Prognostic role of p27Kip1 and apoptosis in human breast cancer

Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread. It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy. Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer. In the present study, we investigated apoptosis, expression of p27Kip1 and p53 retrospectively in 181 human breast cancer specimens. In addition, their relevance to the biological behaviour of breast cancer was examined. Our studies found a significant association among high histological grade, high p53, low apoptosis and low p27. Our results also demonstrated that, in human breast cancer, low levels of p27 and apoptotic index (AI) strongly correlated with the presence of lymph node metastasis and decreased patient survival. In node-negative patients, however, p27 also had prognostic value for relapse-free and overall survival in multivariate analysis. Furthermore p27 and AI had predictive value for the benefits of chemotherapy. These latter observations should prompt prospective randomized studies designed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients. © 1999 Cancer Research Campaig

The Event Horizon General Relativistic Magnetohydrodynamic Code Comparison Project

Recent developments in compact object astrophysics, especially the discovery of merging neutron stars by LIGO, the imaging of the black hole in M87 by the Event Horizon Telescope, and high- precision astrometry of the Galactic Center at close to the event horizon scale by the GRAVITY experiment motivate the development of numerical source models that solve the equations of general relativistic magnetohydrodynamics (GRMHD). Here we compare GRMHD solutions for the evolution of a magnetized accretion flow where turbulence is promoted by the magnetorotational instability from a set of nine GRMHD codes: Athena++, BHAC, Cosmos++, ECHO, H-AMR, iharm3D, HARM-Noble, IllinoisGRMHD, and KORAL. Agreement among the codes improves as resolution increases, as measured by a consistently applied, specially developed set of code performance metrics. We conclude that the community of GRMHD codes is mature, capable, and consistent on these test problems

Auranofin increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart

1.&ensp;Auranofin, an antirheumatic gold compound, is an inhibitor of selenocysteine enzymes, such as thioredoxin reductase and glutathione peroxidase. These enzymes play an important role in protecting cardiac tissue from oxidative stress generated during ischaemia&ndash;reperfusion.2.&ensp;Auranofin (100 mg/kg) was administered to rats and their hearts were subjected to an in vitro model of ischaemia&ndash;reperfusion. The activity of thioredoxin reductase and glutathione peroxidase was determined in liver and heart tissues in an attempt to correlate enzymatic activity with heart recovery after ischaemia&ndash;reperfusion.3.&ensp;There was significantly less thioredoxin reductase activity in rat liver extracts, whereas the level of glutathione activity remained unchanged, demonstrating that the dose of auranofin used was able to selectively inhibit one of these enzyme systems. Rats administered auranofin displayed significantly impaired recovery from ischaemic insult. The end diastolic pressure was increased, whereas the rate pressure product was significantly decreased.4.&ensp;The level of postischaemic apoptosis was also assessed by examining caspase-3 activity in tissue homogenates. Auranofin significantly increased the degree of postischaemic apoptosis, leading to poor postischaemic recovery.<br /

Antiapoptotic compound to enhance hypothermic liver preservation

Background. Apoptosis (programmed cell death) occurs as a consequence of global organ ischemia during isolation and storage prior to transplantation. If apoptosis is inhibited during ischemia, organ preservation should be improved, and the length of time for permissible storage may be increased. The objective of this study was to test the effect of a newly developed antiapoptotic compound, LXR-015, during extended hypothermic liver preservation. Methods. Three groups of 12 rats each were studied, In the normal group, liver function was studied immediately after harvesting, In the study group, harvested livers were flushed with Euro-Collins solution (30 ml/kg body weight) containing LXR-015 at a concentration equivalent to 9 mg/kg animal body weight (300 mu g/ml). The livers were then stored at 4 degrees C for 24 hr before liver function was studied, In the control group, harvested livers were flushed with Euro-Collins solution without LXR-015 and then stored at 4 degrees C for 24 hr before liver function was studied. Results, Portal venous flow was higher (P<0.05) in the normal and study groups compared with the control group, Portal venous resistance was lower (P<0.05) in the normal and study groups compared with the control group, Liver tissue oxygen consumption in the study group was significantly higher than in both the normal and control groups (P<0.05). Liver enzyme production (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase) was higher in the control group than in either the study or normal group (P<0.05). Bile production in both the normal and study groups was higher than in the control group (P<0.05). The liver tissue wet to dry weight ratio in both the normal and study groups was lower than in the control group (P<0.05). Histopathology studies revealed fewer apoptotic bodies (P<0.05) in both the normal (1.70+/-0.15 per high-power field) and study groups (2.08+/-0.1.0 per high-power field) than in the control group (7.92+/-.33 per high-power field). Conclusions. Adding an antiapoptotic compound, LXR-015, to Euro-Collins solution significantly improves hypothermic preservation of the rat Liver compared with Euro-Collins solution alone

Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis

none17noneHendrickx W.; Simeone I.; Anjum S.; Mokrab Y.; Bertucci F.; Finetti P.; Curigliano G.; Seliger B.; Cerulo L.; Tomei S.; Delogu L.G.; Maccalli C.; Wang E.; Miller L.D.; Marincola F.M.; Ceccarelli M.; Bedognetti D.Hendrickx, W.; Simeone, I.; Anjum, S.; Mokrab, Y.; Bertucci, F.; Finetti, P.; Curigliano, G.; Seliger, B.; Cerulo, L.; Tomei, S.; Delogu, L. G.; Maccalli, C.; Wang, E.; Miller, L. D.; Marincola, F. M.; Ceccarelli, M.; Bedognetti, D