanism(s) including the activation of a Ras-guanine nucleotide exchanger

The HIV-1 Nef Protein Interferes with Phosphatidylinositol 3-Kinase Activation 1

nef is a human immunodeficiency virus (HIV) gene encoding a 27-kDa myristoylated protein with structural features of a signal transducing molecule, but whose functions are largely unknown. We studied the interactions of Nef with the signal transduction pathways triggered by the platelet-derived growth factor (PDGF) receptor. The association of phosphatidylinositol (PI) 3-kinase with the activated receptor was severely impaired by nef expression. Conversely, PDGF-induced receptor tyrosine phosphorylation, binding to phospholipase C-gamma and to Ras-GAP were not modified. Microtubule-associated protein kinase activation and intracellular calcium influx in response to PDGF were either unaffected or only slightly enhanced. Nef significantly reduced the proliferative response to the growth factor, while the chemotactic response was unchanged. These data show that Nef affects selectively the PI 3-kinase signaling pathway and suggest that this interference results in some of the HIV adverse effects on host cell functions

Anderson-Fabry’s Disease: A Rare but Treatable Case of Fever of Unknown Origin

Anderson-Fabry’s disease (AFD) is a rare, X-linked lysosomal storage disorder caused by the complete deficiency or attenuated activity of the enzyme α-galactosidase A, leading to progressive systemic intracellular accumulation of glycosphingolipids and subsequent cellular dysfunction, inflammation and fibrosis. Fever is a frequently misinterpreted symptom in the early stages of the disease, leading to diagnostic delay. We present the case of a 35-year-old man admitted to our Periodic Fever Research Centre for long-lasting recurrent episodes of fever of unknown origin. After extensive assessment, we diagnosed AFD associated with a novel GLA mutation. We started enzyme replacement therapy with clinical benefit and complete remission of fever

a multidisciplinary approach in the diagnosis of allergic and non allergic respiratory diseases nasal cytology and feno

n/

An exploratory study on the effectiveness of virtual reality analgesia for children and adolescents with kidney diseases undergoing venipuncture

The current study evaluated the effectiveness of VR analgesia among pediatric and adolescent patients with kidney disease undergoing venipuncture. Patients at an Italian Children’s hospital (N = 82, age range 7–17 years) undergoing venipuncture were randomly assigned to a No VR group (non-medical conversation) vs. a Yes VR group (VR analgesia). After the procedure, patients gave 0–10 Verbal Numeric Pain Scale ratings. Compared with patients in the No VR Group, patients in the Yes VR group reported significantly lower “Pain intensity”(No VR mean = 2.74, SD = 2.76 vs. Yes VR mean = 1.56, SD = 1.83) and the VR group also rated “Pain unpleasantness” significantly lower than the No VR group (No VR mean = 2.41, SD = 0.94 vs. Yes VR mean = 1.17, SD = 1.80). Patients distracted with VR also reported having significantly more fun during the venipuncture procedure. No side effects emerged. In addition to reducing pain intensity, VR has the potential to make venipuncture a more fun and less unpleasant experience for children with CKD, as measured in the present study for the first time. Finally, in exploratory analyses, children aged 7–11 in the VR group reported 55% lower worst pain than control subjects in the same age range, whereas children aged 12 to 17 in the VR group only reported 35% lower worst pain than control subjects. Additional research and development using more immersive VR is recommended.info:eu-repo/semantics/publishedVersio

Inflammasome, T Lymphocytes and Innate-Adaptive Immunity Crosstalk: Role in Cardiovascular Disease and Therapeutic Perspectives

AbstractOver the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque

Neutron irradiation test on ATLAS MDT chambers

Abstract The Monitored Drift Tubes (MDT) chambers of the ATLAS muon spectrometer are crucial for the identification of high-momentum final-state muons, which represent very promising and robust signatures of physics at the LHC. They will operate in a high rate and high background environment and therefore their performances should not significantly degrade for the whole ATLAS data taking. The maximum expected total flux, mainly consisting of neutrons and photons in the MeV range, is of the order of 5 kHz/cm 2 for the barrel MDTs, while at SLHC, with machine working at higher luminosity, fluxes can be 10 times higher. To test detector robustness, a MDT test chamber was exposed to intensive neutron irradiation at the TAPIRO ENEA-Casaccia Research Center facility

Role of Diacylglycerol Kinases in Acute Myeloid Leukemia

: Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability

Identification of tsunami deposits and liquefaction features in the Gargano area (Italy): paleoseismological implication

The Gargano region (Southeastern Italy) was hit by a M = 6.8 earthquake and inundated by a subsequent tsunami in 1627. To better define the hazard in the region, we searched for evidence of this and prior earthquakes in the geologic record. We identified potential earthquake-related liquefaction features and tsunami deposits in the stratigraphic sequences of the marsh areas both north and south of the Gargano promontory. We recognized clear liquefaction features and possible tsunamigenic sands that can be related to the 1627 seismic event in irrigation ditch exposures and gouge cores along the Northern Gargano coast. In total, six potential tsunami sand deposits have been recognized in two areas located close to the northern and southern coasts of the Gargano promontory. However, ambiguous evidence comes from the paleontological analysis of these sands. Although fragments of marine shells have been found in the coarser portion of the sand samples, foraminifera and ostracods assemblages are typical of brackish water condition. Radiocarbon dating of three of these deposits from the Northern Gargano coast, near the town of Lesina, suggests an average recurrence interval of 1700 years for tsunami events in this area. Assuming that all the paleotsunamis are related to the same seismogenic source responsible for the 1627 earthquake, this average recurrence interval may be typical for that source. Radiocarbon dating of three sand layers observed on the southern coast, close to the city of Manfredonia, suggests that the average recurrence time for violent sea inundation there is about 1200 years