Success rate of external cephalic version in relation to the woman's body mass index and other factors-a population-based cohort study.

INTRODUCTION: The aim of this study was to evaluate the impact of women's body mass index (BMI) on the probability of a successful external cephalic version (ECV). MATERIAL AND METHODS: A retrospective population-based observational study including all women that underwent an ECV in the southeast region of Sweden from January 2014 to December 2019. Data were collected from electronic medical records, Obstetrix, Cerner. The women were divided into BMI categories according to the World Health Organization classification. Women with a BMI below 25 kg/m2 formed the reference group. Crude and adjusted odds ratios for unsuccessful ECV in each BMI group were calculated using binary logistic regression. Furthermore, the association between maternal characteristics and clinical and ultrasound variables at the time of the ECV and unsuccessful ECV was evaluated. RESULTS: A total of 2331 women were included. The overall success rate of ECV was 53.4%. Women with a BMI below 25 kg/m2 had a success rate of 51.3% whereas obese women had a success rate of 58.6%. The risk of an unsuccessful ECV among obese women (BMI ≥30 kg/m2 ) had an OR of 0.74 (95% CI 0.59-0.94) compared with women with a BMI below 25 kg/m2 . After adjusting for suitable confounding factors, the association was no longer significant. Higher maternal age, multiparity, higher gestational age, posterior placenta position, polyhydramnios and higher estimated weight of the fetus at the ECV significantly decreased the risk of an unsuccessful ECV. CONCLUSIONS: Maternal obesity does not seem to negatively influence the success rate of ECV. This is a finding that may encourage both caregivers and obese pregnant women to consider an ECV and so avoid a planned cesarean section for breech presentation in this group.

Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies.

Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains. The method can be applied across Igs to design Fc heterodimers and bsAbs. We investigated interfaces from human IgA CH3, IgD CH3, IgG1 CH3, IgM CH4, T-cell receptor (TCR) α/ß, and TCR γ/δ constant domain pairs, and we found that they successfully drive human IgG1 CH3 or IgM CH4 heterodimerization to levels similar to or above those of reference methods. A comprehensive interface exchange between the TCR α/ß constant domain pair and the IgG1 CH3 homodimer was evidenced by X-ray crystallography and used to engineer examples of bsAbs for cancer therapy. Parental antibody pairs were rapidly reformatted into scalable bsAbs that were free of homodimer traces by combining interface exchange, asymmetric Protein A binding, and the scFv × Fab format. In summary, we successfully built several new CH3- or CH4-based heterodimers that may prove useful for designing new bsAb-based therapeutics, and we anticipate that our approach could be broadly implemented across the Ig constant domain family. To our knowledge, CH4-based heterodimers have not been previously reported.

The Wilms' tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2).

The Wilms' tumor gene 1 (WT1) protein is a transcriptional regulator that is highly expressed in immature hematopoietic progenitor cells and in the majority of patients with acute and chronic myeloid leukemia. However, it is still unclear how WT1 exerts its function(s) in hematopoietic cells. The aim of this work was to investigate the function of WT1 as a transcription factor in human hematopoietic progenitor cells. To this end, an oligonucleotide array approach was used to study the gene expression in CD34(+) cells from human cord blood retrovirally transduced with WT1 or a control vector. We found that the expression of the putative tumor suppressor gene N-myc downstream regulated gene 2 (NDRG2) mRNA was induced by WT1 in CD34(+) cells and also in leukemic U937 cells. Furthermore, a novel transcription start site in the NDRG2 gene was identified in WT1-transduced cells, in addition to two previously reported transcription start sites. These results show that the expression of the NDRG2 gene is directly or indirectly induced by WT1, and provide the first insights into transcriptional regulation of the NDRG2 gene, including demonstration of a novel splice variant.

DNA-binding dependent and independent functions of WT1 protein during human hematopoiesis.

The Wilms tumor gene 1 (WT1) encodes a zinc-finger-containing transcription factor highly expressed in immature hematopoietic progenitor cells. Overexpression and presence of somatic mutations in acute leukemia indicate a role for WT1 in the pathogenesis of leukemia. CD34+ progenitor cells were transduced with one splice variant of human WT1 without the KTS insert in the zinc-finger domain, WT1(+/-), and with a deleted mutant of WT1 lacking the entire zinc-finger region, WT1(delZ), thus incapable of binding DNA. We show that inhibition of erythroid colony formation and differentiation is absolutely dependent on the DNA-binding zinc-finger domain of WT1. Unexpectedly, however, WT1(delZ) was equally effective as wild type protein in the reduction of myeloid clonogenic growth as well as in stimulation of myeloid differentiation, as judged by the expression of cell surface CD11b. Expression of neither WT1(+/-) nor WT1(delZ) upregulated mRNA for the cdk inhibitor p21(Waf1/Cip1) or p27Kip1. Our results demonstrate that WT1 affects proliferation and differentiation in erythroid and myeloid cells by different molecular mechanisms, and suggest that mutations affecting the zinc-finger domain of WT1 could interfere with normal differentiation in the pathogenesis of leukemia.