IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis–associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI

Results of the treatment of patients with solid tumours and liver metastases: 8 years experience of one institution

Wstęp. Leczenie chirurgiczne przerzutów nowotworów litych do wątroby powinno odbywać się w ramach zespołu wielodyscyplinarnego.Cel pracy. Celem pracy jest ocena wyników leczenia skojarzonego chorych na różne nowotwory lite z przerzutami do wątroby przez zespół wielodyscyplinarny jednego ośrodka onkologicznego w ciągu ostatnich 8 lat.Materiał i metody. Retrospektywną analizą objęto 166 chorych (84 kobiety i 82 mężczyzn) w wieku od 19 do 78 lat (średnia 58 ± 11,2), leczonych z powodu przerzutów do wątroby pierwotnych nowotworów litych o różnej lokalizacji, z wyjątkiem guzów neuroendokrynnych. Każdorazowo rozważano okołooperacyjne leczenie systemowe zgodnie z aktualnymi zaleceniami Polskiej Unii Onkologii.Wyniki. W czasie obserwacji (mediana 35 miesięcy) zmarło 46% chorych. Resekcje wątroby wykonano u 107 (65%)chorych, w tym u 19 chorych połączono je z (RF-)termoablacją zmian przerzutowych, którą wykonano jako samodzielny zabieg u dalszych 59 (36%) chorych. Śmiertelność pooperacyjna wyniosła 1,2%. Powikłania II° wg klasyfikacji Clavien-Dindo wystąpiły u 33 (19,8%) chorych, natomiast III° i IV° — u 8 (4,8%) chorych. Przeżycia 1-roczne, 3-letniei 5-letnie wyniosły odpowiednio 78%, 41% i 37%. Pięcioletnie przeżycia całkowite u chorych na raka jelita grubego po resekcjach przerzutów metachronicznych wyniosły 48%.Wnioski. Skojarzone leczenie chorych na nieendokrynne nowotwory lite z przerzutami do wątroby przez zespół wielodyscyplinarny jest bezpieczne i skuteczne. W starannie dobranej grupie chorych można osiągnąć blisko 50% całkowitych przeżyć 5-letnich. Resekcja wątroby jest optymalną metodą leczenia chirurgicznego przerzutów do wątroby.Introduction. Surgical treatment of liver metastases from solid tumours should be provided by multidisciplinary teams.Aim. The aim of the present study is to analyse results of the combined treatment of patients with different solid tumours and liver metastases by single institution multidisciplinary team for last 8 years.Material and methods. This is a retrospective analysis of 166 patients (84 females and 82 males), aged from 19 to 78 years (mean 58 ± 11.2), treated due to liver metastases from solid tumours in various primary localizations: except neuroendocrine tumours. In every patient, perioperative systemic therapy was evaluated in agreement with current recommendations of the Polish Union of Oncology.Results. In the follow-up time available (median 35 months) 46% of patients died. Liver resections were performed in 107 (65%) patients, including 19 patients in whom resections were supplemented with (RF-)thermoablations of their liver metastases. This was the sole surgical treatment in the 59 (36%) patients. Perioperative mortality was 1.2%. Grade II complications according to the Clavien-Dindo classification were found in 33 (19.8%) patients, whereas grade III and IV complications were treated in 8 (4.8%) patients. One-, 3-, and 5-year survival rates were respectively 78%, 41%, and 37%. Five-year overall survival in patients with colorectal carcinoma after liver resection of metachronous metastases was 48%. We conclude that combined treatment of patients with liver metastases from non-endocrine solid tumours by the multidisciplinary team is safe and effective. A nearly 50% 5-year survival is achievable in a carefully selected group of patients. We also conclude that hepatic resection is an optimal method of surgical treatment of liver metastases

Commissioning of the J-PET detector in view of the positron annihilation lifetime spectroscopy

The Jagiellonian Positron Emission Tomograph (J-PET) is the first PET device built from plastic scintillators. It is a multi-purpose detector designed for medical imaging and for studies of properties of positronium atoms in porous matter and in living organisms. In this article we report on the commissioning of the J-PET detector in view of studies of positronium decays. We present results of analysis of the positron lifetime measured in the porous polymer. The obtained results prove that J-PET is capable of performing simultaneous imaging of the density distribution of annihilation points as well as positron annihilation lifetime spectroscopy

Testing CPT symmetry in ortho-positronium decays with positronium annihilation tomography

Charged lepton system symmetry under combined charge, parity, and time-reversal transformation (CPT) remains scarcely tested. Despite stringent quantum-electrodynamic limits, discrepancies in predictions for the electron–positron bound state (positronium atom) motivate further investigation, including fundamental symmetry tests. While CPT noninvariance effects could be manifested in non-vanishing angular correlations between final-state photons and spin of annihilating positronium, measurements were previously limited by knowledge of the latter. Here, we demonstrate tomographic reconstruction techniques applied to three-photon annihilations of ortho-positronium atoms to estimate their spin polarisation without magnetic field or polarised positronium source. We use a plastic-scintillator-based positron-emission-tomography scanner to record ortho-positronium (o-Ps) annihilations with single-event estimation of o-Ps spin and determine the complete spectrum of an angular correlation operator sensitive to CPT-violating effects. We find no violation at the precision level of 10−4, with an over threefold improvement on the previous measurement

Mice with Mutation in Dynein Heavy Chain 1 Do Not Share the Same Tau Expression Pattern with Mice with SOD1-Related Motor Neuron Disease

Due to controversy about the involvement of Dync1h1 mutation in pathogenesis of motor neuron disease, we investigated expression of tau protein in transgenic hybrid mice with Dync1h1 (so-called Cra1/+), SOD1G93A (SOD1/+), double (Cra1/SOD1) mutations and wild-type controls. Total tau-mRNA and isoforms 0, 1 and 2 N expression was studied in frontal cortex, hippocampus, spinal cord and cerebellum of presymptomatic and symptomatic animals (age 70, 140 and 365 days). The most significant differences were found in brain cortex and cerebellum, but not in hippocampus and spinal cord. There were less changes in Cra1/SOD1 double heterozygotes compared to mice harboring single mutations. The differences in total tau expression and in profile of its isoforms between Cra1/+ and SOD1/+ transgenics indicate a distinct pathogenic entity of these two conditions

Transglutaminase 6: a protein associated with central nervous system development and motor function.

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second β-barrel domain in man and a variant with truncated β-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca(2+) and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca(2+) and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons