Impact of Bifidobacterium longum1714® on maternal cytokine response in peripheral blood mononuclear cells.

PURPOSE: The maternal immune system is implicated in adverse pregnancy outcomes. Manipulation of maternal immune response by probiotics holds potential to reduce pregnancy complications. The MicrobeMom2 study investigates the impact of probiotic supplementation on maternal immune responses to pathogen associated molecular patterns (PAMPs) in peripheral blood mononuclear cells (PBMCs) during pregnancy. METHODS: This double-blinded randomised-controlled trial involved oral supplementation of Bifidobacterium longum subsp. longum 1714® (B. longum 1714; daily ingestion of a minimum of 1x109 colony forming units) or placebo from 16 to 20-weeks' gestation until delivery in healthy pregnant women. The primary outcome was a change in IL-10 production, after stimulation with Lipopolysaccharide (LPS) or anti-CD3/28/2, in PBMCs isolated from blood samples taken at baseline (11-15 weeks' gestation) and late pregnancy (28-32 weeks' gestation) after 48 h incubation. 68 subjects were needed (34ineachgroup) for 80 % power at an alpha significance of 0.05 to detect differences in IL10. RESULTS: 72 women (mean ± SD age 33.17 ± 4.53 years and median (25th, 75th centile) body mass index 24.93 (21.93, 27.57 kg/m2)) were recruited with primary outcome data. Using LPS, late pregnancy fold change in IL-10 in PBMCs after 48 h incubation was median (25th, 75th centile) 88.45 (4.88, 488.78) in the intervention, 24.18 (6.36, 141.17) in the control group, p = 0.183. Using anti-CD3/28/2, values were 189.69 (425.96, 866.57),148.74 (31.67, 887.03) in intervention and control groups, respectively, p = 0.506. No significant differences were observed between the two groups. CONCLUSION: Maternal antenatal supplementation with B. longum 1714 did not alter cytokine production by maternal PBMCs in response to PAMPs or anti-CD3/28/2. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN43013285.

Diet quality and blood pressure among pregnant women with overweight or obesity: A secondary analysis of two randomized controlled trials.

INTRODUCTION: Maternal obesity is a significant risk factor for hypertensive disorders of pregnancy. High diet quality may protect against this, yet data regarding the relationship between diet quality and blood pressure among pregnant women with raised body mass index (BMI) is limited. MATERIAL AND METHODS: This is a secondary analysis (n = 543) of women with BMI ≥25 kg/m2 from two randomized controlled trials; PEARS (Pregnancy Exercise and nutrition Research Study with smartphone application support) and ROLO (Randomized cOntrol trial of LOw glycemic index diet to prevent macrosomia in euglycemic women). Blood pressure was measured at 10-18 weeks and 28 weeks of pregnancy. Mean arterial pressure was calculated as (diastolic blood pressure + 1 3 × [systolic blood pressure - diastolic blood pressure]). Diet quality was assessed using 3-day food diaries, and Alternative Healthy Eating Index for Pregnancy (AHEI-P) scores were generated, quantifying alignment of food intakes with dietary guidelines in first and early third trimesters. The cohort was divided based on AHEI-P tertiles to explore differences at an alpha significance value of <0.05. RESULTS: The mean age of the group was 32.21 ± 4.39 years with a median body mass index (BMI) of 28.13 (IQR 3.47) kg/m2. Mean arterial pressures in the first and third trimesters were 81.07 ± 9.00 mmHg and 82.33 ± 7.53 mmHg, respectively. Rates of elevated blood pressure (≥120/80 mmHg) were 22.33% in trimester 1 and 24.48% in early trimester 3. Mean AHEI-P scores in trimester 1 and early trimester 3 were 53.90 ± 10.43 and 54.05 ± 10.76, respectively. There was no correlation between AHEI-P score and blood pressure and no differences in blood pressure between AHEI-P tertiles at either timepoint (all P-values <0.05). A higher proportion of those with elevated early third trimester blood pressure had a BMI of ≥30 kg/m2 compared with those with normal blood pressure (40.31% vs 28.64%, P = 0.016). CONCLUSIONS: While diet remains an important factor in maternal health and wellbeing, we did not find a relationship between diet quality as measured by AHEI-P and blood pressure among pregnant women with BMI ≥25 kg/m2. High BMI remains a risk factor for hypertensive disorders of pregnancy.

Impact of previous pregnancy and BMI on cellular and serum immune activity from early to late pregnancy.

Immunological adaptions during pregnancy play a crucial role in healthy fetal development. Aberrant immune modifications however contribute to adverse pregnancy outcomes, which may be driven by maternal factors such as previous pregnancies and BMI. This secondary analysis of the MicrobeMom2 RCT investigates the changes to maternal inflammatory biomarkers derived from serum and stimulated peripheral blood mononuclear cells (PBMCs) during pregnancy, and the effects of previous pregnancies (parity) and BMI on maternal immune responses. Changes in immune and metabolic biomarkers from early (11-15 weeks' gestation) to late (28-32 weeks' gestation) pregnancy were compared using paired t-tests. Participants were then split by parity (nulliparous, parous) and BMI (BMI < 25, BMI > = 25), and the relationship between parity and BMI with immune biomarker levels was examined using independent t-tests, paired t-tests, ANCOVA, and linear regression. Equivalent non-parametric tests were used for skewed data. Recruited women (n = 72) were on average 31.17 (SD ± 4.53) years of age and 25.11 (SD ± 3.82) BMI (kg/m2). Of these, 51 (70.8%) had a previous term pregnancy. Throughout gestation, PBMC cytokines displayed contrasting trends to serum, with a dampening of immune responses noted in PBMCs, and enhanced production of cytokines observed in the serum. Significant decreases in PBMC derived TNF-α, IL-10 and IFN-γ were seen from early to late pregnancy. Serum C3, IL-17A, IL-6, TNF-α, CD163, GDF-15 and leptin increased throughout gestation. First pregnancy was associated with higher levels of leptin in late pregnancy, while parous women showed significant decreases in PBMC derived TNF-α, IL10, and IFN-γ with gestation. Differences in levels of C3, IL-17A, TNF-α, GDF-15 and leptin were observed across BMI groups. Overall, serum-derived cytokines exhibit contrasting levels to those derived from stimulated PBMCs. Maternal immune responses undergo significant changes from early to late pregnancy, which are influenced by parity and BMI. These differences aid our understanding as to why first-time mothers are at greater risk of placental disease such as pre-eclampsia and fetal growth restriction.

Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma.

The molecular, histopathological, genomic and transcriptomic characteristics of uveal melanoma (UM) have identified four molecular subgroups with different clinical outcomes. Despite the improvements in UM classification and biological pathology, current treatments do not reduce the occurrence of metastasis. The development of effective adjuvant and metastatic therapies for UM has been slow and extremely limited. Preclinical models that closely resemble the molecular and genetic UM subgroups are essential for translating molecular findings into improved clinical treatment. In this review, we provide a retrospective view of the existing preclinical models used to study UM, and give an overview of their strengths and limitations. We review targeted therapy clinical trial data to evaluate the gap in the translation of preclinical findings to human studies. Reflecting on the current high attrition rates of clinical trials for UM, preclinical models that effectively recapitulate the human in vivo situation and/or accurately reflect the subtype classifications would enhance the translational impact of experimental data and have crucial implications for the advancement of personalised medicine.