ABSTRACT
Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-κB. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy.
Subject(s)
Butadienes/pharmacology , Colonic Neoplasms/pathology , Nitriles/pharmacology , alpha 1-Antitrypsin/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , HCT116 Cells , Humans , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.
Subject(s)
Arthritis, Juvenile/drug therapy , Methotrexate/therapeutic use , Arthritis, Juvenile/genetics , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Polymorphism, Single NucleotideABSTRACT
During operations of the aneurysms showing anatomical details is the means that leads to the aim, and it is not only a purpose in itself. Data on details that the surgeons come across during their work and which sometimes represent difficulties during interpretations of angiographic findings and planning operations, as well as the intraoperative orientations and identifications of the elements . Frequency of occurrence of such anatomical details and anomalies may be completely different from the one that autopsy series show. Knowledge of this makes the work of surgeons easier and gives a necessary feeling of confidence during operations. Thus, we decided to conduct a clinical, morphological study based on angiographic and surgical analyses of the explored segments of the Wilson circle. The study included 344 patients from the Institute for Neurosurgery, during the period of 2 years; the patients had complete angiographic diagnosing and operative exploration. Our findings confirm differences in localization of aneurysms according to sex. Aneurysms on the front communicant complex are to a great extent associated with anomalies of the front part of the Wilson circle.
Subject(s)
Circle of Willis/abnormalities , Intracranial Aneurysm/complications , Intracranial Arteriovenous Malformations/complications , Adolescent , Adult , Child , Female , Humans , Intracranial Aneurysm/pathology , Intracranial Arteriovenous Malformations/pathology , Male , Middle AgedABSTRACT
Aneurysmal subarachnoid hemorrhage (SAH) is a dramatic, frequently fatal event. With the incidence of 10 to 15 in 100 000 and a total mortality which even today is 40-50%, it represents a significant problem. Early surgical care for the hemorrhaging aneurysms has, without doubt, an importance in prevention of the rupture, however different series show different results as regards surgical timing and they are very different as regards giving advantage to the early or delayed time of the operation. Our aim was to perceive the results of the treatment in our group of 197 consequently operated patients for ruptured aneurysms with a special attention to the time of operation. This was a prospective clinical study and it was carried out at the Institute for Neurosurgery in Belgrade. Mortality of the operative treatment was a total of 15.74% in the entire group. According to operative intervals from the early to the delayed mortality the range is 35.71%, 22.22%, 11.63% and 8.88% respectively. The results of the treatment are in direct connection with the seriousness of the clinical picture. Being in the group graded from 1-3 decreases the probability of a fatal outcome, and graded from 1-2 decreases probability of morbidity. Early operated patients who in our group included also the most serious cases, life endangered ones, although with higher mortality do not have higher morbidity.
