Pregnancy, Microchimerism, and the Maternal Grandmother

A WOMAN OF REPRODUCTIVE AGE OFTEN HARBORS A SMALL NUMBER OF FOREIGN CELLS, REFERRED TO AS MICROCHIMERISM: a preexisting population of cells acquired during fetal life from her own mother, and newly acquired populations from her pregnancies. An intriguing question is whether the population of cells from her own mother can influence either maternal health during pregnancy and/or the next generation (grandchildren).Microchimerism from a woman's (i.e. proband's) own mother (mother-of-the-proband, MP) was studied in peripheral blood samples from women followed longitudinally during pregnancy who were confirmed to have uncomplicated obstetric outcomes. Women with preeclampsia were studied at the time of diagnosis and comparison made to women with healthy pregnancies matched for parity and gestational age. Participants and family members were HLA-genotyped for DRB1, DQA1, and DQB1 loci. An HLA polymorphism unique to the woman's mother was identified, and a panel of HLA-specific quantitative PCR assays was employed to identify and quantify microchimerism. Microchimerism from the MP was identified during normal, uncomplicated pregnancy, with a peak concentration in the third trimester. The likelihood of detection increased with advancing gestational age. For each advancing trimester, there was a 12.7-fold increase in the probability of detecting microchimerism relative to the prior trimester, 95% confidence intervals 3.2, 50.3, p<0.001. None of the women with preeclampsia, compared with 30% of matched healthy women, had microchimerism (p = 0.03).These results show that microchimerism from a woman's own mother is detectable in normal pregnancy and diminished in preeclampsia, supporting the previously unexplored hypothesis that MP microchimerism may be a marker reflecting healthy maternal adaptation to pregnancy

Early phase clinical trials of anticancer agents in children and adolescents — an ITCC perspective

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledge of tumour biology, molecular 'drivers' of disease and a drug's mechanism of action, and therapeutic unmet needs are key elements; these aspects are relevant to early phase paediatric trials, in which molecular profiling is strongly encouraged. Herein, we describe the strategy of the Innovative Therapies for Children with Cancer (ITCC) Consortium, which advocates for the adoption of trial designs that enable uninterrupted patient recruitment, the extrapolation from studies in adults when possible, and the inclusion of expansion cohorts. If a drug has neither serious dose-related toxicities nor a narrow therapeutic index, then studies should generally be started at the adult recommended phase II dose corrected for body surface area, and act as dose-confirmation studies. The use of adaptive trial designs will enable drugs with promising activity to progress rapidly to randomized studies and, therefore, will substantially accelerate drug development for children and adolescents with cancer

Behaviour of nonionic water soluble homopolymers at the air-water interfaces: neutron reflectivity and surface tension results for poly-(vinyl methyl ether)

The composition and structure of layers of poly(vinylmethyl ether) (PVME) adsorbed at the air/water interface have been determined by neutron reflection and surface tension. For temperatures above and below the cloud point and over most of the range of concentration, neutron reflection gives results in agreement with the Gibbs equation. However, an upturn in the surface tension at low concentrations, which has been observed in several related systems, is attributed to two possible contributions. One is depletion, which has been previously identified by others. The other is polydispersity. At higher concentrations, larger molecular weight species dominate the surface activity and lead to a shallow slope in the surface tension (γ) versus ln(concentration) plot, but at low concentrations smaller molecular weight species increasingly occupy the surface and they give rise to steeper slopes in the γ−ln c plot. The segment density profile of PVME normal to the surface is unsymmetrical with a tail extending into the solution. A new method of analyzing reflectivity data that is better able to handle such unsymmetrical distributions is introduced. As the temperature is increased above the cloud point, the adsorbed polymer layer tends to collapse with expulsion of water

Neutron reflectivity of an adsorbed water-soluble block copolymer at the air/water interface: the effects of pH and ionic strength

We describe the effects of pH and added electrolyte on the structure of layers of poly(2-(dimethylamino)-ethyl methacrylate-block-methyl methacrylate) copolymer (poly(DMAEMA-b-MMA)) (70 mol % DMAEMA, Mn = 10 000) adsorbed at the air/water interface. Previously, we had shown by means of neutron reflection measurements that at a pH of 7.5 there is a surface phase transition from a layer about 20 Å thick to one about 40 Å thick and that the adsorbed layer at the higher concentration has a cross sectional structure resembling that expected for a micelle. The present work shows that the "micellar" structure is promoted by any changes in the solution that enhance the surface coverage but is inhibited by an increase in the fractional charge on the polyelectrolyte part of the copolymer. Some surprising lack of correlation between surface tension and surface coverages is also observed, which may be related to this unusual surface structure