TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to ...malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.
Purpose
The aim of this study was to evaluate the effects of intrauterine platelet-rich plasma (PRP) infusion on endometrial thickness and pregnancy outcomes in a population of patients with either ...recurrent implantation failure (RIF), thin endometrium (TE), or both (RIF + TE)
Methods
This retrospective study included patients attending the CReATe Fertility Centre between October 2018 and July 2021 who received intrauterine PRP infusion to prepare the endometrium for frozen embryo transfer. PRP was prepared from 21 cc of whole blood using the 2-step centrifugation method to yield 0.5–0.75 cc of concentrated platelets. Endometrial thickness was measured before infusion and within 72 h after infusion. All embryos transferred were tested for genetic abnormalities using next-generation sequencing.
Results
A total of 85 patients, 133 cycles, and 211 infusions were included. The majority of patients (56.5%) were diagnosed with RIF, some with TE (27.0%), and the remainder with both RIF and TE (16.5%). The majority of patients received one PRP infusion per cycle (55%). The endometrial thickness significantly increased across all diagnoses with a significant increase of 1.0 mm (0.5–1.7), which was also significantly greater than in previous cycles. The clinical pregnancy rate per embryo transfer after intrauterine PRP infusion was significantly greater compared to previous cycles (37% vs 20%, odds ratio 2.2) as was the live birth rate (19% vs 2%, odds ratio 11.6).
Conclusion
Our study suggests that PRP should be considered a noninvasive front-line therapy for improving endometrial thickness and implantation in patients with RIF, a TE, or both.
Background
Early diagnosis of hospitalized elderly patients with infectious stress hyperglycaemia (ISH) is clinically important, especially under the global coronavirus disease 2019 (COVID‐19) ...pandemic, as without timely prevention and effective treatment, it is likely to deteriorate into septic shock, thus worsening patient survival and complications. Moreover, cumulative studies have showed that patients with COVID‐19 are reported to have a greater prevalence of hyperglycaemia. However, the underlying mechanism remained unknown.
Aim and method
Systematic screening of specific biomarkers of serum exosome‐derived microRNAs (sE‐miRNAs) from ISH patient has not yet been reported. In this study, sE‐miRNAs were derived from 10 elderly patients with ISH and 5 control patients with disease‐match without hyperglycaemia (non‐ISH). RNA sequencing identified that a total number of 49 sE‐miRNAs with differential expression between ISH and control group. Of which, top 22 miRNAs ranked by sensitivity × specificity were chosen for further research. Moreover, 7 out of 22 miRNAs that related to glucose metabolism or immune disorder were picked up for further validation in an independent cohort consisting of 52 participants (31 ISH and 21 non‐ISH).
Result
A validation analysis revealed that three miRNAs (hsa‐miR‐21‐5p, hsa‐miR‐335‐5p and hsa‐miR‐28‐3p) were statistically up‐regulated in exosomes from ISH patients. In the validation cohort and discovery cohort, the AUC of three individual miRNAs ranged from 0.73 to 0.88. A logistic model combining three miRNAs achieved an AUC of 0.96. Besides, sE‐miRNAs‐based signatures effectively characterized patients' poor clinical outcome. Survival curve analysis showed that hsa‐miR‐335‐5p, hsa‐miR‐28‐3p but not hsa‐miR‐21‐5p, were significantly closely related to mortality, and the combination of these three miRNAs could also predict patients outcome (p < .05).
Conclusion
This study depicted the circulating exosomal miRNAs change in ISH patient, which could be used as a promising biomarker to detect ISH at an early stage and predict patients clinical outcome.
Our study uncovered three sE‐miRNAs that were up‐regulated in ISH which may serve as diagnostic biomarker.
In particularly, sE‐hsa‐miR‐21‐5p might relate to poor clinical outcome.
hsa‐miR‐335‐5p, hsa‐miR‐28‐3p and hsa‐miR‐21‐5p may serve as potential therapeutic targets for ISH patients.
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