Extremely preterm infants born outside a provincial tertiary perinatal center and transferred postnatally associated with poor outcomes: a real-world observational study

IntroductionExtremely preterm infants (EPIs) have high morbidity and mortality, and are recommended to be born in a tertiary perinatal center (inborn). However, many EPIs in central China are born in lower-level hospitals and transferred postnatally, the outcomes of which remain to be investigated.MethodsEPIs admitted to the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province from January 2013 to December 2022 were retrospectively recruited and divided into the control (inborn) and transfer groups (born in other hospitals). The neonatal and maternal characteristics, neonatal outcomes, and the treatment of survival EPIs were analyzed.ResultsA total of 174 and 109 EPIs were recruited in the control and transfer groups, respectively. EPIs in the transfer group have a higher birth weight and a lower proportion of multiple pregnancies than the control group (all P < 0.05). The proportions of antenatal steroids, magnesium sulfate, cesarean delivery, premature rupture of membranes ≥18 h, gestational diabetes, and amniotic fluid abnormalities were lower in the transfer group (all P < 0.05). Survival rates (64.22% vs. 56.32%), proportions of severe periventricular-intraventricular hemorrhage (PIVH) (11.93% vs. 11.49%), severe bronchopulmonary dysplasia (sBPD) (21.05% vs. 20%), and severe retinopathy of prematurity (ROP) (24.77% vs. 20.11%) were similar in the transfer and control groups (all P > 0.05). However, the transfer group had higher proportions of severe birth asphyxia (34.86% vs. 13.22%, P < 0.001), PIVH (42.20% vs. 29.89%, P = 0.034), and extrauterine growth retardation (EUGR) (17.43% vs. 6.32%, P = 0.003). Less surfactant utilization was found in the transfer group among survival EPIs (70.00% vs. 93.88%, P < 0.001).ConclusionEPIs born outside a tertiary perinatal center and transferred postnatally did not have significantly higher mortality and rates of severe complications (severe PIVH, severe ROP, and sBPD), but there may be an increased risk of severe asphyxia, PIVH and EUGR. This may be due to differences in maternal and neonatal characteristics and management. Further follow-up is needed to compare neurodevelopmental outcomes, and it is recommended to transfer the EPIs in utero to reduce the risk of poor physical and neurological development

Vascular disrupting agent DMXAA enhances the antitumor effects generated by therapeutic HPV DNA vaccines

Antigen-specific immunotherapy using DNA vaccines has emerged as an attractive approach for the control of tumors. Another novel cancer therapy involves the employment of the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). In the current study, we aimed to test the combination of DMXAA treatment with human papillomavirus type 16 (HPV-16) E7 DNA vaccination to enhance the antitumor effects and E7-specific CD8+ T cell immune responses in treated mice. We determined that treatment with DMXAA generates significant therapeutic effects against TC-1 tumors but does not enhance the antigen-specific immune responses in tumor bearing mice. We then found that combination of DMXAA treatment with E7 DNA vaccination generates potent antitumor effects and E7-specific CD8+ T cell immune responses in the splenocytes of tumor bearing mice. Furthermore, the DMXAA-mediated enhancement or suppression of E7-specific CD8+ T cell immune responses generated by CRT/E7 DNA vaccination was found to be dependent on the time of administration of DMXAA and was also applicable to other antigen-specific vaccines. In addition, we determined that inducible nitric oxide synthase (iNOS) plays a role in the immune suppression caused by DMXAA administration before DNA vaccination. Our study has significant implications for future clinical translation

Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding

TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS\u2019s nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization. This is coupled with binding of a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) to p53-RS, but not the p53 form with mutations of four serines/threonines previously shown to be crucial for PIN1 binding. As a result, p53-RS interacts with c-Myc and enhances c-Myc-dependent rDNA transcription key for ribosomal biogenesis. These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for the GOF of p53-RS in HCC

Stressing the Ubiquitin-Proteasome System without 20S Proteolytic Inhibition Selectively Kills Cervical Cancer Cells

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine