Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome

In acute promyelocytic leukemia, differentiation thera-py based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome(DS). DS is a life-threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial lung infiltrates, pleural or pericardial effusions, hypotension and acute renal failure. The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome without any definitive diagnostic criteria. As DS can have subtle signs and symptoms at presentation but progress rapidly, end-stage DS clinical picture resembles the acute respiratory distress syndrome with extremely poor prognosis; so it is of absolute importance to be conscious of these complications and initiate therapy as soon as it was suspected. The radiologic appearance resembles the typical features of cardiogenic pulmonary edema. Diagnosis of DS remains a great skill for radiologists and haematologist but it is of an utmost importance the cooperation in suspect DS, detect the early signs of DS, examine the patients' behaviour and rapidly detect the complications.

All-trans retinoic acid increases ARPE-19 cell apoptosis via activation of reactive oxygen species and endoplasmic reticulum stress pathways

AIM:To explore the apoptosis of ARPE-19 cells after the treatment with different doses of all-trans-retinoic acid(ATRA).METHODS:ARPE-19 cells were used in the in-vitro experiment.Flow cytometry assay was employed to evaluate the level of reactive oxygen species(ROS)and apoptosis.The effects of ATRA(concentrations from 2.5 to 20μmol/L)on the expression of endoplasmic reticulum stress(ERS)markers in vitro were evaluated by Western blot and realtime quantitative polymerase chain reaction(qRT-PCR)assays.The contribution of ROS and ERS-induced apoptosis in vitro was determined by using N-acetyl-L-cysteine(NAC)and Salubrinal,an antagonist of NAC and ERS,respectively.RESULTS:Flow cytometry showed that ATRA significantly increased ARPE-19 cell apoptosis and ROS levels in each group(F=86.39,P<0.001;F=116.839.P<0.001).Western blot and qRT-PCR revealed that levels of CHOP and BIP were elevated in a concentration-dependent pattern after the cells were incubated with ATRA(2.5-20μmol/L).The upregulation of VEGF-A and CHOP induced by ATRA could be inhibited by NAC(antioxidant)and Salubrinal(ERS inhibitor)in vitro.CONCLUSION:ATRA induces the apoptosis of ARPE-19 cells via activated ROS and ERS signaling pathways.

A novel chemotherapy strategy for advanced hepatocellular carcinoma: a multicenter retrospective study

Background:Chemotherapy is a common treatment for advanced hepatocellular carcinoma,but the effect is not satisfactory.The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid(ATRA)to infusional fluorouracil,leucovorin,and oxaliplatin(FOLFOX4)for advanced hepatocellular carcinoma(HCC).Methods:We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital,First Hospital of Jilin University,and Zhejiang Sian International Hospital and retrospectively compared for overall survival.The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age,sex,and disease stage.Results:From July 2013 to July 2018,111 patients with HCC were included in this study.The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group(P<0.001).The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group(3.6 monthsvs.1.8 months,P<0.001).Hazard ratios for overall survival and disease progression were 0.465(95%confidence interval:0.298–0.726;P=0.001)and 0.474(0.314–0.717;P<0.001)after adjusting for potential confounders,respectively.Conclusion:ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.

Quantitative Analysis of Retinoic Acid Combining 2-Nitrophenylhydrazine Derivatization with LC-MS/MS

All-trans-retinoic acid(atRA)plays an essential role in organ formation and differentiation,tissue cell proliferation,and apoptosis,and is closely related to the occurrence and development of various diseases.Liquid chromatography-tandem mass spectrometry(LC-MS/MS)has become a powerful tool for metabolic biological analysis because of the high sensitivity,specificity and throughput.We have developed a new method for the quantification of atRA by chemical derivatization with 2-nitrophe-nylhydrazine(2-NPH)for the first time,which reduced the interference of detection by changing the ion mass of the molecule.atRA from its endogenous geometric isomers,such as,9-cis-RA and 13-cis-RA,has been baseline resolved within 15 minute under the optimized chromatographic conditions.The method was applied to measure atRA in mouse serum and tissues including liver,kidney,brain,pancreas,and subcutaneous tissue.The method is easy to operate,highly sensitive and well selective,and can be used for accurate and rapid determination of at RA in biological samples.