Search

OBJECTIVE: To compare the effectiveness of cardiotocography plus ST analysis with cardiotocography alone during labor. DATA SOURCES: Randomized controlled trials were identified by searching electronic databases. METHODS OF STUDY SELECTION: We included all randomized controlled trials comparing intrapartum fetal monitoring with cardiotocography plus ST analysis with cardiotocography alone. The primary outcome (ie, perinatal composite outcome) was a composite of intrapartum fetal death, neonatal death, Apgar score 3 or less at 5 minutes, neonatal seizure, metabolic acidosis (defined as umbilical arterial pH 7.05 or less, and extracellular fluid base deficit 12 mmol/L or greater), intubation for ventilation at delivery, or neonatal encephalopathy. TABULATION, INTEGRATION, AND RESULTS: Six randomized controlled trials, which included 26,529 laboring singletons with cephalic presentation at term, were analyzed. Compared with women who were randomized to cardiotocography, those who were randomized to ST analysis and cardiotocography had a similar incidence of perinatal composite outcome (1.5% compared with 1.6%; relative risk [RR] 0.90, 95% confidence interval [CI] 0.74-1.10; five studies), neonatal metabolic acidosis (0.5% compared with 0.7%; RR 0.74, 95% CI 0.54-1.02; five studies), admission to the neonatal intensive care unit (5.4% compared with 5.5%; RR 0.99, 95% CI 0.90-1.10; six studies), perinatal death (0.1% compared with 0.1%; RR 1.71, 95% CI 0.67-4.33; six studies), neonatal encephalopathy (0.1% compared with 0.2%; RR 0.62, 95% CI 0.25-1.52; six studies), cesarean delivery (13.8% compared with 14.0%; RR 0.96, 95% CI 0.85-1.08; six studies), and operative delivery (either cesarean or operative vaginal delivery) (23.9% compared with 25.1%; RR 0.93, 95% CI 0.86-1.01; six studies). CONCLUSION: The use of ST analysis during labor as an adjunct to the standard cardiotocography does not improve perinatal outcomes or decrease cesarean delivery.

BACKGROUND: Antiphospholipid syndrome is an autoimmune, hypercoagulable state that is caused by antiphospholipid antibodies. Anticardiolipin antibodies, anti-β2 glycoprotein-I, and lupus anticoagulant are the main autoantibodies found in antiphospholipid syndrome. Despite the amassed body of clinical knowledge, the risk of obstetric complications that are associated with specific antibody profile has not been well-established. OBJECTIVE: The purpose of this study was to assess the risk of obstetric complications in women with primary antiphospholipid syndrome that is associated with specific antibody profile. STUDY DESIGN: The Pregnancy In Women With Antiphospholipid Syndrome study is a multicenter, retrospective, cohort study. Diagnosis and classification of antiphospholipid syndrome were based on the 2006 International revised criteria. All women included in the study had at least 1 clinical criteria for antiphospholipid syndrome, were positive for at least 1 antiphospholipid antibody (anticardiolipin antibodies, anti-β2 glycoprotein-I, and/or lupus anticoagulant), and were treated with low-dose aspirin and prophylactic low molecular weight heparin from the first trimester. Only singleton pregnancies with primary antiphospholipid syndrome were included. The primary outcome was live birth, defined as any delivery of a live infant after 22 weeks gestation. The secondary outcomes were preeclampsia with and without severe features, intrauterine growth restriction, and stillbirth. We planned to assess the outcomes that are associated with the various antibody profile (test result for lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein-I). RESULTS: There were 750 singleton pregnancies with primary antiphospholipid syndrome in the study cohort: 54 (7.2%) were positive for lupus anticoagulant only; 458 (61.0%) were positive for anticardiolipin antibodies only; 128 (17.1%) were positive for anti-β2 glycoprotein-I only; 90 (12.0%) were double positive and lupus anticoagulant negative, and 20 (2.7%) were triple positive. The incidence of live birth in each of these categories was 79.6%, 56.3%, 47.7%, 43.3%, and 30.0%, respectively. Compared with women with only 1 antibody positive test results, women with multiple antibody positive results had a significantly lower live birth rate (40.9% vs 56.6%; adjusted odds ratio, 0.71; 95% confidence interval, 0.51-0.90). Also, they were at increased risk of preeclampsia without (54.5% vs 34.8%; adjusted odds ratio, 1.56; 95% confidence interval, 1.22-1.95) and with severe features (22.7% vs 13.8%, adjusted odds ratio, 1.66; 95% confidence interval, 1.19-2.49), of intrauterine growth restriction (53.6% vs 40.8%; adjusted odds ratio, 2.31; 95% confidence interval, 1.17-2.61) and of stillbirth (36.4% vs 21.7%; adjusted odds ratio, 2.67; 95% confidence interval, 1.22-2.94). In women with only 1 positive test result, women with anti-β2 glycoprotein-I positivity present alone had a significantly lower live birth rate (47.7% vs 56.3% vs 79.6%; P1 antibody positivity, triple-positive women had a lower live birth rate (30% vs 43.3%; adjusted odds ratio,0.69; 95% confidence interval, 0.22-0.91) and a higher incidence of intrauterine growth restriction (70.0% vs 50.0%; adjusted odds ratio,2.40; 95% confidence interval, 1.15-2.99) compared with double positive and lupus anticoagulant negative women. CONCLUSION: In singleton pregnancies with primary antiphospholipid syndrome, anticardiolipin antibody is the most common sole antiphospholipid antibody present, but anti-β2 glycoprotein-I is the one associated with the lowest live birth rate and highest incidence of preeclampsia, intrauterine growth restriction, and stillbirth, compared with the presence of anticardiolipin antibodies or lupus anticoagulant alone. Women with primary antiphospholipid syndrome have an increased risk of obstetric complications and lower live birth rate when

OBJECTIVE: To evaluate whether intrapartum cardiotocography with computer analysis decreases the incidence of newborn metabolic acidosis or obstetric intervention when compared with visual analysis through a systematic review with meta-analysis of randomized controlled trials. METHODS: The research was conducted using Medline, Embase, Web of Science, Scopus, ClinicalTrial.gov, Ovid and Cochrane Library as electronic databases from the inception of each database to May 2018. Selection criteria included randomized trial evaluating women with cephalic presentation at term or late preterm term during labor who were randomized to electronic fetal heart rate monitoring with either computer analysis (i.e. intervention group) or standard visual analysis (i.e. control group). Trials evaluating antenatal fetal heart rate monitoring in women not in labor were excluded. The primary outcome was incidence of newborn metabolic acidosis, defined as pH less than 7.05 and base deficit greater than 12 mmol/L. Secondary outcomes were mode of delivery, admission to neonatal intensive care unit, hypoxic-ischemic encephalopathy, and perinatal death. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Three randomized controlled trials (RCTs), including 54,492 participants, which met inclusion criteria for this meta-analysis, were analyzed. All the included trials enrolled women with cephalic presentation at term or late preterm. Women were randomized in the active first stage of labor and all of them received continuous cardiotocography (CTG) from randomization until delivery. Women who received continuous CTG during labor with computerized analysis had similar risk of newborn metabolic acidosis. No between group differences were found in the secondary outcomes. CONCLUSIONS: Compared with visual analysis, use of computer analysis of fetal monitoring signals during labor did not significantly reduce the rate of metabolic acidosis or obstetric intervention.

KRAS is one of the most mutated genes in human cancer. It is controlled by a G4 motif located upstream of the transcription start site. In this paper, we demonstrate that 8-oxoguanine (8-oxoG), being more abundant in G4 than in non-G4 regions, is a new player in the regulation of this oncogene. We designed oligonucleotides mimicking the KRAS G4-motif and found that 8-oxoG impacts folding and stability of the G-quadruplex. Dimethylsulphate-footprinting showed that the G-run carrying 8-oxoG is excluded from the G-tetrads and replaced by a redundant G-run in the KRAS G4-motif. Chromatin immunoprecipitation revealed that the base-excision repair protein OGG1 is recruited to the KRAS promoter when the level of 8-oxoG in the G4 region is raised by H2O2. Polyacrylamide gel electrophoresis evidenced that OGG1 removes 8-oxoG from the G4-motif in duplex, but when folded it binds to the G-quadruplex in a non-productive way. We also found that 8-oxoG enhances the recruitment to the KRAS promoter of MAZ and hnRNP A1, two nuclear factors essential for transcription. All this suggests that 8-oxoG in the promoter G4 region could have an epigenetic potential for the control of gene expression.

KRAS is one of the most mutated genes in human cancer. Its crucial role in the tumourigenesis of pancreatic ductal adenocarcinoma (PDAC) has been widely demonstrated. As this deadly cancer does not sufficiently respond to conventional chemotherapies, it is important to increase our knowledge of pancreatic cancer biology, in particular how oncogenic KRAS is regulated. The promoter of KRAS contains a GA-element composed of runs of guanines that fold into a G4 structure. This unusual DNA conformation is recognized by several nuclear proteins, including MAZ and hnRNP A1. Recent data have revealed that KRAS is interconnected to ILK and hnRNP A1 in a circuitry that enables pancreatic cancer cells to maintain an aggressive phenotype. The present review illustrates recent advances on how KRAS is regulated in pancreatic cancer cells, focusing on the formation of G4 structures in the KRAS promoter and their interaction with hnRNP A1. The newly discovered KRAS-ILK-hnRNP A1 regulatory loop is discussed, emphasizing its potential as a therapeutic target for PDAC-specific molecules. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

Immunity and cytokines serve crucial roles in cutaneous melanoma. The present study investigated whether a variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RA) gene (IL-1RN) located in intron 2 (rs2234663) is associated with cutaneous melanoma. A total of 515 subjects were studied, 133 of which were cutaneous melanoma cases (72 stage I+II non-metastatic melanoma cases and 61 stage III+IV metastatic melanoma cases), and 382 subjects were matching healthy controls from the Friuli-Venezia-Giulia Region located in Northeast Italy, an area with a high melanoma incidence. The IL-1RN-VNTR polymorphism was determined by DNA fragment length analysis following PCR amplification. According to the number of 86-bp repeats, five different IL-1RN alleles were identified: Allele 1 (4-repeats), allele 2 (2-repeats, short allele), allele 3 (5-repeats), allele 4 (3-repeats) and allele 5 (6-repeats). Alleles with three or more 86-bp repeats, i.e. allele 1, 3, 4 and 5 were collectively denoted as long (L) repeats. The present study revealed that IL-1RN-VNTR 1/2 and 2/L genotypes were more frequent among patients with cutaneous melanoma (43.6 and 45.1%, respectively) compared with healthy controls [29.6 and 30.6%, respectively; odds ratio (OR), 1.84; CI, 1.22–2.77; P=0.003; and OR, 1.66; CI, 1.24–2.79; P=0.002, respectively]. Conversely, the IL-1RN-VNTR 1/1 genotype was less frequent among melanoma cases (45.9%) compared with healthy controls (57.9%; OR, 0.62; CI, 0.41–0.92; P=0.017). Comparison of metastatic vs. non-metastatic melanoma cases identified no significant differences. The present study first demonstrated that carriage of the 1/1 IL-1RN-VNTR genotype was protective, whereas 1/2 and 2/L was a risk factor for patients with cutaneous melanoma vs. healthy controls. The short allele 2 was associated with higher expression levels of IL-1RA, a potent competitive inhibitor of the proinflammatory cytokines IL-1α and IL-1β. VNTR-IL-1RN polymorphism may affect susceptibility to melanoma and, thus, it is a potential novel diagnostic biomarker for melanoma. The present study increased the understanding of genetic melanoma susceptibility/carcinogenesis, and may indicate novel strategies in the personalized prevention of cutaneous melanoma.

Background: Although the evidence regarding the benefit of using ST waveform analysis of the fetal electrocardiogram is conflicting, ST waveform analysis is considered as adjunct to identify fetuses at risk for asphyxia in our center. Most randomized controlled trials and meta-analyses have not shown a significant decrease in umbilical metabolic acidosis, while some observational studies have shown a gradual decrease of this outcome over a longer period of time. Observational studies can give more insight into the effect of implementation of the ST technology in daily clinical practice. Objective: To evaluate the change in frequency of perinatal intervention and adverse neonatal outcome after the implementation of ST waveform analysis of the fetal electrocardiogram from 2000 to 2013. Study Design: This retrospective longitudinal study was conducted in a tertiary referral center. A total of 19,664 medium- and high-risk singleton pregnancies with fetuses in cephalic presentation, a gestational age of ≥36 weeks, and the intention to deliver vaginally were included. ST waveform analysis of the fetal electrocardiogram was implemented in the year 2000 and by 2010 all deliveries were monitored using this technology. Data were collected on the following perinatal outcomes: fetal blood sampling, mode of delivery, umbilical cord blood gases, Apgar scores, neonatal encephalopathy, and perinatal death. Longitudinal trend analysis was used to detect changes over time in all deliveries monitored by cardiotocography either alone or in adjunct to ST waveform analysis of the fetal electrocardiogram. Logistic regression was used to correct for possible confounders. Results: The umbilical artery metabolic acidosis rate declined from 2.5% (average rate of 2000 + 2001 + 2002) to 0.4% (average of 2011 + 2012 + 2013) (P < .001), which represents an 84% decrease. This decrease largely occurred between 2006 and 2008, during the Dutch randomized trial on fetal electrocardiogram ST waveform analysis. At this time, approximately 20% of deliveries were monitored using this method. Furthermore, there were significant reductions in fetal blood sampling rate (P < .001). Overall cesarean and vaginal instrumental deliveries decreased significantly (P < .001), but not for fetal distress. There were no changes in the Apgar scores. The incidence of neonatal encephalopathy was significantly lower in the second part of the study (odds ratio 0.39, 95% confidence interval 0.17–0.89). Conclusion: There was an 84% decrease in the incidence of umbilical artery metabolic acidosis in all deliveries between 2000 and 2013. The neonatal encephalopathy rate, fetal blood sampling rate, and the total number of cesarean and vaginal instrumental deliveries also decreased.

Nowadays, active targeting of nanotherapeutics is a challenging issue. Here, we propose a rational design of a ternary nanoassembly (SAP) composed of nonionic amphiphilic beta-cyclodextrins (amphiphilic CD) incorporating pheophorbide (Pheo) as a phototherapeutic and an adamantanyl-folic acid conjugate (Ada-FA) to target tumor cells overexpressing alpha-folate receptor (FR-alpha(+)). Dynamic light scattering and zeta-potential pointed out the presence of nanoassemblies bearing a negative surface charge (zeta = -51 mV). Morphology of SAP was investigated by atomic force microscopy and microphotoluminescence, indicating the presence of highly emissive near-spherical assemblies of about 280 nm in size. Complementary spectroscopic techniques such as ROESY-NMR, UV/vis and steady-state fluorescence revealed that the folic acid protrudes out of amphiphilic CD rims, prone for recognition with FR-alpha. Pheo was strongly loaded in the nanoassembly mostly in monomeric form, thus generating singlet oxygen (O-1(2)) and consequentely showing phototherapeutic action. SAP remained stable until 2 weeks in aqueous solutions. Stability studies in biologically relevant media pointed out the ability of SAP to interact with serum proteins by means of the oligoethylenglycole fringe, without destabilization. Release experiments demonstrated the sustained release of Pheo from SAP in environments mimiking physiological conditions (similar to 20% within 1 week), plausibly suggesting low Pheo leaking and high integrity of the assembly within 24 h, time spent on average to reach the target sites. Cellular uptake of SAP was confirmed by confocal microscopy, pointing out that SAP was internalized into the tumoral cells expressing FR-alpha more efficiently than SP. SAP showed improved phototoxicity in human breast MCF-7 cancer cells FR-alpha(+) (IC50 = 270 nM) with respect to human prostate carcinoma PC3 cells (IC50 = 700 nM) that express a low level of that receptor (FR-alpha(-)). Finally, an improved phototoxicity in FR-alpha(+) MCF-7 cells (IC50 = 270 nM) was assessed after treatment with SAP vs SP (IC50 = 600 nM) which was designed without Ada-FA as a targeting unit.

In highly proliferating cancer cells oncogenic mutations reprogram the metabolism and increase the production of reactive oxygen species (ROS). Cancer cells prevent ROS accumulation by upregulating antioxidant systems. Here we show that an increase of oxidative stress (ROS and singlet oxygen), generated by photoactivated TMPyP4, results in the upregulation of KRAS and Nrf2, the major regulator of the redox homeostasis. In agreement with a previous observation, the ectopic expression of KRAS G12D or G12 V is found to stimulate Nrf2. This suggests that ROS, KRAS and Nrf2 establish a molecular axis controlling the redox homeostasis in cancer cells. We found that this axis also modulates the function of the NF-kB/Snail/RKIP circuitry, regulating the survival and apoptosis pathways. Our data show that low ROS levels, obtained when Nrf2 is activated by KRAS, results in the upregulation of prosurvival Snail and simultaneous downregulation of proapoptotic RKIP: an expression pattern favouring cell proliferation. By contrast, high ROS levels, obtained when Nrf2 is inhibited by a small molecule (luteolin), favour apoptosis by upregulating proapoptotic RKIP and downregulating prosurvival Snail. The results of this study are useful to design efficient photodynamic therapy (PDT) against cancer. We hypothesize that cancer cells can be sensitized to PDT when the photosensitizer is used in the presence of an inhibitor of Nrf2 (adjuvant). To test this hypothesis, we used luteolin (3′,4′,5,7-tetrahydroflavone) as Nrf2 inhibitor, since it reduces the expression of Nrf2 and increases intracellular ROS. By means of colony formation and viability assays we found that when Nrf2 is inhibited, PDT shows an increase of efficiency up to 45%.

BACKGROUND Cognitive-behavioral therapy (CBT) is the first-choice intervention for obsessive-compulsive disorder (OCD); however, a notable proportion of patients either do not respond to treatment or relapse after CBT. Mindfulness-based treatment has been suggested as an alternative or complementary therapeutic strategy for OCD. However, only a few studies have focused on its application in clinical samples. OBJECTIVE To evaluate the impact of a new treatment, called "Mindfulness-based Cognitive Therapy for OCD." It is an 11-session manualized group intervention that integrates elements of CBT, mindfulness, compassion-focused therapy, and acceptance and commitment therapy. METHODS The program was delivered to 35 patients with a primary diagnosis of OCD. RESULTS Participants demonstrated good adherence to the intervention. There was a significant reduction in mean total score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS-TS) (P