Non-linear and non-additive associations between the pregnancy metabolome and birthweight.

BACKGROUND: Birthweight is an indicator of fetal growth and environmental-related alterations of birthweight have been linked with multiple disorders and conditions progressing into adulthood. Although a few studies have assessed the association between birthweight and the totality of exogenous exposures and their downstream molecular responses in maternal urine and cord blood; no prior research has considered a) the maternal serum prenatal metabolome, which is enriched for hormones, and b) non-linear and synergistic associations among exposures. METHODS: We measured the maternal serum metabolome during pregnancy using an untargeted metabolomics approach and birthweight for gestational age (BWGA) z-score in 410 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. We leveraged a Bayesian factor analysis for interaction to select the most important metabolites associated with BWGA z-score and to evaluate their linear, non-linear and non-additive associations. We also assessed the primary biological functions of the identified proteins using the MetaboAnalyst, a centralized repository of curated functional information. We compared our findings with those of a traditional metabolite-wide association study (MWAS) in which metabolites are individually associated with BWGA z-score. RESULTS: Among 1110 metabolites, 46 showed evidence of U-shape associations with BWGA z-score. Most of the identified metabolites (85%) were lipids primarily enriched for pathways central to energy production, immune function, and androgen and estrogen metabolism, which are essential for pregnancy and parturition processes. Metabolites within the same class, i.e. steroids and phospholipids, showed synergistic relationships with each other. CONCLUSIONS: Our results support that the aspects of the maternal metabolome during pregnancy contribute linearly, non-linearly and synergistically to variation in newborn birthweight.

Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort.

BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms. METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information. RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 ß: -0.22 p = 0.008, BNGF ß: -0.43 p = 0.033, TRANCE ß: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (ß: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation. CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.

CD4+CD25highCD127low/-FoxP3 + Regulatory T-Cell Population in Acute Leukemias: A Review of the Literature.

Regulatory T-cells (Tregs) are a very important subtype of lymphocytes when it comes to self-control in the human immunological system. Tregs are decisive not only in the protection against destruction of own tissues by autoimmune immunocompetent cells but also in the immunological answer to developing cancers. On the other hand, Tregs could be responsible for the progression of acute and chronic leukemias. In our study, we review publications available in the PUMED database concerning acute leukemia, with a particular emphasis on child's leukemias. The percentage of regulatory T-lymphocytes in peripheral blood and bone marrow was elevated compared to those in healthy individuals and correlated with progressive disease. Regulatory T-cells taken from children diagnosed with leukemia showed a higher suppressive capability, which was confirmed by detecting elevated levels of secreted IL-10 and TGF-beta. The possibility of pharmacological intervention in the self-control of the immunological system is now under extensive investigation in many human cancers. Presumably, Treg cells could be a vital part of targeted therapies. Routine Treg determination could be used to assess the severity of disease and prognosis in children with acute lymphoblastic leukemia. This proposition results from the fact that in some studies, higher percentage of Treg cells in peripheral blood was demonstrated. However, observations confirming these facts are scarce; thus, extrapolating them to the population of children with hematological malignancies needs to be verified in additional studies.

Environmental factors driving the occurrence of the invasive cyanobacterium Sphaerospermopsis aphanizomenoides (Nostocales) in temperate lakes.

Cyanobacterial blooms are an increasing threat worldwide. Invasions of certain cyanobacterial species, mainly towards higher latitudes, add to this concern as they enrich the pool of potential bloom-formers in the invaded region. Among the numerous causes of this escalating process, climate warming is commonly considered the most crucial factor, but empirical studies of this issue are lacking. The aim of our study was to identify physical, chemical and biological factors related to the occurrence of an invasive cyanobacterium at the northern border of its putative current range, and thus enabling its expansion. This study focuses on the relatively little studied species Sphaerospermopsis aphanizomenoides (Nostocales, Cyanobacteria; synonyms: Aphanizomenon aphanizomenoides, Anabaena aphanizomenoides), which is predicted to become one of the main nuisance species of the future. Forty-nine freshwater lakes located between latitudes 51° and 55°N were examined for the presence of S. aphanizomenoides, and environmental factors that could drive its occurrence were studied simultaneously. To identify factors correlated with the presence of the species, principal component analysis (PCA) and Mann-Whitney U test were performed. Water temperature did not differentiate lakes with or without S. aphanizomenoides, however the study was conducted in a particularly hot summer. Total phosphorus concentration was identified as the primary driving factor of the occurrence of S. aphanizomenoides. The species grew in poor light conditions and high phytoplankton biomass, mainly in shallow lakes. As shown by detrended correspondence analysis (DCA), the species accompanied shade tolerant, eutrophic species of native and invasive cyanobacteria as well as eukaryotic algae. Our results indicate that eutrophication may be the primary factor enabling the increasing occurrence of S. aphanizomenoides in temperate environments, and suggest that this process may stimulate expansion of cyanobacterial species towards high latitudes.

CD4+CD25highCD127low/-FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report.

CD4+CD25highCD127low/-FoxP3+ regulatory T cells (Tregs) are currently under extensive investigation in childhood acute lymphoblastic leukemia (ALL) and in other human cancers. Usually, Treg cells maintain the immune cell homeostasis. This small subset of T cells has been, in fact, considered to be involved in the pathogenesis of autoimmune diseases and progression of acute and chronic leukemias. However, whether Treg dysregulation in CLL and ALL plays a key role or it rather represents a simple epiphenomenon is still a matter of debate. Treg cells have been proposed as a prognostic indicator of the clinical course of the disease and might also be used for targeted immune therapy. Our study revealed statistically higher percentage of Treg cells in the bone marrow than in peripheral blood in the group of 42 children with acute lymphoblastic leukemia. By analyzing Treg subpopulations, it was shown that only memory Tregs in contact with leukemic antigens showed statistically significant differences. We noticed a low negative correlation between Treg cells in the bone marrow and the percentage of blasts (R = -0.36) as well as a moderate correlation between Treg cells in the bone marrow and Hb level (R = +0.41) in peripheral blood before therapy. The number of peripheral blood blasts on day 8th correlates negatively (R = -0.36) with Tregs. Furthermore, statistical analysis revealed low negative correlation between the number of Tregs in the bone marrow and the minimal residual disease measured on day 15th, the percentage of blasts in the bone marrow and leukocytosis after 15 days of chemotherapy. These results indicate the influence of Tregs on the final therapeutic effect.

Decrease of Airway Allergies After Lung Transplantation Is Associated With Reduced Basophils and Eosinophils.

BACKGROUND: Allergies are hypersensitive reactions of the immune system on antigen exposure similar to immune reactions after transplantation (Tx). Their activity can change after Tx. The lung as a transplantable organ is challenged two-fold, by antigens from the blood and the air environment. Herein we analyzed if airway allergies change after lung Tx. METHODS: We systematically reviewed patients' airway allergies before and after lung Tx between 1992 and 2014. The course of lymphocytes, thrombocytes, and leukocytes, among them neutrophils, eosinophils, and basophils, was analyzed in patients in whom airway allergies have changed and in whom they did not change. RESULTS: From 362 lung transplanted patients, 44 patients had suffered from allergies before Tx (12.2%). In 20 of these patients (45.5%), airway allergies disappeared completely within 1 year after lung Tx and were persistently absent thereafter. In these patients, basophils and eosinophils decreased significantly (P < .0012); in contrast, cells did not decrease in patients whose allergies did not disappear. Leukocytes overall, and in particular, neutrophils, decreased significantly in patients whose allergy disappeared (P < .014, P < .012, respectively). CONCLUSIONS: Airway allergies disappeared in almost half of cases after lung Tx. Along with this reduction, basophils and eosinophils decreased as potentially responsible cells for this phenomenon. These findings may stimulate intensified research on basophils and eosinophils as major drivers of airway allergies.

The immunophenotypes of blast cells in B-cell precursor acute lymphoblastic leukemia: how different are they from their normal counterparts?

BACKGROUND: Currently, there are three major maturational stages of CD19 antigen expressing B-cell precursors (hematogones). In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the malignant counterpart of hematogones, the leukemic blasts share common phenotypic features. The aim of the study was to enumerate the actual differences between the leukemic blasts in the CD10+ and CD10- subgroups of BCP-ALL and hematogones by assessing the expression of the antigens: TdT, CD34, CD45, CD10, CD38, CD20 and CD22. METHODS: To enable quantitative assessment of antigen expression on the different cell types, an objective scale of antigen expression was developed, the basis of which was direct fluorescence measurement using multicolor flow cytometry. RESULTS: All cases of CD10+ BCP-ALL clustered with type 1 hematogones. Among CD10-- BCP-ALL subgroup, 54.5%, 27.3% and 18.2% of cases clustered with type 1, 2 and 3 hematogones, respectively. In contrast to the CD10- blasts, the CD10+ blasts exhibited significantly higher levels of TdT, CD22, CD34 and CD20 expression. Conversely, CD10- blasts showed significantly higher expression of CD45 than CD10+ blasts, and a higher rate of CD45 antigen overexpression than CD10+ blasts (54.5% vs. 14.9% of cases, respectively). CONCLUSIONS: Multiparameter flow cytometry combined with the use of absolute antigen expression scale based on direct fluorescence measurement, has enabled a clear distinction between blasts in BCP-ALL cases and their normal counterparts. This novel and previously undescribed method has allowed the comparative analysis of antigen expression between leukemic blasts and different types of their normal counterparts.

Prenatal exposure to allergen, DNA methylation, and allergy in grandoffspring mice.

BACKGROUND: Prenatal allergen exposure has been linked to both induction and protection of allergic sensitization in offspring. We hypothesized that prenatal exposure of mice (F0) to Aspergillus fumigatus (A. fumigatus) would be associated with decreased immunoglobulin (Ig) E and airway eosinophilia and alterations in CpG methylation of T-helper genes in third-generation mice (F2). METHODS: Female BALB/c mice were sensitized to A. fumigatus (62.5, 125, 1250 µg, or saline) and re-exposed to the same dose on days 7 and 14 (early) or days 12 and 17 (late) gestation. Grandoffspring were treated with A. fumigatus (62.5 µg) at 9 weeks. IgE, IgG(1) , and IgG(2a) levels and cell counts from bronchoalveolar lavage fluid were determined. Lung DNA was pyrosequenced at multiple sites in the interferon (IFN)-γ and interleukin (IL)-4 promoters. RESULTS: Grandoffspring of mothers dosed with 1250 µg early during pregnancy developed increased airway eosinophilia (P < 0.05). Grandoffspring of mothers dosed late in pregnancy developed lower IgE (P < 0.05) and airway eosinophilia (P < 0.05). Grandoffspring of mothers dosed early had lower methylation at IL-4 CpG(-408) and CpG(-393) compared to late dosed mice (P < 0.005 across all doses). Few correlations were found between methylation levels and airway eosinophilia and IgE. CONCLUSION: Prenatal exposure to A. fumigatus late during pregnancy, but not early, was associated with lower IgE and airway eosinophilia in grandoffspring. Prenatal exposure to A. fumigatus was associated with changes in CpG methylation in the IFN-γ and IL-4 promoters that did not correlate consistently with indicators of allergic sensitization.

A correlation of microvascular density and proliferative activity to clinical and histological characteristics in neuroblastoma.

Seventy-four neuroblastoma patients were analyzed according to the clinical data including age, stage, bone metastases, primary tumor localization, tumor diameter, LDH, and serum ferritin. Histological examination of tumor specimens comprised calculation of proliferative index (PI) on slides stained with anti Ki-67 antibody and assessment of microvascular density (MVD) on anti-CD34 stained sections. Wide range of PI (1.5-79; median 37.8%) and MVD (41-385; median 172/mm2) values was observed. Significant relationship between higher PI and tumor diameter more than 5 cm (40.3 vs 37.2%) was found. Lower PI was found more frequently in stroma-rich tumors. Significantly higher median MVD was found in infant tumors and in smaller tumors <5 cm. Tendency to inverse relationship between PI and MVD was observed. The high values of both PI and MVD were found in some aggressive tumors in patients >1-year old. We evaluated the new parameter: proliferative-vascular index (PVI) as PVI=PIxMVD which ranged from 213-18333. Among eleven patients >1 year old, with PVI >7000, seven (64%) had a poor outcome within the mean period of 22 months. Our results suggest that the simultaneous estimation of proliferative activity and vascularity of neuroblastomas could be studied as a prognostic indicator. Further investigations are needed to confirm this finding.

[Acute leukemia in children with Down syndrome: analysis of cases]. / Ostra bialaczka u dzieci z zespolem Downa--analiza przypadków wlasnych.

An analysis of clinical and laboratory parameters and the results of treatment of 14 children with Down Syndrome and acute leukaemia was performed. The children were treated between 1986-1997. Their age ranged from 1 day to 13 years (average 5.5). There were 9 girls and 5 boys. Four of them had congenital heart disease. ALL was observed in 10, AML in 3 and TAM (Transient Abnormal Myelopoesis) in 1. Half of the children with ALL was classified as L1 according to FAB with the majority of common phenotypes and M6 in ANLL group. Remission was achieved in all ALL patients, six of them are still free of symptoms, the remaining four died of brain haemorrhage as a consequence of myelosuppression. Only 1 of 3 children with ANLL achieved remission. The child died of cardiac arrest after induction phase of BFM 95 programme (ADE). The 2 remaining children with ANLL also died of circulation failure before initiation of chemotherapy. The children had complicated cyanotic heart disease. The neonate with TAM is in clinical and hematological remission. In conclusion all children with ALL achieved hematological remission but tolerance of treatment was a problem. The majority of patients had diminished bone marrow reserve. Mortality was frequently related to circulatory failure in children with associated heart defects. It seems necessary to discuss the modification of accepted programmes for leukemia for the treatment of children with Down Syndrome.