A Novel NUTM1-NSMCE2 Fusion Gene in a Pediatric Chest NUT Carcinoma.

Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.

Characterization of Maternal Circulating MicroRNAs in Obese Pregnancies and Gestational Diabetes Mellitus.

Maternal obesity (MO) is expanding worldwide, contributing to the onset of Gestational Diabetes Mellitus (GDM). MO and GDM are associated with adverse maternal and foetal outcomes, with short- and long-term complications. Growing evidence suggests that MO and GDM are characterized by epigenetic alterations contributing to the pathogenesis of metabolic diseases. In this pilot study, plasma microRNAs (miRNAs) of obese pregnant women with/without GDM were profiled at delivery. Nineteen women with spontaneous singleton pregnancies delivering by elective Caesarean section were enrolled: seven normal-weight (NW), six obese without comorbidities (OB/GDM(-)), and six obese with GDM (OB/GDM(+)). miRNA profiling with miRCURY LNA PCR Panel allowed the analysis of the 179 most expressed circulating miRNAs in humans. Data acquisition and statistics (GeneGlobe and SPSS software) and Pathway Enrichment Analysis (PEA) were performed. Data analysis highlighted patterns of significantly differentially expressed miRNAs between groups: OB/GDM(-) vs. NW: n = 4 miRNAs, OB/GDM(+) vs. NW: n = 1, and OB/GDM(+) vs. OB/GDM(-): n = 14. For each comparison, PEA revealed pathways associated with oxidative stress and inflammation, as well as with nutrients and hormones metabolism. Indeed, miRNAs analysis may help to shed light on the complex epigenetic network regulating metabolic pathways in both the mother and the foeto-placental unit. Future investigations are needed to deepen the pregnancy epigenetic landscape in MO and GDM.

Assessment of Cardiovascular Function in Childhood Leukemia Survivors: The Role of the Right Heart.

Childhood acute lymphoblastic leukemia (ALL) survivors who underwent chemotherapy with anthracyclines have an increased cardiovascular risk. The aim of the study was to evaluate left and right cardiac chamber performances and vascular endothelial function in childhood ALL survivors. Fifty-four ALL survivors and 37 healthy controls were enrolled. All patients underwent auxological evaluation, blood pressure measurements, biochemical parameters of endothelial dysfunction, flow-mediated dilatation (FMD) of the brachial artery, mean common carotid intima-media thickness (c-IMT), antero-posterior diameter of the infra-renal abdominal aorta (APAO), and echocardiographic assessment. The ALL subjects had significantly lower FMD (p = 0.0041), higher left (p = 0.0057) and right (p = 0.0021) echocardiographic/Doppler Tei index (the non-invasive index for combined systolic and diastolic ventricular function) as compared to controls. Tricuspid annular plane excursion (TAPSE) was 16.9 ± 1.2 mm vs. 24.5 ± 3.7 mm, p < 0.0001. Cumulative anthracycline doses were related to TAPSE (p < 0.001). The ALL survivors treated with anthracyclines demonstrated systo/diastolic alterations of the right ventricle and reduced endothelial function compared with healthy controls. The early recognition of subclinical cardiac and vascular impairment during follow up is of utmost importance for the cardiologist to implement strategies preventing overt cardiovascular disease considering the growing number of young adults cured after childhood ALL.

Longitudinal Nutritional Intakes in Italian Pregnant Women in Comparison with National Nutritional Guidelines.

BACKGROUND: Nutritional quality during pregnancy is crucial for mother and child health and their short/long-term outcomes. The aim of this study is to evaluate the adherence to nutritional recommendations in Italy during the three pregnancy trimesters in Normal Weight (NW) and Over Weight (OW) women. METHODS: Data from a multicenter randomized controlled trial included 176 women (NW = 133; OW = 43) with healthy singleton pregnancies enrolled within 13 + 6 weeks of gestation. Dietary intake was assessed every trimester by a Food Frequency Questionnaire. RESULTS: OW and NW had similar gestational weight gain. However, as Institute of Medicine (IOM) recommend lower gestational weight gain (GWG) for OW, they exceeded the suggested range. In both groups, caloric intake during the three trimesters never met recommendations. Protein intake in first and second trimester was higher than recommendations, as was sugars percentage. Dietary fiber intake was lower in OW. Polyunsaturated fatty acids, calcium, iron and folic acid requirements were never satisfied, while sodium intake exceeded recommendations. CONCLUSIONS: NW and OW women in Italy do not adhere to nutritional recommendations during pregnancy, with lower caloric intake, protein and sugars excess and inadequacies in micronutrients intake. Pregnant women in Italy should be provided with an adequate counseling and educational intervention as well as supplementation when indicated.

Mitochondrial and Oxidative Unbalance in Placentas from Mothers with SARS-CoV-2 Infection.

SARS-CoV-2 infection has been related to adverse pregnancy outcomes. A placental role in protecting the fetus from SARS-CoV-2 infection has been documented. Nevertheless, it is still unclear how the placenta is affected in SARS-CoV-2 infection. Here we assessed placental mitochondrial (mt) and oxidative features in COVID-19 and healthy mothers. mtDNA levels, DNA oxidative damage, expression levels of genes involved in antioxidant defenses, mitochondrial dynamics and respiratory chain subunits were investigated in placentas from singleton pregnancies of 30 women with SARS-CoV-2 infection during the third trimester (12 asymptomatic, 18 symptomatic) and 16 controls. mtDNA levels decreased in COVID-19 placentas vs. controls and inversely correlated with DNA oxidative damage, which increased in the symptomatic group. Antioxidant gene expressions decreased in SARS-CoV-2 mothers (CAT, GSS). Symptomatic cases also showed a lower expression of respiratory chain (NDUFA9, SDHA, COX4I1) and mt dynamics (DNM1L, FIS1) genes. Alterations in placental mitochondrial features and oxidative balance in COVID-19-affected mothers might be due to the impaired intrauterine environment, generated by systemic viral effects, leading to a negative vicious circle that worsens placental oxidative stress and mitochondrial efficiency. This likely causes cell homeostasis dysregulations, raising the potential of possible long-term effects.

Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus.

Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(-)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (CAT, GPX1, GSS) decreased, the pro-autophagic ULK1 gene increased and the chaperone-mediated autophagy regulator PHLPP1 decreased in OB GDM(-) vs. NW. On the other hand, PHLPP1 expression increased in OB GDM(+) vs. OB GDM(-). When analyzing results in relation to fetal sex, we found sexual dimorphism for both antioxidant and CMA-related gene expressions. These preliminary results can pave the way for further analyses aimed at elucidating the placental autophagy role in metabolic pregnancy disorders and its potential targetability for the treatment of diabetes outcomes.

Effects of α-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women: A preliminary study.

Obesity is becoming pandemic and is associated with impaired reproductive potential. Oxidative stress, low-grade chronic inflammation and mitochondrial dysfunctions, which characterize obesity, strongly affect oocyte environment and function. Supplementation with antioxidant and anti-inflammatory compounds has been suggested to improve fertility. Here we evaluated the effect of α-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women. Nineteen normal-weight and twenty-three obese women, infertile for non-ovarian reasons, were recruited. For two months before ovarian stimulation, all women received 400 µg/die folic acid, whereas 15 obese were additionally supplemented with 800 mg α-lipoic acid, 2 g myo-inositol/die. Antioxidant capacity was measured in follicular fluid by enzymatic assay; mitochondrial DNA (mtDNA) content and mRNA levels of two respiratory chain subunits were analyzed in granulosa cells by Real-time PCR. Pregnancy rate was similar between normal-weight and treated obese, and lower in untreated obese patients. Supplemented women showed significantly higher antioxidant levels in follicular fluid compared to the two groups taking only folic acid. Conversely, granulosa cells mtDNA content was decreased in treated and higher in untreated obese patients compared to normal-weight women, suggesting mtDNA increases to compensate for oxidative-stress damages. Reduced expression of respiratory subunits in untreated obese may confirm mitochondria impairment. Interestingly, mtDNA levels inversely correlated to both total and metaphase II oocyte number. In this preliminary study, combined supplementation of α-lipoic acid and myo-inositol in infertile obese women was associated with amelioration in the oxidative status of the oocyte environment, possibly contributing to a higher pregnancy rate.

Multiple Micronutrients and Docosahexaenoic Acid Supplementation during Pregnancy: A Randomized Controlled Study.

Maternal dietary intake during pregnancy needs to meet increased nutritional demands to maintain metabolism and to support fetal development. Docosahexaenoic acid (DHA) is essential for fetal neuro-/visual development and in immunomodulation, accumulating rapidly within the developing brain and central nervous system. Levels available to the fetus are governed by the maternal diet. In this multicenter, parallel, randomized controlled trial, we evaluated once-daily supplementation with multiple micronutrients and DHA (i.e., multiple micronutrient supplementation, MMS) on maternal biomarkers and infant anthropometric parameters during the second and third trimesters of pregnancy compared with no supplementation. Primary efficacy endpoint: change in maternal red blood cell (RBC) DHA (wt% total fatty acids) during the study. Secondary variables: other biomarkers of fatty acid and oxidative status, vitamin D, and infant anthropometric parameters at delivery. Supplementation significantly increased RBC DHA levels, the omega-3 index, and vitamin D levels. Subscapular skinfold thickness was significantly greater with MMS in infants. Safety outcomes were comparable between groups. This first randomized controlled trial of supplementation with multiple micronutrients and DHA in pregnant women indicated that MMS significantly improved maternal DHA and vitamin D status in an industrialized setting-an important finding considering the essential roles of DHA and vitamin D.

Isavuconazole Treatment of Cerebral and Pulmonary Aspergillosis in a Pediatric Patient With Acute Lymphoblastic Leukemia: Case Report and Review of Literature.

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

Cardiovascular dysfunction and vitamin D status in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: Vitamin D (25-OHD) has a role in bone health after treatment for cancer. 25-OHD deficiency has been associated with risk factors for cardiovascular disease, but no data focusing on this topic in childhood cancer survivors have been published. We investigated the 25-OHD status in children treated for acute lymphoblastic leukemia (ALL), and evaluated its influence on vascular function. METHODS: 25-OHD levels were evaluated in 52 ALL survivors and 40 matched healthy controls. Patients were grouped according to 25-OHD level (< 20 ng/m or ≥ 20 ng/ml). Auxological parameters, biochemical and hemostatic markers of endothelial function (AD, HMW-AD, ET-1, vWFAg, TAT, D-dimers, Fbg, and hs-CRP), ultrasound markers of vascular endothelial function (flow-mediated dilatation, FMD, common carotid intima-media thickness, C-IMT, and antero-posterior diameter of infra-renal abdominal aorta, APAO) were evaluated in the patients. RESULTS: Cases showed higher prevalence of 25-OHD deficiency than controls (p = 0.002). In univariate analysis via mean comparisons, 25-OHD deficient (< 20 ng/ml) patients showed higher C-IMT values compared to the 25-OHD non-deficient (≥ 20 ng/ml) group (P = 0.023). Significant differences were also found for ET-1 (P = 0.035) and AD-HMW (P = 0.015). In the multiple regression models controlling for some confounders, 25-OHD still was associated with C-IMT (P = 0.0163), ET-1 (P = 0.0077), and AD-HMW (P = 0.0008). CONCLUSIONS: Childhood ALL survivors show higher prevalence of 25-OHD deficiency as compared to controls. The 25-OHD levels appear to be linked to indicators of endothelial and vascular dysfunction. Careful monitoring of 25-OHD balance may help to prevent cardiovascular diseases in childhood ALL survivors, characterized by high cardiovascular risk.

Placental ESRRG-CYP19A1 Expressions and Circulating 17-Beta Estradiol in IUGR Pregnancies.

Introduction: Sex steroids are regulating factors for intrauterine growth. 17-ß Estradiol (E2) is particularly critical to a physiological pregnancy, as increased maternal E2 was correlated to lower fetal weight at delivery. The placenta itself is a primary source of estrogens, synthetized from cholesterol precursors. Cytochrome P450 aromatase (encoded by CYP19A1 gene) is a rate-limiting enzyme for E2 biosynthesis. CYP19A1 transcription is supported by Estrogen Related-Receptor Gamma (ERRγ- ESRRG gene), which thus has an indirect role in placental steroidogenesis. Here we investigated maternal E2 levels and placental CYP19A1 and ESRRG expressions in pregnancies with IntraUterine Growth Restriction (IUGR). Methods: Singleton pregnancies were studied. E2 was measured in maternal plasma by electrochemiluminescence in 16 term controls and 11 IUGR (classified by umbilical artery doppler pulsatility index) at elective cesarean section, and also in 13 controls during pregnancy at a gestational age comparable to IUGR. CYP19A1 and ESRRG expressions were analyzed in placental tissue. Maternal/fetal characteristics, placental and molecular data were compared among study groups and tested for correlations. Results: Maternal E2 plasma concentrations were significantly decreased in IUGR compared to controls at delivery. When analyzing normal pregnancies at a gestational age similar to IUGR, E2 levels were not different to pathological cases. However, E2 levels at delivery positively correlated with placental efficiency. Placental CYP19A1 levels were significantly higher in IUGR placental tissue vs. controls, and specifically increased in female IUGR placentas. ESRRG expression was not different among groups. Discussion: We report a positive correlation between 17-ß Estradiol levels and placental efficiency, that might indicate a disrupted steroidogenesis in IUGR pregnancies. Moreover, we show alterations of CYP19A1 expression in IUGR placentas, possibly indicating a compensatory effect to the adverse IUGR intrauterine environment, also depending on fetal sex. Further studies are needed to deeper investigate IUGR alterations in the complex interaction among molecules involved in placental steroidogenesis.

Impact of Obesity and Hyperglycemia on Placental Mitochondria.

A lipotoxic placental environment is recognized in maternal obesity, with increased inflammation and oxidative stress. These changes might alter mitochondrial function, with excessive production of reactive oxygen species, in a vicious cycle leading to placental dysfunction and impaired pregnancy outcomes. Here, we hypothesize that maternal pregestational body mass index (BMI) and glycemic levels can alter placental mitochondria. We measured mitochondrial DNA (mtDNA, real-time PCR) and morphology (electron microscopy) in placentas of forty-seven singleton pregnancies at elective cesarean section. Thirty-seven women were normoglycemic: twenty-one normal-weight women, NW, and sixteen obese women, OB/GDM(-). Ten obese women had gestational diabetes mellitus, OB/GDM(+). OB/GDM(-) presented higher mtDNA levels versus NW, suggesting increased mitochondrial biogenesis in the normoglycemic obese group. These mitochondria showed similar morphology to NW. On the contrary, in OB/GDM(+), mtDNA was not significantly increased versus NW. Nevertheless, mitochondria showed morphological abnormalities, indicating impaired functionality. The metabolic response of the placenta to impairment in obese pregnancies can possibly vary depending on several parameters, resulting in opposite strains acting when insulin resistance of GDM occurs in the obese environment, characterized by inflammation and oxidative stress. Therefore, mitochondrial alterations represent a feature of obese pregnancies with changes in placental energetics that possibly can affect pregnancy outcomes.

Inflammatory and Oxidative Responses in Pregnancies With Obesity and Periodontal Disease.

BACKGROUND: Maternal obesity is related to immunologic and inflammatory systemic modifications that may worsen the pregnancy inflammatory status. Hormonal changes during pregnancy can adversely affect oral biofilms and oral health initiating or worsening periodontal diseases, with enhanced local and systemic oxidative stress and inflammation. OBJECTIVE: The aim of this study was to examine the relationship between local salivary and systemic parameters of oxidative stress and inflammation in relation to obesity and periodontal diseases. STUDY DESIGN: Sixty-two women with singleton pregnancies were enrolled. Twenty-seven women were normal weight (NW; 18.5< body mass index [BMI] <25 kg/m2) and 35 obese (BMI ≥30 kg/m2). Seventeen of the obese had gestational diabetes mellitus (GDM). During third trimester, periodontal status was evaluated, saliva (s) was collected to assess total antioxidant capacity (s-TAC) and C-reactive protein (s-CRP) levels, and venous plasma (p) was used to measure CRP levels (p-CRP). Maternal, fetal, and placental data were registered at delivery. RESULTS: Levels of s-TAC, s-CRP, and p-CRP were significantly higher in obese, particularly in the presence of GDM, compared to NW and related to each other ( P = .000; r > 0.59), to maternal BMI ( P = .000; r > 0.52), and fasting glycemia ( P < .002; r > 0.47). Periodontal disease was more frequent in obese groups (80%) versus NW (52%; P = .04), particularly when GDM was diagnosed ( P = .009). A significant interaction effect between maternal BMI and oral condition was found for s-TAC levels. Obese with periodontitis showed significant increase in local and systemic parameters versus NW. CONCLUSION: Obesity and periodontal disease could synergistically amplify the inflammatory and oxidative status, resulting in increased local and systemic biomarkers particularly when GDM is diagnosed.

Preliminary metabolomics analysis of placenta in maternal obesity.

INTRODUCTION: Metabolomics identifies phenotypical groups with specific metabolic profiles, being increasingly applied to several pregnancy conditions. This is the first preliminary study analyzing placental metabolomics in normal weight (NW) and obese (OB) pregnancies. METHODS: Twenty NW (18.5 ≤ BMI< 25 kg/m2) and eighteen OB (BMI≥ 30 kg/m2) pregnancies were studied. Placental biopsies were collected at elective caesarean section. Metabolites extraction method was optimized for hydrophilic and lipophilic phases, then analyzed with GC-MS. Univariate and PLS-DA multivariate analysis were applied. RESULTS: Univariate analysis showed increased uracil levels while multivariate PLS-DA analysis revealed lower levels of LC-PUFA derivatives in the lipophilic phase and several metabolites with significantly different levels in the hydrophilic phase of OB vs NW. DISCUSSION: Placental metabolome analysis of obese pregnancies showed differences in metabolites involved in antioxidant defenses, nucleotide production, as well as lipid synthesis and energy production, supporting a shift towards higher placental metabolism. OB placentas also showed a specific fatty acids profile suggesting a disruption of LC-PUFA biomagnification. This study can lay the foundation to further metabolomic placental characterization in maternal obesity. Metabolic signatures in obese placentas may reflect changes occurring in the intrauterine metabolic environment, which may affect the development of adult diseases.

Mitochondrial DNA content and methylation in fetal cord blood of pregnancies with placental insufficiency.

INTRODUCTION: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are pregnancy disorders characterized by placental insufficiency with oxygen/nutrient restriction and oxidative stress, all influencing mitochondria functionality and number. Moreover, IUGR and PE fetuses are predisposed to diseases later in life, and this might occur through epigenetic alterations. Here we analyze content and methylation of mitochondrial DNA (mtDNA), for the first time in IUGR and PE singleton fetuses, to identify possible alterations in mtDNA levels and/or epigenetic control of mitochondrial loci relevant to replication (D-loop) and functionality (mt-TF/RNR1: protein synthesis, mt-CO1: respiratory chain complex). METHODS: We studied 35 term and 8 preterm control, 31 IUGR, 17 PE/IUGR and 17 PE human singleton pregnancies with elective cesarean delivery. Fetal cord blood was collected and evaluated for biochemical parameters. Extracted DNA was subjected to Real-time PCR to assess mtDNA content and analyzed for D-loop, mt-TF/RNR1 and mt-CO1 methylation by bisulfite conversion and pyrosequencing. RESULTS: mtDNA levels were increased in all pathologic groups compared to controls. Mitochondrial loci showed very low methylation levels in all samples; D-loop methylation was further decreased in the most severe cases and associated to umbilical vein pO2. mt-CO1 methylation levels inversely correlated to mtDNA content. DISCUSSION: Increased mtDNA levels in IUGR, PE/IUGR and PE cord blood may denote a fetal response to placental insufficiency. Hypomethylation of D-loop, mt-TF/RNR1 and mt-CO1 loci confirms their relevance in pregnancy.

Non-alcoholic fatty liver disease is associated with early left ventricular dysfunction in childhood acute lymphoblastic leukaemia survivors.

BACKGROUND: Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction. METHODS: In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study. RESULTS: NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction. CONCLUSIONS: Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients.

Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction.

UNLABELLED: Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. SIGNIFICANCE: This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR.

Sex specific adaptations in placental biometry of overweight and obese women.

INTRODUCTION: Placental biometry at birth has been shown to predict chronic disease in later life. We hypothesized that maternal overweight/obesity, a state of low-grade inflammation and risk factor for adverse pregnancy outcome, could negatively influence placental development and that differences would be sex-specific. METHODS: 696 women (537 normal-weight, NW; 112 overweight, OW; 47 obese, OB) with singleton uncomplicated pregnancies were prospectively enrolled at term delivery. Gestational age, maternal (age, height, pre-pregnancy BMI, gestational weight gain -GWG, hemoglobin, hematocrit and glycemia), fetal (weight, length, ponderal index, cranial circumference) and placental (weight, diameters) data were collected. Placental area, thickness and efficiency (fetal/placental weight ratio, F/P) were calculated. RESULTS: GWG was within standard recommendations in OB, while OW exceeded it. Placental weight was significantly higher in OW versus NW, but not in OB, leading to significantly higher placental thickness and lower F/P in this group. In the total population, a significant interaction effect between maternal BMI and fetal sex on placental weight and efficiency was found. Indeed, differences in placental parameters were present only in female offspring. DISCUSSION: In our population of OW and OB uncomplicated pregnancies only OW women, presenting GWG over standard recommendations, had thicker and less efficient placentas. We also reported different placental adaptation depending on fetal sex, with significant changes only in female fetuses. This may be part of a female-specific strategy aiming to ensure survival if another adverse event occurs. Customized counseling according to maternal BMI and fetal sex should be evaluated in clinical care.

TRIM8 downregulation in glioma affects cell proliferation and it is associated with patients survival.

BACKGROUND: Human gliomas are a heterogeneous group of primary malignant brain tumors whose molecular pathogenesis is not yet solved. In this regard, a major research effort has been directed at identifying novel specific glioma-associated genes. Here, we investigated the effect of TRIM8 gene in glioma. METHODS: TRIM8 transcriptional level was profiled in our own glioma cases collection by qPCR and confirmed in the independent TCGA glioma cohort. The association between TRIM8 expression and Overall Survival and Progression-free Survival in TCGA cohort was determined by using uni-multivariable Cox regression analysis. The effect of TRIM8 on patient glioma cell proliferation was evaluated by performing MTT and clonogenic assays. The mechanisms causing the reduction of TRIM8 expression were explored by using qPCR and in vitro assays. RESULTS: We showed that TRIM8 expression correlates with unfavorable clinical outcome in glioma patients. We found that a restored TRIM8 expression induced a significant reduction of clonogenic potential in U87MG and patient's glioblastoma cells. Finally we provide experimental evidences showing that miR-17 directly targets the 3' UTR of TRIM8 and post-transcriptionally represses the expression of TRIM8. CONCLUSIONS: Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients.

Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) plays a role in cell cycle progression and cytoskeletal dynamics.

MARK4 is a serine-threonine kinase that phosphorylates MAP proteins, increasing microtubule dynamics. MARK4 differs from the other members of the MARK family for encoding two isoforms (MARK4L and MARK4S), differentially expressed in the nervous system, and for the peculiar localisation at the centrosome and the midbody. By cytofluorimetric analysis we showed that MARK4 is expressed throughout the cell cycle and preferentially activated during mitosis. Depletion of MARK4S affected the morphology and proliferation of fibroblasts and glioma cells, as the percentages of cells in S and G2/M phases were reduced and the percentage of cells in G1 was increased. In MARK4S silenced cells, centrosomes were duplicated and positioned apically to the nucleus, indicating that the centrosome cycle was altered and the cells arrested in G1 phase. Overexpression of MARK4L or MARK4S reduced the density of the microtubule network, confirming microtubules as the main target of MARK4, and revealed a novel co-localisation of MARK4 and vimentin. Taken together, our data confirm that MARK4 is a key component in the regulation of microtubule dynamics and highlight its major role in cell cycle progression, particularly at the G1/S transition. The co-localisation of vimentin and MARK4L suggests that MARK4 has a wide-ranging influence on cytoskeleton.