The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer.

BACKGROUND: An effect of non-oncology medications on cancer outcome has been proposed. In this study, we aimed to systematically examine the impact of commonly prescribed non-oncology drugs on clinical risk and on the genomic risk [based on the Oncotype DX recurrence score (RS)] in early breast cancer (BC). EXPERIMENTAL DESIGN: We collected data on clinical risk (stage and grade), genomic risk (Oncotype DX RS), and on non-oncology medications administered to 1423 patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative BC during the month of their surgery. The influence of various medications on clinical and genomic risks was evaluated by statistical analysis. RESULTS: Out of the multiple drugs we examined, levothyroxine was significantly associated with a high Oncotype DX RS (mean 24.78; P < 0.0001) and metformin with a low Oncotype DX RS (mean 14.87; P < 0.01) compared with patients not receiving other non-oncology drugs (mean 18.7). By contrast, there were no differences in the clinical risk between patients receiving metformin, levothyroxine, or no other non-oncology drugs. Notably, there was no association between the consumption of levothyroxine and metformin and proliferation marker (Ki67) levels, but both drugs were significantly associated with progesterone-related features, suggesting that they influence genomic risk through estrogen-dependent signaling. CONCLUSIONS: The results of this study indicate a significant impact of metformin and levothyroxine on clinical decisions in luminal BC, with potential impact on the clinical course of these patients.

Publisher Correction: Tidal and diel orchestration of behaviour and gene expression in an intertidal mollusc.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Characterization of the miRNA regulators of the human ovulatory cascade.

Ovarian follicular development and ovulation are complex and tightly regulated processes that involve regulation by microRNAs (miRNAs). We previously identified differentially expressed mRNAs between human cumulus granulosa cells (CGCs) from immature early antral follicles (germinal vesicle - GV) and mature preovulatory follicles (metaphase II - M2). In this study, we performed an integrated analysis of the transcriptome and miRNome in CGCs obtained from the GV cumulus-oocyte complex (COC) obtained from IVM and M2 COC obtained from IVF. A total of 43 differentially expressed miRNAs were identified. Using Ingenuity IPA analysis, we identified 7288 potential miRNA-regulated target genes. Two hundred thirty-four of these target genes were also found in our previously generated ovulatory gene library while exhibiting anti-correlated expression to the identified miRNAs. IPA pathway analysis suggested that miR-21 and FOXM1 cooperatively inhibit CDC25A, TOP2A and PRC1. We identified a mechanism for the temporary inhibition of VEGF during ovulation by TGFB1, miR-16-5p and miR-34a-5p. The linkage bioinformatics analysis between the libraries of the coding genes from our preliminary study with the newly generated library of regulatory miRNAs provides us a comprehensive, integrated overview of the miRNA-mRNA co-regulatory networks that may play a key role in controlling post-transcriptomic regulation of the ovulatory process.

Tidal and diel orchestration of behaviour and gene expression in an intertidal mollusc.

Intertidal inhabitants are exposed to the 24-hour solar day, and the 12.4 hour rising and falling of the tides. One or both of these cycles govern intertidal organisms' behaviour and physiology, yet little is known about the molecular clockworks of tidal rhythmicity. Here, we show that the limpet Cellana rota exhibits robust tidally rhythmic behaviour and gene expression. We assembled a de-novo transcriptome, identifying novel tidal, along with known circadian clock genes. Surprisingly, most of the putative circadian clock genes, lack a typical rhythmicity. We identified numerous tidally rhythmic genes and pathways commonly associated with the circadian clock. We show that not only is the behaviour of an intertidal organism in tune with the tides, but so too are many of its genes and pathways. These findings highlight the plasticity of biological timekeeping in nature, strengthening the growing notion that the role of 'canonical' circadian clock genes may be more fluid than previously thought, as exhibited in an organism which has evolved in an environment where tidal oscillations are the dominant driving force.

CircosVCF: circos visualization of whole-genome sequence variations stored in VCF files.

Summary: Visualization of whole-genomic variations in a meaningful manner assists researchers in gaining new insights into the underlying data, especially when it comes in the context of whole genome comparisons. CircosVCF is a web based visualization tool for genome-wide variant data described in VCF files, using circos plots. The user friendly interface of CircosVCF supports an interactive design of the circles in the plot, and the integration of additional information such as experimental data or annotations. The provided visualization capabilities give a broad overview of the genomic relationships between genomes, and allow identification of specific meaningful SNPs regions. Availability and Implementation: CircosVCF was implemented in JavaScript and is available at http://www.ariel.ac.il/research/fbl/software. Contact: malisa@ariel.ac.il. Supplementary information: Supplementary data are available at Bioinformatics online.

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation.

Cumulus expansion and oocyte maturation are central processes in ovulation. Knowledge gained from rodent and other mammalian models has revealed some of the molecular pathways associated with these processes. However, the equivalent pathways in humans have not been thoroughly studied and remain unidentified. Compact cumulus cells (CCs) from germinal vesicle cumulus oocyte complexes (COCs) were obtained from patients undergoing in vitro maturation (IVM) procedures. Expanded CCs from metaphase 2 COC were obtained from patients undergoing IVF/ICSI. Global transcriptome profiles of the samples were obtained using state-of-the-art RNA sequencing techniques. We identified 1746 differentially expressed (DE) genes between compact and expanded CCs. Most of these genes were involved in cellular growth and proliferation, cellular movement, cell cycle, cell-to-cell signaling and interaction, extracellular matrix and steroidogenesis. Out of the DE genes, we found 89 long noncoding RNAs, of which 12 are encoded within introns of genes known to be involved in granulosa cell processes. This suggests that unique noncoding RNA transcripts may contribute to the regulation of cumulus expansion and oocyte maturation. Using global transcriptome sequencing, we were able to generate a library of genes regulated during cumulus expansion and oocyte maturation processes. Analysis of these genes allowed us to identify important new genes and noncoding RNAs potentially involved in COC maturation and cumulus expansion. These results may increase our understanding of the process of oocyte maturation and could ultimately improve the efficacy of IVM treatment.

Is severe macrosomia manifested at 11-14 weeks of gestation?

OBJECTIVE: To determine the association between fetal biometry in the first or early second trimester and severe macrosomia at delivery. METHODS: This case-control study included 30 term severely macrosomic neonates; 90 appropriate-for-gestational age (AGA) neonates served as controls. All pregnancies underwent nuchal translucency (NT) screening at 11-14 weeks' gestation. Pregnancies were dated by accurate last menstrual period consistent with crown-rump length (CRL) measurements at the time of screening, early pregnancy CRL or date of fertilization. The association between birth weight and the difference between the measured and the expected CRL at the time of NT screening was analyzed. RESULTS: The difference between measured and expected CRL, expressed both in mm and in days of gestation, was statistically greater in the severely macrosomic neonates compared with controls (mean, 6.66 +/- 4.78 mm vs. 1.17 +/- 4.6 mm, P < 0.0001 and 3 +/- 2.2 days vs. 0.5 +/- 2.3 days, P < 0.0001, respectively). Furthermore, there were significant correlations between the extent of macrosomia and the discrepancy between expected and measured fetal size at the time of NT screening (r = 0.47, P < 0.01 and r = 0.48, P < 0.01, respectively). CONCLUSION: Severe macrosomia apparently manifests as early as 11-14 weeks' gestation.

Does the availability of maternal HbA1c results improve the accuracy of sonographic diagnosis of macrosomia?

OBJECTIVE: To determine whether measuring maternal glycosylated hemoglobin (HbA1c) can improve the accuracy of sonographic estimation of fetal macrosomia. METHODS: Sonographic estimation of fetal weight (EFW) and maternal HbA1c were obtained in term, non-diabetic patients within 1 week before delivery. Neonatal birth weights were recorded at delivery and compared with both sonographic estimations and HbA1c. Macrosomia was defined as birth weight of >or=4000 g. The absolute error of the sonographic EFW was calculated. Receiver-operating characteristics (ROC) curve analysis was used to evaluate sonographic EFW and HbA1c as predictors of birth weight >or=4000 g. Variables were tested using regression analysis and student's t-test. RESULTS: One hundred and sixty two patients were evaluated between July and December 2002. Twenty-eight patients (17.3%) delivered macrosomic infants. Sonographic EFW >or=4000 g predicted macrosomia with sensitivity, specificity and positive and negative predictive values of 66.6%, 88.8%, 54.5% and 93.0%, respectively. Its overall accuracy was 85.5%. The area under the ROC curve of sonographic EFW in the prediction of macrosomia was 0.9 (P < 0.001). HbA1c levels in women delivering macrosomic and non-macrosomic neonates were 5.3 +/- 0.7% and 5.2 +/- 0.5%, respectively (P = 0.27). The area under the ROC curve of HbA1c in the prediction of macrosomia was 0.53 (P = 0.27). CONCLUSIONS: Maternal HbA1c is not a useful test in the prediction of birth weight. It therefore cannot be used to improve the accuracy of sonographic EFW.

Inferior vena cava thrombosis presenting as non-immune hydrops in the fetus of a woman with diabetes.

We present a rare case of non-immune hydrops fetalis (NIHF) caused by a thrombus in the inferior vena cava in a neonate with low levels of anti-thrombin III. The diagnosis of (NIHF) was made in utero in a 43-year-old woman with poorly controlled gestational diabetes who subsequently developed pre-eclampsia. Cesarean section was performed due to fetal compromise and worsening pre-eclampsia. The thrombus resolved after neonatal treatment with heparin.

Nucleated red blood cells in human fetal scalp capillary blood samples: a feasibility study.

OBJECTIVE: Elevated umbilical cord nucleated red blood cell (NRBC) counts have been suggested as a predictor of adverse perinatal outcome. We sought to evaluate the feasibility of obtaining fetal scalp capillary blood NRBC counts during labor and to assess their correlation with umbilical cord NRBC counts. METHODS: Fetal scalp capillary blood specimens were prospectively collected in laboring patients who underwent scalp sampling because of the presence of an abnormal fetal heart rate pattern. Matched umbilical cord blood samples were collected immediately after birth. Outcome measures were the feasibility of obtaining fetal scalp NRBC counts and their correlation with umbilical cord NRBC counts. RESULTS: Thirteen term singleton pregnancies formed the study population. In four patients, fetal scalp capillary blood sampling was performed twice. Of the attempts to evaluate fetal scalp capillary samples for NRBC counts, 16 out of 17 (94.1%) were successful. The mean fetal scalp capillary blood NRBC count per 100 white blood cells was 12.6 +/- 7.6 (+/- SD). Umbilical cord mixed, venous and arterial NRBC counts were 15.5 +/- 8.8, 13.4 +/- 10.7 and 12.6 +/- 10.7, with p = 0.09, p = 0.59 and p = 0.68, respectively, when compared to the corresponding scalp sample. The Spearman rank correlation between fetal scalp capillary samples and umbilical cord mixed, venous and arterial NRBC counts were r = 0.86, r = 0.92 and r = 0.95, respectively, with all p values < 0.001. CONCLUSION: Previous studies have established the clinical utility of umbilical cord NRBC counts. Our study demonstrated that it was possible to obtain NRBC counts from a fetal scalp capillary sample and that these counts correlated highly with umbilical cord NRBC counts. Future studies are needed to evaluate fetal scalp NRBC counts as a predictor of perinatal outcome.

The association between fetal and maternal sleep patterns in third-trimester pregnancies.

OBJECTIVE: We sought to investigate the association between fetal heart rate and maternal electroencephalogram patterns during overnight sleep. STUDY DESIGN: Data were collected prospectively between December 1, 1999, and June 30, 2001. Initially, the participating patients were asked to complete a 66-question survey for the assessment of maternal perception of sleep quality that was referred to as the sleep disturbance score: a continuous score from 0 (no evidence of sleep disturbance) to 110 (extreme sleep disturbance). Second, a subgroup of patients was monitored overnight by concomitant fetal heart rate and maternal electroencephalogram tracings. Statistical analysis included the Student t test, chi2 test, logistic regression, and Cramer's V contingency correlation. RESULTS: One hundred two singleton pregnancies formed the study population. The mean sleep disturbance score was 26.7 +/- 9.9. Maternal age was the only variable that correlated with sleep disturbance score. A subgroup of 11 patients was studied overnight. A significant correlation between active fetal sleep and maternal wakefulness was demonstrated in 6 patients. The mean sleep disturbance score for these patients was significantly higher than for patients without such correlation (P =.04). CONCLUSION: This study establishes an association between fetal activity and maternal wakefulness, which explains many of the maternal awakenings during sleep in the third trimester.

Maternal pain and anxiety in genetic amniocentesis: expectation versus reality.

OBJECTIVE: To investigate maternal perceptions of both pain and anxiety before and after genetic amniocentesis. STUDY DESIGN: This prospective study of midtrimester, singleton pregnancies was conducted between March 2000 and July 2000. Study variables included patient demographics, medical and obstetric histories, indication for amniocentesis and a description of the source of information used by the patient regarding the procedure and technical degree of difficulty. Maternal pain and anxiety associated with performing amniocentesis were subjectively quantified with the use of the visual analog scale (VAS). Statistical analysis included Wilcoxon signed rank test, anova, and simple and stepwise regression analyses. RESULTS: One hundred and eighty-three women participated in the study. Perception of pain before amniocentesis was significantly higher compared to that expressed immediately after the procedure, with a mean VAS score of 3.7 +/- 2.5 vs. 2.1 +/- 2.0 (P < 0.0001). Similarly, perception of anxiety was significantly greater prior to the procedure, with a mean VAS score of 4.6 +/- 2.8 vs. 2.8 +/- 2.4 after the amniocentesis (P < 0.0001). Perceptions of pain and anxiety were significantly and positively correlated to each other both before and after the procedure (P < 0.0001). History of a prior amniocentesis was the only variable associated with reducing expected pain and anxiety (negative correlation, P < 0.001), whereas the technical degree of difficulty was the only significant variable impacting on the actual pain and anxiety (positive correlation, P < 0.005). CONCLUSIONS: Preamniocentesis counseling should emphasize the fact that, for most women, the actual pain and anxiety experienced during the procedure are significantly lower than expected. In fact, on a scale of 0-10, the mean level of pain was only 2.1, with a slightly higher mean level of anxiety.

Non-reassuring fetal status in the prolonged pregnancy: the impact of fetal weight.

OBJECTIVE: To evaluate the incidence of abnormal fetal findings and Cesarean delivery for non-reassuring fetal status as a function of birth weight in the uncomplicated prolonged pregnancy. METHODS: Seven hundred and ninety-two patients at or beyond 41 weeks' gestation were managed expectantly. Population-specific birth-weight percentiles were calculated. Fetuses were retrospectively categorized as small (birth weight < 10th percentile), average (10th percentile < or = birth weight < or = 90th percentile) or large (birth weight > 90th percentile). The incidences of abnormal antepartum fetal testing results (i.e. oligohydramnios and/or abnormal non-stress testing) and Cesarean delivery for intrapartum non-reassuring fetal status were calculated for these three birth-weight categories. RESULTS: There was a significant inverse relationship between the incidence of abnormal fetal testing and birth-weight category (36%, 14% and 9% for small, average and large fetuses, respectively, P < 0.001). Small fetuses were more likely to require a Cesarean delivery for non-reassuring fetal status during labor than were all other fetuses (12.3% vs. 5.3%, P = 0.024). CONCLUSIONS: The frequency of oligohydramnios and abnormal non-stress testing is inversely related to birth weight in the expectantly managed prolonged pregnancy. In addition, small fetuses born at or beyond 41 weeks' gestation have an increased rate of Cesarean delivery for intrapartum non-reassuring fetal status.

Umbilical artery Doppler velocimetry--an update.

Doppler ultrasonography was introduced into clinical obstetric practice over 20 years ago. It is also accepted that a variety of common obstetrical complications such as preeclampsia and intrauterine growth restriction have their origin in abnormal development of the placental vasculature and this could be reflected in abnormal Doppler velocimetry. Doppler velocimetry of the umbilical artery has been the subject of multiple clinical studies but results have often been disputed due to differences in study populations and methodologies. In recent years, meta-analysis of randomized clinical trials have shown that incorporation of Doppler velocimetry into clinical practice will reduce perinatal mortality in high-risk patients. This article reviews the data of the meta-analyses as it pertains to the management of high-risk pregnant patients.

The impact of maternal ketonuria on fetal test results in the setting of postterm pregnancy.

OBJECTIVE: The aim of this study was to determine whether ketonuria, a commonly assessed urinary marker of maternal starvation and dehydration, is associated with abnormal fetal test results in the setting of postterm pregnancy. STUDY DESIGN: During a 4-year period (January 1993-December 1996), a total of 3655 visits for antepartum maternal-fetal testing of postterm pregnancies (> or =41 weeks' gestation) occurred at our institution. Maternal assessment included vital signs and urinalysis. The presence and degree of maternal ketonuria was correlated against abnormal results of fetal heart rate tests, nonstress tests, amniotic fluid index measurements, and biophysical profile scores performed on the same day. RESULTS: There were 3601 encounters suitable for inclusion in the study. Clinically detectable ketonuria occurred in 10.9% of the patients studied. Patients with clinically detectable ketonuria were at increased risk relative to patients without ketonuria for abnormal outcomes during postterm testing, including the presence of oligohydramnios (24% vs. 9.3%; P<.0001 ), nonreactive nonstress tests (6.2% vs. 2.15%; P<.0001), and fetal heart rate decelerations (14% vs 9.2%; P =.0039 ). CONCLUSION: Maternal ketonuria among patients with postterm pregnancy was associated with a >2-fold increase in the occurrence of oligohydramnios, a 3-fold increase in nonreactive nonstress tests, and a significant increase in fetal heart rate decelerations. Further studies are required to evaluate the potential benefits of treating ketonuria before fetal testing.

Sonographic and clinical methods in the diagnosis of macrosomia.

Receiver operator characteristic curves for both clinical and sonographic predictions of macrosomia subsume areas between 0.81 and 0.95, significantly larger than the area of 0.5 that indicates a useless test. Thus, these tests are defined as useful from a statistical point of view. Prediction of macrosomia by clinical or imaging techniques, however, is limited by the substantial false-positive and false-negative rates inherent in these tests. We recommend that physicians continue to use clinical methods to estimate fetal weight, including asking women with parity to provide their own estimates. We recognize that the relative error associated with clinical or sonographic estimates of fetal weight limits their use in clinical practice. Sonographic laboratories may improve their results by performing ROC curve analysis on their own data and by selecting cutoff values that best predict macrosomia in their setting. Serial sonographic measurements that are above the limits chosen to define macrosomia increase the likelihood that a birth weight will be macrosomic. Separate ROC curves must be generated for twins and breech presentations and for patients with diabetes to answer weight-related clinical questions such as mode and timing of delivery. Three-dimensional ultrasound and magnetic resonance imaging are expected to generate ROC curves for estimates of fetal weight that are better than those for two-dimensional ultrasound or clinical estimates. Such analyses have yet to be published.