A prospective study of angiogenic markers and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.

PURPOSE: Pro-angiogenic factors are positively associated with breast tumor staging and poorer prognosis, but their role in the etiology of breast cancer has not been assessed. METHODS: We measured serum levels of the pro-angiogenic vascular endothelial growth factor A (VEGF), and placental growth factor (PlGF) and anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) in 352 incident breast cancer cases [mean age at diagnosis 67 (range 55-83)] and 352 non-cases in the prostate, lung, colorectal, and ovarian screening trial (women enrolled 1993-2001, followed through 2005) matched on age and date of enrollment. Cases were followed on average 4.2 years from blood draw to diagnosis, range 3.9-12.8 years; 53 % were estrogen receptor positive/progesterone receptor positive (ER+/PR+), and 13 % were ER-/PR-. Quartile-specific hazard ratios (HR) and 95 % confidence intervals (CI) were estimated using weighted Cox proportional hazards regression models adjusted for known breast cancer risk factors. An ordinal variable for the angiogenic markers was used to test for trend in the HR. RESULTS: Comparing the highest to lowest quartile, multivariable HR were 0.90 for VEGF (95 % CI 0.33-2.43, p trend = 0.88), 1.38 for sFlt-1 (95 % CI 0.63-3.04, p trend = 0.63), and 0.62 for PlGF (95 % CI 0.19-2.00, p trend = 0.73). Risk patterns were not altered when all angiogenic markers were included in the model simultaneously, or by restricting analyses to invasive breast cancers, to cases diagnosed two or more years after blood collection or to ER+ tumors. CONCLUSIONS: There was no evidence of an increased breast cancer risk associated with circulating levels of pro-angiogenic markers VEGF and PlGF or a reduced risk with circulating levels of anti-angiogenic marker sFlt-1.

A longitudinal study of postpartum depressive symptoms: multilevel growth curve analyses of emotion regulation strategies, breastfeeding self-efficacy, and social support.

Postpartum depression is a serious health issue affecting as many as 10-15 % of postpartum women. This longitudinal study aimed to explore how psychological variables such as cognitive emotion regulation strategies, breastfeeding self-efficacy (BSE), and dimensions of social support predicted postpartum depressive symptoms (Edinburgh Postnatal Depression Scale). The data were collected with web-based survey questionnaires between May 2008 and December 2009, in a sample of 737 new mothers. The same questionnaire was surveyed at three points in time: 6 weeks, 3 months, and 6 months postpartum. Data were analyzed using multilevel modeling (level 1, time points; level 2, person). Results showed that BSE, certain cognitive emotion regulation strategies, perceived available support, and need for support predicted the rate of postpartum depressive symptoms. Only breastfeeding self-efficacy predicted change in postpartum depressive symptoms. This study illustrates the importance of psychological variables with regard to postpartum depressive symptoms. Implications for preventative efforts are discussed.

Levels of blood pressure, cardiovascular biomarkers and their correlations in women with previous pre-eclamptic pregnancy within 7 years postpartum: a cross-sectional study in Thailand.

OBJECTIVE: To assess the levels of blood pressure, cardiovascular biomarkers and their correlations measured within 7 years postpartum in women with previous pre-eclamptic pregnancies compared with women with previous normotensive pregnancies. DESIGN: Cross-sectional study. SETTING: Two tertiary hospitals in the southern region of Thailand. PARTICIPANTS: Women with pre-eclamptic and normotensive pregnancies in the past 7 years were enrolled from 1 October 2019 to 30 April 2021. Eligible women were interviewed, examined for body mass index (BMI) and blood pressure, and donated morning spot urine and blood samples. PRIMARY OUTCOME MEASURES: Serum high-sensitivity C reactive protein, creatinine, fasting blood glucose (FBS), glycated haemoglobin (HbA1c), low-density lipoprotein (LDL) cholesterol, urine microalbumin to creatinine ratio (UACR) and sodium were measured. Group differences in biomarkers were tested using unpaired t-test, Wilcoxon rank-sum test or χ2 test. The levels of blood pressure and biomarkers between the two study groups at <2 years, 2-4 years and >4 years were also compared. The correlations between blood pressure and biomarkers were analysed using Pearson's correlation and partial correlation methods. RESULTS: From 206 women included in the analysis, 88 had pre-eclamptic pregnancies and 118 had normotensive pregnancies. Compared with women with previous normotensive pregnancies, women with previous pre-eclamptic pregnancies had significantly increased rates of hypertension (31.8% vs 7.6%, p<0.001) and obesity (55.7% vs 40.7%, p=0.038), as well as higher serum levels of FBS (p<0.001), HbA1c (p<0.001), LDL cholesterol (p=0.03), creatinine (p<0.001) and UACR (p<0.001). Correlation coefficients of BMI, serum creatinine and UACR with blood pressure ranged from 0.27 to 0.31. CONCLUSION: The risk of hypertension after a pre-eclamptic pregnancy increased. Blood pressure measurement combined with BMI, serum creatinine and UACR screening at least once during 7 years postpartum is suggested for early detection of cardiovascular risk.

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis.

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

PP013. Single nucleotide polymorphisms of the maternal cystathionine-b-synthase gene are associated with preeclampsia (PE).

INTRODUCTION: Cystathionine-b-synthase (CBS) produces the vasodilatory and anti-inflammatory hydrogen sulfide (H2S) by conversion of homocysteine (Hcy). H2S is involved in placental vascular tone regulation. Previously, we showed that woman with PE have hyperhomocysteinemia and decreased placental CBS gene expression. OBJECTIVES: Aberrant CBS gene expression may play a role in hyperhomocysteinemia and decreased H2S and could be involved in pathogenesis of PE. We studied whether the presence of CBS single nucleotide polymorphisms (SNPs) is associated with the development of PE. METHODS: Six CBS SNPs (rs12329764, rs2851391, rs234713, rs234706, rs1789953, rs11203172) were genotyped in 99 controls, 60 severe, and 39 mild PE cases. Severe and mild PE cases were additionally subdivided into late- (>34 weeks) and early-onset (<34 weeks) PE. The association of the alleles with development PE was tested with logistic regression. RESULTS: Two of the six SNPs are associated with PE. The minor allele for rs11203172 reduces the risk for developing severe PE (OR[95% CI]=0.54[0.21-0.94], p=0.023). The minor allele for rs234706, which is associated with low Hcy, increased the risk to develop mild, late-onset PE (2.10[1.15-3.85], p=0.016). CONCLUSION: SNPs in the CBS gene are associated with risk of developing PE. Within the CBS gene, SNPs associated with both a decreased and an increased risk to develop PE were found. Altered effectiveness of CBS may affect PE through decreased H2S production or Hcy accumulation.

Cancer risk with folic acid supplements: a systematic review and meta-analysis.

Objective To explore if there is an increased cancer risk associated with folic acid supplements given orally. Design Systematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included. Data sources Cochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals. Results From 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta-analysis of the 10 RCTs reporting overall cancer incidence (N=38 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality. Conclusions A meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk.

SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer.

INTRODUCTION: The MDM2 promoter polymorphism (SNP309T > G) extends a binding site for the transcription factor Sp1 and has been linked to elevated cancer risk and/or young age at cancer diagnosis, especially in females. Recently, we reported an adjacent polymorphism (SNP285G > C). SNP285C antagonises the effect of SNP309G by reducing Sp1 binding and lowers the risk of breast and ovarian cancer. METHODS: We assessed the potential gender specificity in the effect of this polymorphism. We performed in silico predictions of transcription factor binding sites in the MDM2 promoter and analysed MDM2 SNP285 and SNP309 status in two independent cohorts of endometrial (n = 438 and 472) and 666 prostatic cancer patients, and compared to 3.140 healthy controls. RESULTS: We identified three oestrogen-receptor binding elements (EREs) within the MDM2 intronic promoter, one of which overlapping the Sp1 binding-site harbouring SNP285. The SNP285C/309G haplotype was associated with a reduced Odds Ratio (OR) for endometrial cancer (OR1: 0.55; Confidence Interval (CI) 0.32-0.97; OR2: 0.65; CI 0.40-1.08, especially for ER+ tumours; OR: 0.48; CI 0.28-0.87) but not for prostatic cancer among SNP309TG heterozygotes. SNP309G (SNP309TG or SNP309GG genotype) was associated with a moderately increased risk of endometrial cancer (OR: 1.17; CI 1.00-1.37) compared to SNP309TT homozygotes. Removing individuals harbouring the SNP309G-counteracting SNP285C polymorphism from the analysis strengthened this association (OR: 1.20; CI 1.02-1.41). CONCLUSION: The finding of an ERE overlapping with the Sp1-binding site affected by SNP285, taken together with the significant impact of SNP285 on the risk of breast, ovarian and now endometrial cancer but not prostatic cancer, suggests a gender specific effect of SNP285C on cancer risk.