Stillbirth in women with Type 1 Diabetes mellitus-still a current topic.

PURPOSE: Compared to the general stillbirth rate in Germany for term deliveries of 0.12% the risk in type 1 diabetes mellitus is reported to be up to ten times higher. The reasons for this excess risk of intrauterine demise are still not fully elucidated. Risk factors named in the literature include poor glycemic control before and during pregnancy and the occurrence of ketoacidosis. Additionally there might be a diabetes related type of placental dysfunction leading to organ failure in late pregnancy. Understanding the underlying causes is mandatory to develop strategies to reduce the incidences. The Purpose of this publication is to point out the difficulties in prediction of intrauterine death in pregnant type 1 diabetes patients and thus emphasizing the necessity of constant awareness to all caregivers. METHODS: We present a case series of four cases of stillbirth that occurred in patients with type 1 diabetes mellitus at our tertiary care obstetric unit during a five-year period. RESULTS: In all four presented cases the underlying cause of intrauterine demise was different and we could not find a common mechanism or risk profile. Furthermore, established monitoring tools did not become peculiar to raise awareness. We compared our cases to published data. Underlying causes of intrauterine death in type 1 diabetes are discussed in the light of the current literature. CONCLUSIONS: The main risk factors of stillbirth in diabetic pregnancies are high maternal blood glucose levels including pre-conceptional HbA1c and diabetic ketoacidosis. Late acute placental insufficiency are associated with intrauterine death in type 1 diabetes. Despite the elevated risk of near term intrauterine demise there are currently no guidelines on how to monitor pregnancies in type 1 diabetes for fetal distress during the third trimester. Established thresholds for fetal Doppler data indicating fetal distress in normal and growth restricted fetuses may not be applicable for overgrown fetuses. Future research on how to monitor the diabetic fetus needs to be initiated.

A 3'UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1.

BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5' and 3'UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3'UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3'untranslated region (3'UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors.

Experimental study on different combination schedules of VEGF-receptor inhibitor PTK787/ZK222584 and fractionated irradiation.

BACKGROUND: Inhibition of the vascular endothelial growth factor receptor (VEGFR) has been shown to improve the radiation response of several experimental tumors. The present experimental study compares the effect of neoadjuvant, concomitant and adjuvant treatment with PTK787/ZK222584, a specific inhibitor of the VEGFR, in combination with fractionated irradiation. MATERIALS AND METHODS: Growth delay after daily oral application of 50 mg per kg bodyweight PTK787/ZK222584 or carrier was tested in five different human squamous cell carcinoma growing in nude mice. Two of these tumor models, a responder (UT-SCC-14) and a non-responder (FaDu), were selected for the irradiation experiments (15 fractions of 2 Gy within 15 days). PTK787/ZK222584 was applied daily for 4-18 days and stopped before start of irradiation (neoadjuvant), for 15 days during fractionated irradiation (concomitant) or for 45 days after the course of irradiation (adjuvant). RESULTS: Adjuvant application of PTK787/ZK222584 after fractionated irradiation retarded regrowth of UT-SCC-14 tumors and, surprisingly, also of FaDu tumors which did not respond to the agent when given alone. No effects on radiation response were observed after short-term neoadjuvant or concomitant PTK787/ZK222584 application. CONCLUSION: Combined with fractionated irradiation, only adjuvant application of PTK787/ZK222584 retarded regrowth of UT-SCC-14 and FaDu tumors. The data suggest that preirradiated vasculature might be more sensitive to VEGFR inhibition compared to unirradiated vasculature. Whether the effect of adjuvant VEGFR inhibition on growth delay translates into improved local tumor control after irradiation needs further investigation.