Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1.

Cyclophosphamide is an alkylating agent used to treat a variety of cancers, including leukemia. Here, we show a previously unrecognized role of cyclophosphamide in triggering the protein degradation of glutathione peroxidase 4 (GPX4), a phospholipid hydroperoxidase that protects cells from oxidative damage. Mechanistically, we found that the ubiquitin-proteasome system, but not autophagy, mediates cyclophosphamide-induced degradation of GPX4 in human leukemia cell lines. Surprisingly, cyclophosphamide-induced degradation of GPX4 leads to caspase-independent parthanatos, but not lipid peroxidation-mediated ferroptosis, through the nuclear translocation of apoptosis-inducing factor mitochondria-associated 1 (AIFM1). Consequently, the overexpression of GPX4 or the knockdown of AIFM1 limits the anticancer activity of cyclophosphamide in vitro and in xenograft tumor models. These findings establish a new framework for understanding the central role of GPX4 in blocking oxidative cell death.

[Clinical application of hepatic venous pressure gradient to predict early bleeding after esophageal variceal ligation].

OBJECTIVE: To investigate the predictive value of hepatic venous pressure gradient (HVPG) for early bleeding after esophageal variceal ligation (EVL) by analyzing the differences in HVPG in patients with and without post-EVL bleeding. METHODS: The medical records of patients who had been diagnosed with cirrhosis and esophageal varices and who had pre-EVL HVPG measurement data were surveyed. The study population included 105 patients from October 2010 to March 2014. Data of HVPG value, previous treatment history, endoscopic manifestation, and whether bleeding and serious complications occurred within 2 weeks after the ligation procedure were investigated as independent risk factors. STATISTICAL METHODS: included the chi-square test and Wilcoxon test, logistic regression modeling and receiver operating characteristic (ROC) analysis using the SPSS software version 16. RESULTS: Only HVPG value was identified as an independent risk factor of early bleeding after EVL.According to the ROC analysis, the area under the curve (AUC) of HVPG for early bleeding after EVL was 0.866; when HVPG was more than or equal to 16 mmHg, AUC was 0.838. The sensitivity was 90.9% and the specificity was 76.4%. CONCLUSION: HVPG is an independent factor of early bleeding after EVL and when HVPG cut-off value of more than or equal to 16 mmHg is used the predictive ability has certain accuracy and high sensitivity and specificity.

Cancer in 22q11.2 deletion syndrome: A case report and literature review.

Clinically, the 22q11.2 deletion syndrome (22q11.2DS) is considered the most commonly detected microdeletion syndrome. Hepatoblastoma is the most prevalent malignant liver cancer in childhood. However, cases of hepatoblastoma in children with 22q11.2DS have only been reported in four patients. In this report, we present a-13-year-old male treated at our center due to growth retardation, and later diagnosed with hepatoblastoma. Whole genome sequencing (WGS) identified 22q11.2DS. Chromosomal microarray analysis (CMA) of peripheral blood sample showed a 2.9 Mb deletion of chromosome 22q11.2. While underlying mechanisms remain unclear, our literature review suggests that patients with 22q11.2DS may show an elevated risk of malignancy. After reviewing 21 previously reported cases, we identified 33 individuals with both cancer and 22q11.2 DS or DiGeorge syndrome. Of these cases, 7 out of 33 (21%) were hematologic tumors, while 26 out of 33 (78%) were solid tumors.