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Although previously found to be quite safe and potentially useful as a metabolic sensitizer against a wide spectrum of cancer subtypes, 2-Deoxy-D-Arabinohexose, commonly known as 2-Deoxy-D-Glucose (2DG), has remained somewhat ignored in the clinical setting. As a glycolysis inhibitor, 2DG preferentially targets tumour cells, which densely overexpress glucose transporters (GLUTs) in their cytoplasmic membranes, as well as glycolytic and fermentation enzymes hexokinase 2 (HK-2) and lactic dehydrogenase isoenzyme A (LDH-A). The pronounced functional asymmetry, the distinct metabolic phenotypes that set apart neoplastic and normal cells offer a therapeutic window of opportunity to overcome multidrug resistance in the treatment of cancer. Nutripharmacological corrections of blood glucose, followed by the timely introduction of several nonmetabolizable structural analogues, is a cost-effective, minimally invasive coadjuvant treatment for solid tumours. Further, our research group has shown that a metabolic intervention with antimetabolites of glucose and pyruvate is strongly enhanced by a systemic suppression of the natural substrates of their catalyzing, rate-limiting enzymes within cancer cells. Here, we demonstrate that 2DG, perhaps the archetypal glucose antimetabolite, is very safe in humans.

The present report describes our clinical findings regarding the use of high dose intravenous insulin in cancer patients, as a means to deplete the blood compartment of glucose molecules. The purpose of this intervention is to create a favorable physiological state for the competitive inhibition of several rate-limiting enzymes within cancer cells, with structural analogues that behave as antimetabolites. Regardless of their histological origin, virtually all solid tumors reported on to date (February 2020) are found to be hypercaptant in PET-CT scans following the intravenous injection of 2-¹⁸fluoro-deoxy-D-glucose. Most solid tumors display a hypermetabolic phenotype (SUVmax ≥ 3), with marked overexpression of glucose transporters (GLUTs) in the outer membrane of their anaplastic cells subpopulations. The fact that neoplastic cells also overexpress glycolytic, fermentative and glutaminolytic enzymes up to an order of magnitude relative to healthy cells further strengthens the argument for a competitive inhibition with antimetabolites. The rationale for a deep, systemic deprivation of glucose was suggested by classical enzymological work concerning competitive inhibition (the Woods principle), and our group has shown that a metabolic intervention with structural analogues of glucose and pyruvate is strongly enhanced by a systemic suppression of the natural substrates of hexokinase 2 (HK-2) and lactic dehydrogenase isozyme A (LDH-A), followed by the timely introduction of several non- metabolizable analogues. Sustained, deep hypoglycemia (

OBJECTIVE: To evaluate the impact of preoperative cervical length on pregnancy outcome in monochorionic diamniotic twin pregnancies complicated by twin-twin transfusion syndrome that underwent laser surgery or cord occlusion. MATERIALS AND METHODS: Retrospective study of 330 patients stratified by preoperative cervical length (=25 mm, 16-24 mm,=15 mm). Maternal characteristics, operative data, and pregnancy outcomes were compared between the cervical length groups as well as between the subgroups of patients with a cervical length=15 mm according to management (expectant vs. cerclage). RESULTS: A preoperative cervical length=25 mm was observed in 82% (n=271) of cases, 16-24 mm in 9% (n=29), and=15 mm in 9% (n=30). Patients with a preoperative cervical length=15 mm showed shorter median procedure-to-delivery interval (5.5 weeks vs. 11.6 (16-24 mm) vs. 13.0 (=25 mm); p

OBJECTIVE: To determine the prevalence of pulmonary hypertension(PAH) in left-sided congenital diaphragmatic hernia(CDH); how we could predict it; and how PAH contributed to the model for mortality prediction.; STUDY DESIGN: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day(d)1,7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio(o/e LHR), liver-herniation, FETO, and gestational age(GA) at delivery. The combined effect of pre-and postnatal variables on mortality was modeled by Cox regression.; RESULTS: Of the 197 neonates, 56(28.4%) died. At d1, 67.5%(133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge.At d1, o/eLHR(OR 0.96) and FETO(OR 2.99) independently correlated to PAH(AUC:0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9;AUC:0.65). None were significant for PAH at discharge.Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction(p=0.02), in a model including o/eLHR(HR:0.94), FETO(HR:0.35), liver herniation(HR:16.78), and PAH(HR:15.95).; CONCLUSIONS: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

OBJECTIVE: To explore and compare fetal cortical brain development and infant neurobehaviour in spontaneously conceived (SC) and assisted reproductive technologies (ART) offspring. METHODS: A prospective cohort study of 210 singleton pregnancies including 70 SC pregnancies, 70 conceived by in vitro fertilization (IVF) following frozen embryo transfer (ET), and 70 IVF after fresh ET. Fetal neurosonography was performed at 32±2 weeks to assess cortical development. Sulci depths were measured off-line and normalized by biparietal diameter. Additionally, Ages & Stages Questionnaires (ASQ) were obtained postnatally, at 12±1 months of corrected age. Comparisons were adjusted by maternal age, ethnicity, nulliparity, fetal sex, weight centile and gestational age at scan for neurosonography, and by maternal age, ethnicity, nulliparity, educational level, employment status, new-born's gestational age at birth, breastfeeding, infant's sex and age at the ASQ evaluation. RESULTS: In comparison to the SC, the fetuses conceived by ART showed statistically significant differences in cortical development, with reduced parieto-occipital (fresh ET mean[SD] 12.5mm[2.5] vs. frozen ET 13.4[2.6] vs. SC 13.4[2.6], p

OBJECTIVE: This study aims to predict perinatal death or severe sequelae in isolated small-for-gestational-age fetuses, diagnosed at a periviable gestational age, based on ultrasound and Doppler parameters at diagnosis. DESIGN: Observational study. SETTING: A tertiary perinatal centre. POPULATION: A cohort of singleton non-malformed fetuses suspected to be small for gestational age (estimated fetal weight, EFW

Fetal Heart Quantification (FetalHQ(®)) is a novel speckle tracking software that permits the study of global and regional ventricular shape and function from a 2D four-chamber-view loop. The 4D-Spatio Temporal Image Correlation (STIC) modality enables the offline analysis of optimized and perfectly aligned cardiac planes. We aimed to evaluate the feasibility and reproducibility of 4D-STIC speckle tracking echocardiography (STE) using FetalHQ(®) and to compare it to 2D STE. We conducted a prospective study including 31 low-risk singleton pregnancies between 20 and 40 weeks of gestation. Four-chamber view volumes and 2D clips were acquired with an apex pointing at 45° and with a frame rate higher than 60 Hz. Morphometric and functional echocardiography was performed by FetalHQ(®). Intra- and interobserver reproducibility were evaluated by the intraclass correlation coefficient (ICC). Our results showed excellent reproducibility (ICC > 0.900) for morphometric evaluation (biventricular area, longitudinal and transverse diameters). Reproducibility was also good (ICC > 0.800) for functional evaluation (biventricular strain, Fractional Area Change, left ventricle volumes, ejection fraction and cardiac output). On the contrary, the study of the sphericity index and shortening fraction of the different ventricular segments showed lower reproducibility (ICC < 0.800). To conclude, 4D-STIC is feasible, reproducible and comparable to 2D echocardiography for the assessment of cardiac morphometry and function.

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition.

BACKGROUND: COVID-19 presents a spectrum of signs and symptoms in pregnant women that might resemble preeclampsia. Differentiation between severe COVID-19 and preeclampsia is difficult in some cases. OBJECTIVE: To study biomarkers of endothelial damage, coagulation, innate immune response, and angiogenesis in preeclampsia and COVID-19 in pregnancy in addition to in vitro alterations in endothelial cells exposed to sera from pregnant women with preeclampsia and COVID-19. STUDY DESIGN: Plasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) and from women with normotensive pregnancies as controls (n=10) and patients with preeclampsia (n=13). A panel of plasmatic biomarkers was assessed, including vascular cell adhesion molecule-1, soluble tumor necrosis factor-receptor I, heparan sulfate, von Willebrand factor antigen (activity and multimeric pattern), a2-antiplasmin, C5b9, neutrophil extracellular traps, placental growth factor, soluble fms-like tyrosine kinase-1, and angiopoietin 2. In addition, microvascular endothelial cells were exposed to patients' sera, and changes in the cell expression of intercellular adhesion molecule 1 on cell membranes and von Willebrand factor release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of p38 mitogen-activated protein kinase phosphorylation. Statistical analysis included univariate and multivariate methods. RESULTS: Biomarker profiles of patients with mild COVID-19 were similar to those of controls. Both preeclampsia and severe COVID-19 showed significant alterations in most circulating biomarkers with distinctive profiles. Whereas severe COVID-19 exhibited higher concentrations of vascular cell adhesion molecule-1, soluble tumor necrosis factor-a receptor I, heparan sulfate, von Willebrand factor antigen, and neutrophil extracellular traps, with a significant reduction of placental growth factor compared with controls, preeclampsia presented a marked increase in vascular cell adhesion molecule-1 and soluble tumor necrosis factor-a receptor I (significantly increased compared with controls and patients with severe COVID-19), with a striking reduction in von Willebrand factor antigen, von Willebrand factor activity, and a2-antiplasmin. As expected, reduced placental growth factor, increased soluble fms-like tyrosine kinase-1 and angiopoietin 2, and a very high soluble fms-like tyrosine kinase-1 to placental growth factor ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and neutrophil extracellular traps was also detected in preeclampsia compared with controls. Principal component analysis demonstrated a clear separation between patients with preeclampsia and the other groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to von Willebrand factor, soluble tumor necrosis factor-receptor I, heparan sulfate, and soluble fms-like tyrosine kinase-1. Von Willebrand factor multimeric analysis revealed the absence of von Willebrand factor high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A), whereas in healthy pregnancies and COVID-19 patients, von Willebrand factor multimeric pattern was normal. Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of intercellular adhesion molecule 1 and von Willebrand factor in endothelial cells in culture compared with controls. However, the effect of preeclampsia was less pronounced than the that of severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19 and preeclampsia sera showed an increase in p38 mitogen-activated protein kinase phosphorylation. Patients with severe COVID-19 and preeclampsia were statistically different from controls, suggesting that both severe COVID-19 and preeclampsia sera can activate inflammatory signaling pathways. CONCLUSION: Although similar in in vitro endothelial dysfunction, preeclampsia and severe COVID-19 exhibit distinctive profiles of circulating biomarkers related to endothelial damage, coagulopathy, and angiogenic imbalance that could aid in the differential diagnosis of these entities.

BACKGROUND: The persistent changes in cardiac structure and function in children who survived twin-to-twin transfusion syndrome remain a matter of concern and controversy. Current fetal echocardiographic parameters and their postnatal evolution can help improve our understanding of the subject. OBJECTIVE: To describe the echocardiographic changes of monochorionic fetuses affected by twin-to-twin transfusion syndrome, the recipient and the donor, before and after laser photocoagulation and to determine their evolution in the third trimester and during their first year of life. STUDY DESIGN: An observational study was conducted including 55 uncomplicated monochorionic diamniotic twins and 78 pairs with twin-to-twin transfusion syndrome, 44 stage I-II and 34 stage III-IV, prospectively enrolled from 2015 until 2018. Comprehensive echocardiography was performed at 4 time periods: before laser photocoagulation, at 24 to 72 hours after surgery, at 28 to 30 weeks of gestation, and at 6 to 12 months after birth. Echocardiographic parameters were transformed to z-scores or indexed for heart area, estimated fetal weight, or body mass surface. RESULTS: At diagnosis, recipients in all stages presented larger hearts (cardiothoracic ratio z-score: 2.77 [0.8] vs controls: -0.03 [0.5]; P

The information available on the effects of maternal dietary habits on systemic inflammation and adverse maternal outcomes is limited. We aimed to evaluate whether Dietary Inflammatory Index (DII) score during pregnancy is associated with maternal body mass index (BMI), Mediterranean diet (MD) adherence, and perinatal outcomes. At 19-23 weeks' gestation, 1028 pregnant women were recruited. Dietary information was assessed using a 17-item dietary score to evaluate MD adherence and a validated 151-item food frequency questionnaire. DII score was established according to 33 food and nutritional proinflammatory and anti-inflammatory items. Participants were distributed into tertiles according to the DII score, where a lower DII score (first tertile) represented an anti-inflammatory diet and the third tertile represented the more proinflammatory diet. Maternal characteristics and perinatal outcomes were collected, and newborns' birthweight percentiles were calculated. Adjusted logistic regression models were used to assess the association of the DII score with maternal and perinatal characteristics, setting the third tertile as the reference group. Women in the third tertile showed lower adherence to MD score compared to the first tertile: median (25th to 75th percentile) 9 (7 to 11) vs. 6 (4.25 to 8), p < 0.001. The proinflammatory diet was significantly associated with a higher maternal pre-pregnancy BMI (adjusted ß = 0.88; 95% CI: 0.31 to 1.45) and lower newborn's birthweight percentile (adjusted ß = -9.84th; 95% CI: -19.6 to -0.12). These data show that a proinflammatory diet profile may be associated with maternal overweight and fetal undergrowth.