Activity

Hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancer, is commonly treated with surgical resection. OICR-9429 mouse However, most patients lose the opportunity to receive this therapeutic strategy due to delayed diagnosis and rapid tumor progression. Long noncoding RNAs (lncRNAs) have been demonstrated to play essential roles in the initiation and progression of HCC. However, the function of the novel lncRNA neuropeptide S receptor 1 antisense RNA 1 (NPSR1-AS1) in HCC and its potential mechanism, is unclear. Here, our microarray data revealed NPSR1-AS1 as a novel hypoxia-responsive lncRNA in HCC cells. Interestingly, hypoxia-inducible factor-1α (HIF-1α) knockdown abolished hypoxia-induced NPSR1-AS1 expression in HCC cells. NPSR1-AS1 expression was upregulated in HCC tissues and cell lines. Next, the ectopic expression of NPSR1-AS1 facilitated the proliferation and glycolysis of HCC cells. In contrast, NPSR1-AS1 silencing repressed HCC cell proliferation and glycolysis. Mechanistically, NPSR1-AS1 overexpression increased the levels of p-ERK1/2 and pyruvate kinase M2 (PKM2) in HCC cells. NPSR1-AS1 knockdown abrogated hypoxia-induced the activation of the MAPK/ERK pathway in HCC cells. Importantly, NPSR1-AS1 depletion partially reversed hypoxia-induced proliferation and glycolysis of HCC cells in vitro. In conclusion, hypoxia-inducible NPSR1-AS1 promotes the proliferation and glycolysis of HCC cells, possibly by regulating the MAPK/ERK pathway, suggesting an underlying therapeutic strategy for HCC.BET inhibitor (BETi) has potential therapeutic effects on human cancer especially in breast cancer. However, the detailed mechanisms remain unclear. Herein, we found that BETi JQ1 and I-BET-151 (I-BET) activated ATF2 through JNK1/2 pathway in breast cancer cells MDA-MB-231 (MB-231). In addition, overexpression of ATF2 blocked the reduction of cell viability induced by JQ1 or I-BET in breast cancer MB-231 and BT-549 cells, cervical cancer HeLa cells and lung cancer A549 cells. The induction of cell death by BETi was also attenuated by ATF2 in MB-231 and BT-549 cells. By contrast, depletion of ATF2 increased cancer cell sensitivity to BETi. In MB-231 cells xenograft model, ATF2 significantly inhibited the anti-tumor effects of JQ1. By detection of the oxidized form gluthione, malondialdehyde and lipid ROS, we showed that overexpression of ATF2 inhibited ferroptosis induced by BETi, whereas depletion of ATF2 promoted ferroptosis by BETi. Furthermore, the underlying mechanisms of ATF2-reduced ferroptosis were investigated. Overexpressed and depleted ATF2 were found to significantly upregulate and downregulate NRF2 protein and mRNA expression, respectively. The significantly positive correlations between NRF2 and ATF2 gene expression were found in breast, lung and cervical cancer tissues from TCGA database. In NRF2-depleted MB-231 cells, ATF2 failed to attenuate JQ1-stimulated ferroptosis. All these results suggested that ATF2 inhibited BETi-induced ferroptosis by increasing NRF2 expression. Altogether, our findings illustrated ATF2 suppressed ani-tumor effects of BETi in a negative feedback manner by attenuating ferroptosis. BETi combined with ATF2 or NRF2 inhibitor might be a novel strategy for treatment of human cancer.

The safe ischemic time after a single-dose del Nido cardioplegia (DNC) infusion has not yet been established. This study evaluated the progression of myocardial ischemic injury to establish the safe ischemic time after a single-dose DNC infusion in the human heart using a transmission electron microscope.

Seven hearts extracted from heart transplant recipients after infusion of 1000mL single-dose DNC were evaluated. Serial left ventricular myocardial tissuesamples were collected every 30minutes for 180minutes. Ischemic injuries in the mitochondria and nuclei were scored from 0 to 3 (0=normal, 0.5=slight, 1=moderate, 2=severe, and 3=irreversible).

At the time of extraction, 83.5% of the mitochondria were normal. The proportion of mitochondria with moderate ischemic injury increased gradually from 1.4% at extraction to 52.5% at 180minutes. From 90minutes to 180minutes, the proportion of mitochondria with severe and irreversible injury increased from 0.8% to 4.4% and 0.3% to 1.3%, respectively. A significant linear correlation was identified between the average ischemic injury score of mitochondria and ischemic time (P<.001). Most nuclei showed moderate to severe ischemic injury at every time point (61.0%-85.2%). A significant linear correlation was also found between the average ischemic injury score of nuclei and ischemic time (P<.001).

Myocardial ischemic injury progresses gradually, and irreversible ischemic injury begins to occur 90minutes after initial DNC infusion in the adult human heart. Therefore, redosing of DNC may be required after 90minutes of aortic crossclamp time during adult cardiac surgery.

Myocardial ischemic injury progresses gradually, and irreversible ischemic injury begins to occur 90 minutes after initial DNC infusion in the adult human heart. Therefore, redosing of DNC may be required after 90 minutes of aortic crossclamp time during adult cardiac surgery.

On November 24, 2017, Organ Procurement and Transplantation Network implemented a change to lung allocation replacing donor service area with a 250 nautical mile radius around donor hospitals. We sought to evaluate the experience of a small to medium size center following implementation.

Patients (47 pre and 54 post) undergoing lung transplantation were identified from institutional database from January 2016 to October 2019. Detailed chart review and analysis of institutional cost data was performed. Univariate analysis was performed to compare eras.

Similar short-term mortality and primary graft dysfunction were observed between groups. Decreased local donation (68% vs 6%; P<.001), increased travel distance (145 vs 235 miles; P=.004), travel cost ($8626 vs $14,482; P<.001), and total procurement cost ($60,852 vs $69,052; P=.001) were observed postimplementation. We also document an increase in waitlist mortality postimplementation (6.9 vs 31.6 per 100 patient-years; P<.001).

Following implementation of the new allocation policy in a small to medium size center, several changes were in accordance with policy intention.