N4-Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF-1α Positive Feedback Loop.

Anti-angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti-angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4-acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF-1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP-sequencing, Ribosome profiling sequencing, RNA-sequencing, and functional studies confirm that NAT10 in turn activates the HIF-1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF-1α positive feedback loop leads to excessive activation of the HIF-1 pathway and induces glycolysis addiction. Combined anti-angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti-angiogenic therapy by combining apatinib with ac4C inhibition.

Effect of HIF-1αsiRNA-linked AuNRs on radiotherapy of nasopharyngeal carcinoma.

The radiation sensitivity of tumor cells is closely related to tumor cell hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is considered a key transcription factor which regulates the sensitivity of hypoxic tumor cells to radiotherapy. On the other hand, some studies have shown that gold nanomaterials improve radiation sensitivity. However, studies on the effect of gold nanomaterials carrying HIF-1αsiRNA on tumor radiotherapy, and the underlying mechanisms are limited. Thus, the present study was aimed at investigating the effect of gold nanocomposites (AuNRs) carrying HIF-1αsiRNA (AuNRs-HIF-1αsiRNA) on the radiation sensitivity of nasopharyngeal carcinoma (NPC) hypoxia cells. The effect of AuNRs-HIF-1αsiRNA on radiation sensitivity of hypoxic NPC cells was determined under X-ray irradiation. The results showed that Au-HIF-1αsiRNA improved the radio-sensitivity of NPC tumor. Thus, this study has demonstrated that gold nanomaterials carrying HIF-1αsiRNA effectively increased the radio-sensitivity of hypoxic tumor, thereby improving the effect of radiotherapy on NPC cells.

PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer.

The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC.

[Hypothermia treatment in asphyxiated neonates - a single center experience in Hungary]. / Terápiás hypothermia alkalmazása az asphyxiás újszülöttek kezelésében ­ egy hazai neonatológiai centrum eredményei.

INTRODUCTION AND AIM: We aimed to analyze patient characteristics of term neonates with hypoxic-ischemic encephalopathy treated with hypothermia at the 3rd level Neonatal Intensive Care Unit of the 1st Department of Pediatrics, Semmelweis University. METHOD: We conducted a retrospective cohort analysis between 2013-2015, including 97 asphyxiated neonates with HIE who received hypothermia treatment, using our in-house developed novel registry database. RESULTS: 59.8% of neonates were born with Cesarean section and the first blood gas analysis showed a pH of 7.0 ± 0.2, pCO2 55.9 ± 27.3 mmHg, base deficit 16.7 ± 7.2 mmol/l, and lactate levels of 13.3 ± 4.7 mmol/l (x ± SD). Hypothermia treatment was started during neonatal transport in 93.7% of the cases, at 2.5 ± 0.3 hours of age. Multiorgan failure associated with the perinatal asphyxia was present in 83.2% of the patients. Patients received intensive therapy for a median of 10.8 days, 61.3% of neonates were discharged home directly, 32.2% required further hospital treatment, and 6.5% died. CONCLUSION: Our novel registry database allowed for a quick, user-friendly and time-efficient analysis of patient characteristics in neonates with HIE. This registry could aid institutional audit work and prospective clinical data collection. Orv. Hetil., 2017, 158(9), 331-339.