STI571 reduces TRAIL-induced apoptosis in colon cancer cells: c-Abl activation by the death receptor leads to stress kinase-dependent cell death

<p>Abstract</p> <p>Background</p> <p>In an effort to achieve better cancer therapies, we elucidated the combination cancer therapy of STI571 (an inhibitor of Bcr-Abl and clinically used for chronic myelogenous leukemia) and TNF-related apoptosis-inducing ligand (TRAIL, a developing antitumor agent) in leukemia, colon, and prostate cancer cells.</p> <p>Methods</p> <p>Colon cancer (HCT116, SW480), prostate cancer (PC3, LNCaP) and leukemia (K562) cells were treated with STI571 and TRAIL. Cell viability was determined by MTT assay and sub-G1 appearance. Protein expression and kinase phosphorylation were determined by Western blotting. c-Abl and p73 activities were inhibited by target-specific small interfering (si)RNA. In vitro kinase assay of c-Abl was conducted using CRK as a substrate.</p> <p>Results</p> <p>We found that STI571 exerts opposite effects on the antitumor activity of TRAIL. It enhanced cytotoxicity in TRAIL-treated K562 leukemia cells and reduced TRAIL-induced apoptosis in HCT116 and SW480 colon cancer cells, while having no effect on PC3 and LNCaP cells. In colon and prostate cancer cells, TRAIL caused c-Abl cleavage to the active form via a caspase pathway. Interestingly, JNK and p38 MAPK inhibitors effectively blocked TRAIL-induced toxicity in the colon, but not in prostate cancer cells. Next, we found that STI571 could attenuate TRAIL-induced c-Abl, JNK and p38 activation in HCT116 cells. In addition, siRNA targeting knockdown of c-Abl and p73 also reduced TRAIL-induced cytotoxicity, rendering HCT116 cells less responsive to stress kinase activation, and masking the cytoprotective effect of STI571.</p> <p>Conclusions</p> <p>All together we demonstrate a novel mediator role of p73 in activating the stress kinases p38 and JNK in the classical apoptotic pathway of TRAIL. TRAIL via caspase-dependent action can sequentially activate c-Abl, p73, and stress kinases, which contribute to apoptosis in colon cancer cells. Through the inhibition of c-Abl-mediated apoptotic p73 signaling, STI571 reduces the antitumor activity of TRAIL in colon cancer cells. Our results raise additional concerns when developing combination cancer therapy with TRAIL and STI571 in the future.</p

Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation

<p>Abstract</p> <p>Background</p> <p>Apoptosis, neuroinflammation and blood-brain barrier (BBB) damage affect the susceptibility of the developing brain to hypoxic-ischemic (HI) insults. c-Jun N-terminal kinase (JNK) is an important mediator of insulin resistance in obesity. We hypothesized that neonatal overweight aggravates HI brain damage through JNK hyperactivation-mediated upregulation of neuronal apoptosis, neuroinflammation and BBB leakage in rat pups.</p> <p>Methods</p> <p>Overweight (OF) pups were established by reducing the litter size to 6, and control (NF) pups by keeping the litter size at 12 from postnatal (P) day 1 before HI on P7. Immunohistochemistry and immunoblotting were used to determine the TUNEL-(+) cells and BBB damage, cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP), and phospho-JNK and phospho-Bim_ELlevels. Immunofluorescence was performed to determine the cellular distribution of phospho-JNK.</p> <p>Results</p> <p>Compared with NF pups, OF pups had a significantly heavier body-weight and greater fat deposition on P7. Compared with the NF-HI group, the OF-HI group showed significant increases of TUNEL-(+) cells, cleaved levels of caspase-3 and PARP, and ED1-(+) activated microglia and BBB damage in the cortex 24 hours post-HI. Immunofluorescence of the OF-HI pups showed that activated-caspase 3 expression was found mainly in NeuN-(+) neurons and RECA1-(+) vascular endothelial cells 24 hours post-HI. The OF-HI group also had prolonged escape latency in the Morris water maze test and greater brain-volume loss compared with the NF-HI group when assessed at adulthood. Phospho-JNK and phospho-Bim_ELlevels were higher in OF-HI pups than in NF-HI pups immediately post-HI. JNK activation in OF-HI pups was mainly expressed in neurons, microglia and vascular endothelial cells. Inhibiting JNK activity by AS601245 caused more attenuation of cleaved caspase-3 and PARP, a greater reduction of microglial activation and BBB damage post-HI, and significantly reduced brain damage in OF-HI than in NF-HI pups.</p> <p>Conclusions</p> <p>Neonatal overweight increased HI-induced neuronal apoptosis, microglial activation and BBB damage, and aggravated HI brain damage in rat pups through JNK hyperactivation.</p

Pringle manoeuvre versus selective hepatic vascular exclusion in partial hepatectomy for tumours adjacent to the hepatocaval junction: A randomized comparative study

AbstractObjectiveTo compare the efficacy of selective hepatic vascular exclusion versus Pringle manoeuvre in partial hepatectomy for tumours adjacent to the hepatocaval junction.MethodsA randomized comparative trial was carried out. The primary endpoint was intraoperative blood loss. The secondary endpoints were operation time, blood transfusion, postoperative liver function recovery, procedure-related morbidity and in-hospital mortality.Results160 patients were randomized into 2 groups: the Pringle manoeuvre group (n = 80) and the selective hepatic vascular exclusion (SHVE) group (n = 80). Intraoperative blood loss and transfusion requirements were significantly less in the SHVE group. In the SHVE group, laceration of hepatic veins happened in 18 patients. Profuse intraoperative blood loss of over 2 L happened in 2 patients but no patient suffered from air embolism because the hepatic veins were controlled. In the Pringle group, the hepatic veins were lacerated in 20 patients, with profuse blood loss of over 2 L in 7 patients and air embolism in 3 patients. The rates of postoperative bleeding, reoperation, liver failure and mortality were significantly higher and the ICU stay and hospital stay were significantly longer in the Pringle group.ConclusionsSHVE was more efficacious than Pringle manoeuvre for partial hepatectomy in patients with tumours adjacent to the hepatocaval junction

Climatology and Change of Extreme Precipitation Events in Taiwan Based on Weather Types

Taiwan\u27s most significant natural hazards are caused by hydrological extremes resulting from excessive precipitation. The threat of extreme precipitation is posed by several different types of weather patterns that affect Taiwan. This study examined the bi‐decadal changes in rainfall by defining an extreme precipitation occurrence (EPO) for a range of event durations from 1 to 24 hr. Three major weather types affecting EPO in Taiwan were identified from 1993 to 2015: the front type consisting of either a frontal zone or convective systems developing with an apparent Meiyu cloudband, diurnal rainfall events when no apparent synoptic features are present, and a tropical cyclone (TC) type according to the maximum sustained wind radius of a TC. Results show that TC‐type events have the greatest overall contribution to EPO at longer (\u3e6 hr) durations. Diurnal/afternoon convection events contribute most to the shorter (\u3c3 hr) duration EPO, while frontal/Meiyu systems prevail in the medium (3–6 hr) duration. EPO of almost all durations have experienced an increase, with the 3‐ and 12‐hr EPO having increased by 4.6 days each over the 23 years. However, apparent decadal‐scale variability exists in these EPO associated with the decreasing tendency of EPO after the mid‐2000s, particularly the longer duration (\u3e6 hr) EPO associated with the TC‐type events in summer. The distinction between EPO trends for the entire island of Taiwan and for the Taipei metropolitan area alone (northern Taiwan, population of 7 million) were compared, and an intriguing interannual variation is reported in the TC‐type EPO associated with the TC season 1 year to a year and half just before an El Niño–Southern Oscillation event. The analysis here provides refined statistical distributions of extreme rainfall, and these can contribute to the revision of governmental definitions for weather disasters that are used in mitigation and response strategies

Epidemiology and Clinical Peculiarities of Norovirus and Rotavirus Infection in Hospitalized Young Children with Acute Diarrhea in Taiwan, 2009

Background/PurposeAcute diarrhea is one of the most common morbidities in pediatrics worldwide. We conducted a study to investigate the incidence of norovirus in young children hospitalized with acute diarrhea in Taiwan and its clinical peculiarity compared with rotavirus gastroenteritis.MethodsBetween January and December, 2009, patients younger than 5 years and admitted to hospital with acute diarrhea were randomly selected; and their stool samples were collected and tested for presence of rotavirus and norovirus by enzyme immunoassay and reverse transcription-polymerase chain reaction, respectively. The clinical manifestations and laboratory findings of the enrolled patients were analyzed.ResultsA total of 989 cases were enrolled with a mean age of 21.6 ± 13.7 months and a male proportion of 56.0%. Rotavirus and norovirus was detected in 20.2% and 14.6% of all patients, respectively. Genogroup II was the predominant strain of norovirus (80.6%). Children aged 6-36 months accounted for the majority of patients positive for rotavirus and norovirus (73.0% and 81.3%, respectively). The incidences of norovirus and rotavirus infection were higher during winter and early spring. Most patients with rotavirus and norovirus diarrhea experienced vomiting (74.9% vs. 74.8%, respectively) and fever (94.7% vs. 71.3%, respectively).ConclusionMost young diarrheal patients presenting with vomiting were likely to have norovirus or rotavirus infection. Patients with norovirus diarrhea experienced an absence of, or low-grade fever and longer duration of vomiting compared with those positive for rotavirus infection. A family history of current gastroenteritis may suggest the possibility of norovirus infection