Gender and preterm birth: Is male fetal gender a clinically important risk factor for preterm birth in high-risk women?

Gender differences in several adverse pregnancy outcomes have been described, including preterm labour and delivery. In the low risk population, the male fetus is at significantly higher risk of spontaneous preterm birth. OBJECTIVES: Our objective was to examine the risk effect of fetal gender on pregnant women at higher risk of preterm birth, and therefore its potential impact on targeting management. STUDY DESIGN: This was an analysis of prospectively collected data from a dedicated inner-city Prematurity Surveillance Clinic over a sixteen-year period. All women were high-risk for preterm delivery in view of their history, which included previous late miscarriage, PTB or significant cervical surgery. Obstetric variables and pregnancy outcomes were compared in male and female babies. Demographic and risk factors were compared between groups, and both spontaneous and iatrogenic preterm delivery rates interrogated (<24, <28, <34 and <37 weeks' gestation). Risk ratios (with 95% confidence intervals) were calculated for each gestational band. RESULTS: In this cohort, 14.5% of women (363/2505) delivered before 37 weeks. Pregnant women were stratified by fetal gender and were comparable for referral risk factors and demographic characteristics. There was no significant association between fetal gender and incidence of miscarriage less than 24 weeks (RR 1.17, 95% CI 0.65-2.10, p = 0.607), or preterm births 24 to 37 weeks RR 1.07 (95% CI 0.82-1.40, p = 0.383). Furthermore, analysis by gestational band [<28 RR 0.91 (95% CI 0.60-1.37, p = 0.647), <34 RR 1.18 (95% CI 0.89-1.57, p = 0.257 and <37 weeks RR 1.10 (95% CI 0.91-1.33, p = 0.309)] also showed no effect. This held true for both spontaneous and iatrogenic preterm delivery. In our high-risk cohort there was no gender difference for preeclampsia (RR 0.93, 95% CI 0.61 to 1.41, p = 0.725) or preterm premature rupture of membranes (PPROM) (RR 1.14, 95% CI 0.86 to 1.50, p = 0.384) CONCLUSIONS: In a high-risk cohort there was no significant increased risk of miscarriage, spontaneous or iatrogenic PTB, preeclampsia or PPROM for the male fetus. This is contradictory to low-risk populations and confirms that gender need not be integrated into high-risk management protocols for preterm birth.

p53 abnormalities and potential therapeutic targeting in multiple myeloma.

p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma.

p53 haploinsufficiency and functional abnormalities in multiple myeloma.

Hemizygous deletion of 17p13, which harbors the TP53 gene, has been identified in >10% of newly diagnosed multiple myeloma (MM) patients and is associated with poor prognosis. To date, there is no conclusive evidence that TP53 is the critical gene. Furthermore, the functional effect of TP53 haploinsufficiency is not well characterized. By utilizing human myeloma cell lines, we showed that TP53 hemizygous loss was associated with decreased basal expression level with a partially or severely inactivated p53 response upon genotoxic and non-genotoxic stress. The pathway deficiency was manifested as defective p53 transcriptional activities, together with significant resistance to apoptosis. In some cases with p53 WT/- and no p53 protein expression, the remaining allele was silenced by promoter hypermethylation. We also developed a p53 target gene signature to summarize the complexity of the p53 pathway abnormalities in MM and showed that it is strongly associated with genomic complexity and patient survival. In conclusion, this study identified TP53 as the critical gene located in 17p13, and revealed its haploinsufficiency properties in MM. Furthermore, we have elucidated that multiple mechanisms can deregulate the p53 functions and that this has important prognostic impact in MM.