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The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

Microbiota composition is progressively being connected to different physiologic effects, such as glucose metabolism, and also to different pathologies, such as gestational diabetes mellitus (GDM). GDM is a public health concern that affects an important percentage of pregnancies and is correlated with many adverse maternal and neonatal outcomes. An increasing number of studies are showing some connections between specific microbial composition of the gut microbiota and development of GDM and adverse outcomes in mothers and neonates. The aim of this review is to analyze the available data on microbial changes that characterize healthy pregnancies and pregnancies complicated by GDM and to understand the correlation of these changes with adverse maternal outcomes; this review will also discuss the consequences of these maternal gut microbiome alterations on neonatal microbiota composition and neonatal long-term outcomes.

Pre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women. peripheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry. circulating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01). Aberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.

Background Platinum-resistant high-grade serous ovarian cancer (HGSOC) is a fatal disease. The main goal of current study is to develop new strategies to predict platinum resistance, moving towards personalized therapy. Currently, there are no validated biomarkers able to predict at diagnosis platinum resistance. Circulating tumor-derived extracellular vesicles (EVs) represent a liquid biopsy of the tumor of origin and reflect its biological profile. EpCAM-expressing EVs are largely used biomarkers of epithelial cancers in translational research. Aim of this study was to quantify, by nano-flow cytometry, circulating EpCAM+ EVs in patients with histologically confirmed diagnosis of HGSOC FIGO stage III/IV, before and after intravenous administration of the first dose of chemotherapy with paclitaxel and carboplatin, and correlate EVs levels to platinum-sensitivity. As comparison, leukocyte-derived EVs were also assessed using the pan-leukocyte marker CD45. Results Patients with platinum-sensitive HGSOC showed significantly lower pre-chemotherapy circulating levels of both EpCAM+ and CD45+ EVs compared to platinum-resistant cases ( p< 0.01). Platinum-sensitive patients displayed significantly higher levels of circulating EpCAM+ and CD45+ EVs 21 days post administration of the first dose of chemotherapy compared to pre-treatment levels ( p< 0.05 and p< 0.01, respectively). Platinum-resistant and platinum-refractory patients showed significantly higher EpCAM + CD45 + EVs levels than platinum-sensitive patients ( p< 0.01, p< 0.05, respectively). Conclusions Tumor-derived EVs are valuable candidate biomarkers for early prediction of platinum resistance and need to be investigated in larger prospective clinical studies.

The aim of our study was to identify characteristics associated with postpartum hemorrhage (PPH defined as blood loss >1000 mL) in twin pregnancies in order to select patients at higher risk to be treated. This retrospective study includes multiple pregnancies between 2015 and 2020. The possible association between pregnancy characteristics and the primary endpoint (occurrence of PPH) was conducted using chi-square or Fisher exact test and Wilcoxon test. Then, univariate logistic models were performed considering as outcome the PPH, and the odds ratios with 95% CI were estimated. Finally, a multivariate logistic model was implemented, including all significant covariates. Seven hundred seven twin pregnancies giving birth beyond 32 weeks were included and of those, 120 (16.97%) had a PPH. The univariate analysis showed that factors significantly associated with PPH were: Preterm delivery, episiotomy, neonatal weight, and mode of delivery. The multivariate analysis showed that the most important factors were episiotomy and neonatal weight. The results show that the performance of episiotomy and the neonatal weight are the factors that most impact the risk of PPH in twin pregnancies. The correct identification of factors associated with PPH in twins could ideally allow to modify the clinical management and positively affect the rate of complications.

PurposeVaginal birth after caesarean (VBAC) is an option to avoid major abdominal surgery and many consequences related to repeated caesarean delivery. In the last years, many efforts have been made to increase the number of patients attempting trial of labour after caesarean (TOLAC). The aim of our study was to identify the most important factors associated with the success of VBAC.MethodsA retrospective study was conducted in two Italian referral centres. Subjects included were singleton and morphologically normal pregnancy with previous C-section. Subjects with an inter-pregnancy interval shorter than 18 months, a large for gestational age baby, a pregnancy complicated with gestational diabetes and a previous unclassified uterine scar were excluded. The characteristics of the subjects were compared and a logistic regression was performed to evaluate variables associated with successful VBAC.ResultsOf the 300 patients included, 224 (74.7%) achieved VBAC while 76 (25.3%) underwent C-section after failed TOLAC. The number of previous C-sections was not significantly associated with the success of TOLAC. Factors positively associated with achievement of VBAC were previous vaginal delivery (OR of 6.88 for one and 9.68 for more than one) and oxytocin implementation (OR 3.32). No maternal and neonatal adverse events occurred.ConclusionOur results show that attempting VBAC is a feasible option in referral centres after adequate evaluation of the potential factors affecting the probability of success. A careful record of obstetrical history and management of labour can provide clinicians useful information to counsel women before and during labour.

Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4 and CD8 T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer. Intragenic DNA methylation, dependent on Dnmt3b, protects the gene body from spurious entry of RNA Polymerase II and aberrant transcription initiation events. The role of intragenic DNA methylation The DNA methylation of CpG sequences at gene promoters is associated with the silencing of gene expression, but the function of DNA methylation along the gene body has been less clear. Here, Salvatore Oliviero and colleagues show that this intragenic DNA methylation, dependent on the enzyme Dnmt3b, protects the gene body from the spurious entry of RNA polymerase II and the aberrant initiation of transcription. Elongating RNA polymerase triggers crosstalk between DNA methylation and histone H3 K36 methylation to ensure the fidelity of transcription.

This work is focused on performing a quantitative assessment of the environmental impacts associated with an organic synthesis reaction, optimized using an experimental design approach. A nucleophilic substitution reaction was selected, employing vanillin as the substrate, a phenolic compound widely used in the food industry and of pharmaceutical interest, considering its antioxidant and antitumoral potential. To carry out the reaction, three different solvents have been chosen, namely acetonitrile (ACN), acetone (Ace), and dimethylformamide (DMF). The syntheses were planned with the aid of a multivariate experimental design to estimate the best reaction conditions, which simultaneously allow a high product yield and a reduced environmental impact as computed by Life Cycle Assessment (LCA) methodology. The experimental results highlighted that the reactions carried out in DMF resulted in higher yields with respect to ACN and Ace; these reactions were also the ones with lower environmental impacts. The multilinear regression models allowed us to identify the optimal experimental conditions able to guarantee the highest reaction yields and lowest environmental impacts for the studied reaction. The identified optimal experimental conditions were also validated by experimentally conducting the reaction in those conditions, which indeed led to the highest yield (i.e., 93%) and the lowest environmental impacts among the performed experiments. This work proposes, for the first time, an integrated approach of DoE and LCA applied to an organic reaction with the aim of considering both conventional metrics, such as reaction yield, and unconventional ones, such as environmental impacts, during its lab-scale optimization.

Long-term data series (1971–2015) of physical and biogeochemical parameters were analyzed in order to assess trends and variability of oceanographic conditions in the northern Adriatic Sea (NAS), a mid-latitude shallow continental shelf strongly impacted by river discharges, human activities and climate changes. Interpolation maps and statistical models were applied to investigate seasonal and spatial variability, as well as decadal trends of temperature, salinity, chlorophyll-a and nutrients. This analysis shows that sea surface temperature increased by +0.36% year−1 over four decades. Annual mean flow of the Po River markedly changed due to the occurrence of periods of persistent drought, whereas the frequency of flow rates higher than 3000 m3 s−1 decreased between 2006 and 2015. Moreover, we observed a long-term decrease in surface phosphate concentrations in Po River water (−1.34% year−1) and in seawater (in summer −2.56% year−1) coupled, however, to a significant increase in nitrate concentration in seawater (+3.80% year−1) in almost all seasons. These changes indicate that the nutrient concentrations in the NAS have been largely modulated, in the last forty years, by the evolution of environmental management practices and of the runoff. This implies that further alteration of the marine environment must be expected as a consequence of the climate changes.