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Stavros Sifakis - Top 30 Publications

Placental expression of PAPPA, PAPPA-2 and PLAC-1 in pregnacies is associated with FGR.

Fetal growth restriction (FGR) is a gynecological disorder of varying etiology. In the present study, an expression analysis of pregnancy-associated plasma protein A (PAPPA), pregnancy-associated plasma protein A2 (PAPPA2) and placenta-specific-1 (PLAC-1) was conducted in pregnancies with FGR and control pregnancies. Placental tissues were collected from pregnancies with FGR (n=16) and control pregnancies (n=16) and the expression of the genes of interest was examined by qPCR. The mean expression levels of PAPPA and PAPPA2 were significantly lower (P<0.001) in placental tissues from FGR pregnancies compared with tissues from healthy subjects, whereas the opposite pattern was observed for PLAC-1 (P<0.001). PAPPA and PLAC-1 expression in FGR and control subjects correlated with birth weight (P<0.001). The findings suggest a possible pathophysiological link between the development of FGR and the expression of PAPPA, PAPPA2 and PLAC-1.

Endocrine Disruptors Leading to Obesity and Related Diseases.

The review aims to comprehensively present the impact of exposure to endocrine disruptors (EDs) in relation to the clinical manifestation of obesity and related diseases, including diabetes mellitus, metabolic syndrome, cardiovascular diseases, carcinogenesis and infertility. EDs are strong participants in the obesity epidemic scenery by interfering with cellular morphological and biochemical processes; by inducing inflammatory responses; and by presenting transcriptional and oncogenic activity. Obesity and lipotoxicity enhancement occur through reprogramming and/or remodeling of germline epigenome by exposure to EDs. Specific population groups are vulnerable to ED exposure due to current dietary and environmental conditions. Obesity, morbidity and carcinogenicity induced by ED exposure are an evolving reality. Therefore, a new collective strategic approach is deemed essential, for the reappraisal of current global conditions pertaining to energy management.

Partial monosomy 8p and trisomy 16q in two children with developmental delay detected by array comparative genomic hybridization.

Two cases of liveborn unrelated children with developmental delay and overlapping unbalanced translocations der(8)t(8;16)(p23.2;q23.3) and der (8)t(8;16)(p23.1;q23.1), leading to partial monosomy 8p and partial trisomy 16q, are reported in the present study. The first patient was a 10‑year‑old boy with mild developmental delay and minor congenital anomalies (borderline microcephaly, clinodactyly, hypertelorism, epicanthus, mild systolic murmur and kidney reflux). The second patient was a 3 year‑old girl with developmental delay, gross motor milestone delay and dysmorphic features. Array‑comparative genomic hybridization analysis revealed that partial chromosome 8p monosomy extended from 8p23.2 to 8pter (4.8 Mb) in Patient 1 and from 8p23.1 to 8pter (9.5 Mb) in Patient 2, and partial chromosome 16 trisomy extended from 16q23.3 to 16qter (5.6 Mb) in Patient 1 and from 16q23.1 to 16qter (11.7 Mb) in Patient 2. The mechanism of appearance of the rearrangement in association with the genes involved and the architecture of the region is discussed.

Human placental growth hormone in normal and abnormal fetal growth.

Human placental growth hormone (PGH), encoded by the growth hormone (GH) variant gene on chromosome 17, is expressed in the syncytiotrophoblast and extravillous cytotrophoblast layers of the human placenta. Its maternal serum levels increase throughout pregnancy, and gradually replaces the pulsatile secreted pituitary GH. PGH is also detectable in cord blood and in the amniotic fluid. This placental-origin hormone stimulates glyconeogenesis, lipolysis and anabolism in maternal organs, and influences fetal growth, placental development and maternal adaptation to pregnancy. The majority of these actions are performed indirectly by regulating maternal insulin-like growth factor-I levels, while the extravillous trophoblast involvement indicates a direct effect on placental development, as it stimulates trophoblast invasiveness and function via a potential combination of autocrine and paracrine mechanisms. The current review focuses on the role of PGH in fetal growth. In addition, the association of PGH alterations in maternal circulation and placental expression in pregnancy complications associated with abnormal fetal growth is briefly reviewed.

Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.

Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.

Plasma biomarkers for the identification of women at risk for early-onset preeclampsia.

To identify potential biomarkers in the 1st trimester of pregnancy for the identification of women destined to develop early onset preeclampsia (EOPE).

A global assessment of phthalates burden and related links to health effects.

Phthalates are ubiquitous environmental contaminants which are used in industry as plasticizers and additives in cosmetics. They are classified as Endocrine Disrupting Chemicals (EDCs) which impair the human endocrine system inducing fertility problems, respiratory diseases, childhood obesity and neuropsychological disorders. The aim of this review is to summarize the current state of knowledge on the toxicity that phthalates pose in humans based on human biomonitoring studies conducted over the last decade. Except for conventional biological matrices (such as urine and serum), amniotic fluid, human milk, semen, saliva, sweat, meconium and human hair are also employed for the estimation of exposure and distribution of pollutants in the human body, although data are not enough yet. Children are highly exposed to phthalates relative to adults and in most studies children's daily intake surpasses the maximum reference dose (RfD) set from US Environmental Protection Agency (US EPA). However, the global trend is that human exposure to phthalates is decreasing annually as a result of the strict regulations applied to phthalates.

DNA methylation in endometriosis (Review).

Endometriosis is defined by the presence and growth of functional endometrial tissue, outside the uterine cavity, primarily in the ovaries, pelvic peritoneum and rectovaginal septum. Although it is a benign disease, it presents with malignant characteristics, such as invasion to surrounding tissues, metastasis to distant locations and recurrence following treatment. Accumulating evidence suggests that various epigenetic aberrations may play an essential role in the pathogenesis of endometriosis. Aberrant DNA methylation represents a possible mechanism repsonsible for this disease, linking gene expression alterations observed in endometriosis with hormonal and environmental factors. Several lines of evidence indicate that endometriosis may partially be due to selective epigenetic deregulations influenced by extrinsic factors. Previous studies have shed light into the epigenetic component of endometriosis, reporting variations in the epigenetic patterns of genes known to be involved in the aberrant hormonal, immunologic and inflammatory status of endometriosis. Although recent studies, utilizing advanced molecular techniques, have allowed us to further elucidate the possible association of DNA methylation with altered gene expression, whether these molecular changes represent the cause or merely the consequence of the disease is a question which remains to be answered. This review provides an overview of the current literature on the role of DNA methylation in the pathophysiology and malignant evolution of endometriosis. We also provide insight into the mechanisms through which DNA methylation-modifying agents may be the next step in the research of the pharmaceutical treatment of endometriosis.

Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male.

Interstitial deletions of the long arm of chromosome 11 are rare, and they could be assumed as non-recurrent chromosomal rearrangements due to high variability of the size and the breakpoints of the deleted region. The exact region of the deletion was difficult to be determined before the use of molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH). Here, a 13-year old boy with severe learning difficulties, mental retardation and mild heart defects is described. Conventional G-band karyotyping was performed and it is found that the patient is a carrier of a de novo interstitial deletion on the long arm of chromosome 11, involving 11q14 and 11q22 breakpoints. Further investigation, using aCGH, specified the deleted region to 11q14.2-11q22.1. There was a difficulty in correlating the genotype with the phenotype of the patient due to lack of similar cases in literature. More studies should be done in order to understand the genetic background that underlies the phenotypic differences observed in similar cases.

Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives.

Diabetes mellitus, the prevalence of which has increased dramatically worldwide, may put patients at a higher risk of cancer. The aim of our study is the clarification of the possible mechanisms linking diabetes mellitus and gynecological cancer and their epidemiological relationship.

Downregulation of notch signaling pathway in late preterm and term placentas from pregnancies complicated by preeclampsia.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3-5% of all pregnancies. The Notch signaling pathway plays an important role during placental development, activating several target genes. Defects in the Notch pathway have adverse effect on placentation. The aim of this study was to investigate the expression of receptors NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tissue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2 (NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p = 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical analysis revealed several significant associations: of NOTCH3 mRNA expression with smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p = 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregulation is associated with PE. Further studies are required in order to determine the role of these molecules in PE pathogenesis and to evaluate their potential use for the early detection and treatment of PE.

Awareness of prenatal screening for fetal aneuploidy among pregnant women in Greece.

To estimate the level of awareness of prenatal screening (PS) and explore the underlying demographic, lifestyle and medical history parameters of Greek and non-Greek pregnant women undergoing prenatal diagnosis.

Cell-free fetal DNA and pregnancy-related complications (review).

Cell‑free fetal DNA (cff‑DNA) is a novel promising biomarker that has been applied in various aspects of obstetrical research, notably in prenatal diagnosis and complicated pregnancies. It is easily detected by semi‑quantitative PCR for the SRY target gene. It is well recognized that the levels of circulating cff‑DNA play a role in various complications of pregnancy. In this review, we explore the implications of the detection of cff‑DNA in a range of pregnancy-related complications, such as preeclampsia, intrauterine growth restriction (IUGR), preterm labor, placenta previa and hyperemesis gravidarum. cff‑DNA is released due to apoptotic mechanisms occurring on trophoblastic cells, although recent in vivo studies support the existence of additional mechanisms. The increase in the levels of cff‑DNA can be used to predict pregnancy-related complications and has great value in the field of prenatal diagnosis and in common pregnancy-related complications, as it precedes the clinical symptoms of the disease. Gestational age is a factor that determines the elevation in cff‑DNA levels in response to pathological conditions. In conclusion, the detection of cff‑DNA levels has a number of valuable applications in prenatal screening; however, the detection of cff‑DNA levels has not yet been applied in clinical practice for the diagnosis of pregnancy-related disorders. Thus, studies are focusing on unraveling the etiology of alterations in its levels under pathological conditions during pregnancy, in order to determine the potential predictive and diagnostic applications of this biomarker.

Expression profile of CYP1A1 and CYP1B1 enzymes in endometrial tumors.

The cytochrome P450 CYP1A1 and CYP1B1 enzymes are phase I extrahepatic enzymes involved in the activation of pro-carcinogenic compounds to carcinogenic metabolites. Although differential overexpression of CYP1A1 and CYP1B1 has been documented at the messenger RNA (mRNA) and protein level, studies that have examined CYP1 expression by enzyme activity assays are limited. In the current study, the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of endometrial origin by quantitative reverse transcriptase PCR (qRT-PCR), Western blotting, and enzyme activity assays. The data revealed that approximately 36 % (5/14) and 43 % (6/14) of the endometrial tumors overexpressed CYP1A1 and CYP1B1 mRNA, whereas in 57 % of the endometrial tumors, CYP1 mRNA levels were downregulated. The mean mRNA levels of CYP1B1 and CYP1A1 in endometrial tumors did not show a significant difference compared to normal tissues (p > 0.05). Western blotting confirmed the qRT-PCR results and CYP1A1 and CYP1B1 proteins were shown to be downregulated in 7/14 (50 %) of the tumors and overexpressed in 4/14 (29 %) of the tumors. As regards to enzyme activity, 21 % (3/14) of the endometrial samples revealed elevated CYP1 activity levels across the tumor counterparts. Overall, the data suggest a putative downregulation of CYP1A1 and CYP1B1 expression in endometrial tumors, whereas overexpression of active CYP1 enzymes in 21 % of the tumors highlights the potential use of the latter enzymes as chemotherapeutic targets in endometrial cancer.

Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review).

The insulin-like growth factors (IGF)-I and -II have a predominant role in fetal growth and development. IGFs are involved in the proliferation, differentiation and apoptosis of fetal cells in vitro and the IGF serum concentration has been shown to be closely correlated with fetal growth and length. IGF transcripts and peptides have been detected in almost every fetal tissue from as early in development as pre‑implantation to the final maturation stage. Furthermore, IGFs have been demonstrated to be involved in limb morphogenesis. However, although ablation of Igf genes in mice resulted in growth retardation and delay in skeletal maturation, no impact on outgrowth and patterning of embryonic limbs was observed. Additionally, various molecular defects in the Igf1 and Igf1r genes in humans have been associated with severe intrauterine growth retardation and impaired skeletal maturation, but not with truncated limbs or severe skeletal dysplasia. The conflicting data between in vitro and in vivo observations with regard to bone morphogenesis suggests that IGFs may not be the sole trophic factors involved in fetal skeletal growth and that redundant mechanisms may exist in chondro- and osteogenesis. Further investigation is required in order to elucidate the functions of IGFs in skeletal development.

DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).

Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non‑gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.

Prenatal diagnosis of proximal partial trisomy 1q confirmed by comparative genomic hybridization array: molecular cytogenetic analysis, fetal pathology and review of the literature.

Partial trisomy of the long arm of chromosome 1 (1q) is an exceptionally rare chromosomal abnormality and most of the prenatally diagnosed cases are associated with either complete (q11-qter) or large (q21-qter) duplications with pre- or perinatal demise of all reported cases. The most common sonographic findings associated with this karyotype abnormality include ventriculomegaly, increased nuchal translucency or nuchal fold, renal and cardiac abnormalities, craniofacial dysmorphism, and limb deformities. However, there is a wide spectrum of clinical manifestations due to the great variability in the extent of the duplication size and the possible contribution of additional genetic rearrangements in the final phenotype.

Reduced ANXA5 mRNA and protein expression in pregnancies complicated by preeclampsia.

The placental anticoagulant protein Annexin A5 (ANXA5) is a multifunctional protein that is highly expressed on the apical surfaces of syncytiotrophoblasts, and plays an important role in haemostatic regulations, maintaining blood fluidity of the placenta. The aim of this study was to investigate the expression of ANXA5 in pregnancies complicated by preeclampsia (PE).

Acute lung injury in preterm fetuses and neonates: mechanisms and molecular pathways.

Acute lung injury (ALI) results in high morbidity and mortality among preterm neonates and efforts have therefore been devoted to both antenatal and postnatal prevention of the disease. ALI is the result of an inflammatory response which is triggered by a variety of different mechanisms. It mostly affects the fetal lung and, in particular, causes damage to the integrity of the lung's alveolar-capillary unit while weakening its cellular linings. Chemotactic activity and inflammatory products, such as proinflammatory cytokines TNF-α, IL-1, IL-6, IL-11, VEGF,TGF-α and TGF-β, provoke serious damage to the capillary endothelium and the alveolar epithelium, resulting in hyaline membrane formation and leakage of protein-rich edema fluid into the alveoli. Chorioamnionitis plays a major part in triggering fetal lung inflammation, while mechanical ventilation, the application of which is frequently necessary in preterm neonates, also causes ALI by inducing proinflammatory cytokines. Many different ventilation-strategies have been developed in order to reduce potential lung injury. Furthermore, tissue injury may occur as a result of injurious oxygen by-products (Reactive Oxygen Species, ROS), secondary to hyperoxia. Knowledge of the inflammatory pathways that connect intra-amniotic inflammation and ALI can lead to the formulation of novel interventional procedures. Future research should concentrate on the pathophysiology of ALI in preterm neonates and οn possible pharmaceutical interventions targeting prevention and/or resolution of ALI.

Endocrine, paracrine, and autocrine placental mediators in labor.

Considering that preterm birth accounts for about 6-10% of all births in Western countries and of more than 65% of all perinatal deaths, elucidation of the particularly complicated mechanisms of labor is essential for determination of appropriate and effective therapeutic interventions. Labor in humans results from a complex interplay of fetal and maternal factors, which act upon the uterus to trigger pathways leading gradually to a coordinated cervical ripening and myometrial contractility. Although the exact mechanism of labor still remains uncertain, several components have been identified and described in detail. Based on the major role played by the human placenta in pregnancy and the cascade of labor processes activated via placental mediators exerting endocrine, paracrine, and autocrine actions, this review article has aimed at presenting the role of these mediators in term and preterm labor and the molecular pathways of their actions. Some of the aforementioned mediators are involved in myometrial activation and preparation and others in myometrial stimulation leading to delivery. In the early stages of pregnancy, myometrial molecules, like progesterone, nitric oxide, and relaxin, contribute to the retention of pregnancy. At late stages of gestation, fetal hypothalamus maturation signals act on the placenta causing the production of hormones, including CRH, in an endocrine manner; the signals then enhance paracrinically the production of more hormones, such as estrogens and neuropeptides, that contribute to cervical ripening and uterine contractility. These molecules act directly on the myometrium through specific receptors, while cytokines and multiple growth factors are also produced, additionally contributing to labor. In situations leading to preterm labor, as in maternal stress and fetal infection, cytokines trigger placental signaling sooner, thus leading to preterm birth.

Placental growth factor (PlGF): a key to optimizing fetal growth.

The needs of the uterus and the fetus for the provision of nutrients and oxygen, supplied by the blood flow, are understandably extremely high, with the circulatory system playing the most important role in this action. Abnormal vascular growth and transformation that create a high vessel resistance network have been associated with various pregnancy pathologies, including miscarriage, small for gestational age (SGA) fetuses with or without preeclampsia and intrauterine growth restriction (IUGR). Placental growth factor (PlGF) has a major role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF and high concentrations of its inhibitor-soluble Fms-like tyrosine kinase-1 (sFlt-1) are linked with impaired angiogenesis and placental development, leading to the above pregnancy complications. The activity of vascular endothelial growth factor (VEGF), which is the most potent of all angiogenic mediators, is partly modulated by PlGF. Although the mechanisms via which PlGF exerts its various effects are still under investigation, we herein discuss the known actions exerted by this major mediator together with its results on fetal growth.

Prognostic value of tgfb1 protein in endometrioid adenocarcinoma.

Angiogenesis is a prerequisite for tumour development, progression and metastasis; however, its underlying molecular mechanisms in endometrial carcinoma are poorly understood.

Therapeutic management of fetal anemia: review of standard practice and alternative treatment options.

Fetal anemia, mainly due to red cell alloimmunization, is still a significant cause of fetal and neonatal mortality and morbidity. The focus of current clinical research has shifted from an invasive approach to non-invasive management and treatment of affected pregnancies, and the progress in this field is associated with a major improvement in perinatal outcome. During the last 50 years, intrauterine red cells transfusion (IUT), fi rst via the intraperitoneal route and later directly to fetal circulation, is the standard practice in most centers, with survival rates that exceed 90 % , particularly if anemia is diagnosed early and treated in a timely manner. In addition, plasmapheresis and intravenous administration of highdose immunoglobulin have been implicated in the treatment of pregnancies complicated with early-onset severe red cell alloimmunization, alone or in combination with IUTs before the 20(th) week of pregnancy, but there are still issues to be clarified further. This review article aims to provide an overview of the current standard therapeutic management and alternative treatment modalities in pregnancies complicated by fetal anemia.

Review: Impact of mediators present in amniotic fluid on preterm labour.

Preterm birth continues to be one of the most important issues in current obstetric medicine, being the single largest cause of perinatal morbidity and mortality. The signals that initiate preterm and term labour remain a mystery. Intrauterine inflammation with the secretion of cytokines is one of the accepted explanations for the mechanism of initiation of preterm labour. This review discusses the current understanding of the molecular mechanisms for the initiation of preterm labour, focusing chiefly on the role of intra-amniotic fluid mediators, whether endogenous or infection-induced, in the regulation of inflammatory response pathways associated with spontaneous preterm labour. Prostaglandins (PGs) are considered to be one of the key mediators of preterm labour, with the concentration of biologically active PGs in the amniotic fluid, particularly PGE(2) and PGF(2α), being significantly higher in women with preterm labour. Cytokines, such as interleukins and tumour necrosis factor alpha, additionally play a dominant role in preterm labour, particularly in association with infection. Elevated amniotic fluid concentrations of extracellular matrix mediators, including metalloproteases, are also implicated in the process of foetal membrane rupture in preterm labour. Allelic variations in the main amniotic fluid mediators may be the key to understanding the disparity in the rates of preterm birth between different ethnic populations. We also discuss the role of other potential mediators such as cell-adhesion molecules, nitric oxide and novel biomarkers found in the amniotic fluid.

Endoreduplication in cervical trophoblast cells from normal pregnancies.

Fetal cells represented by extravillous trophoblasts (EVT) obtained from the cervix by a minimally invasive procedure are important for prenatal diagnosis in early pregnancies. Endoreduplication is a duplication of chromosomes without mitosis, leading to polyploidy that might represent increased cellular metabolic activity. In this study, we estimated the normal prevalence of polyploid trophoblasts exfoliated to the cervix between 5 and 13 weeks of gestation.

Noninvasive prenatal diagnosis of Down syndrome: current knowledge and novel insights.

The noninvasive prenatal diagnosis of trisomy 21 (Down syndrome) is an actively researched area of prenatal medicine, as this is the most common aneuploidy compatible with life and a major cause of mental retardation. The isolation of intact fetal cells, and most importantly, the successful detection of fetal-origin nucleic acids (cell-free fetal DNA and RNA), in maternal plasma even from the early stages of pregnancy has inspired scientists to develop discriminative genetic markers for the prenatal detection of aneuploidy. In the near future, the development of epigenetic fetal-specific markers will possibly allow the universal application of a cell-free fetal DNA-based diagnostic test regardless of the gender of the fetus or its polymorphic status. Other promising approaches rely upon the detection of free placentally derived RNA transcribed from genes located on chromosome 21 and the application of highly sensitive techniques, such as digital polymerase chain reaction and high-throughput shotgun sequencing. However, irrespective of which strategy is selected for isolating or distinguishing fetal genetic material in maternal plasma, the small quantity of fetal origin nucleic acids poses severe technical challenges. In this review article, we present an overview of the current knowledge in the field of noninvasive prenatal assessment of fetuses with Down syndrome and the future perspectives regarding new fetal markers and novel molecular techniques that may eventually be applied in the clinical setting as a valid and safe option for women who opt for noninvasive accurate prenatal diagnosis.

Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells.

Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells. Incubation of nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the flavone moiety. Among the three CYP1 isoforms, CYP1A1 exhibited the highest rate of metabolism of nobiletin in recombinant CYP microsomal enzymes. The intracellular CYP1-mediated bioconversion of the flavone was reduced in the presence of the CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and acacetin. In addition nobiletin induced CYP1 enzyme activity, CYP1A1 protein and CYP1B1 mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with nobiletin and CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of CYP1A1 inhibitor. Taken together the data suggests that the dietary flavonoid nobiletin induces its own metabolism and in turn enhances its cytostatic effect in MCF7 breast adenocarcinoma cells, via CYP1A1 and CYP1B1 upregulation.

Fetal longitudinal myocardial function assessment by anatomic M-mode.

To evaluate the feasibility of offline anatomic M-mode (AMM) to study fetal atrioventricular annulus long-axis displacement (LAD) and compare its performance against real-time conventional M-mode (MM).

Angiogenic factors in placentas from pregnancies complicated by fetal growth restriction (review).

The placenta is the organ that is responsible for providing the developing fetus with all the nutrients necessary for its growth and is also responsible for removing fetal waste. Placentation is a crucial process that includes angiogenesis. Angiogenesis involves not only the fetal circulation, but also placental and endometrial vascular changes. In this study, we review the literature regarding any impairment in the angiogenic process in placentas from pregnancies complicated by fetal growth restriction (FGR). Angiogenesis is regulated by a list of factors, also known as growth factors, such as the vascular endothelial growth factor (VEGF), the placental growth factor (PlGF) and the basic fibroblastic growth factor (bFGF), as well as the partial pressure of oxygen in the fetoplacental vessels. Other factors, such as transcriptional factors, also play a pivotal role, controlling the above-mentioned growth factors. Alterations in these pathways have been described in cases of growth-restricted fetuses. In this review, we provide an insight into these processes and identify the most crucial factors involved.

Role of adipokines and other inflammatory mediators in gestational diabetes mellitus and previous gestational diabetes mellitus.

Previous Gestational Diabetes Mellitus (pGDM) is a common condition and has been associated with future development of Type 2 Diabetes Mellitus (T2DM) and Metabolic Syndrome (MS) in women affected. The pathogenesis and risk factors implicated in the development of these conditions later in the lives of women with pGDM are not as yet fully understood. Research has recently focused on a group of substances produced mainly by adipose tissue called adipokines, this group including, among others, adiponectin, leptin, Retinol-Binding Protein-4 (RBP-4), and resistin. These substances as well as other inflammatory mediators (CRP, IL-6, PAI-1, TNF-α) seem to play an important role in glucose tolerance and insulin sensitivity dysregulation in women with pGDM. We summarize the data available on the role of these molecules.