Corrigendum to "Triazolo[4,5-d]pyrimidines as validated general control nonderepressible 2 (GCN2) protein kinase inhibitors reduce growth of leukemia cells" [Comput. Struct. Biotechnol. J. 16 (2018) 350-360].

[This corrects the article DOI: 10.1016/j.csbj.2018.09.003.].

Triazolo[4,5-d]pyrimidines as Validated General Control Nonderepressible 2 (GCN2) Protein Kinase Inhibitors Reduce Growth of Leukemia Cells.

Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), of which the unfolded protein response (UPR) is a subset. These pathways converge at the phosporylation of eIF2α. Drug-like, potent and selective chemical inhibitors (valid chemical probes) targeting major ISR kinases have been previously identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo[4,5-d]pyrimidine scaffold. Several compounds potently inhibited GCN2 in vitro and displayed good selectivity over the related kinases PERK, HRI, and IRE1. The compounds inhibited phosporylation of eIF2α in HEK293T cells with an IC50 < 150 nM, validating them as chemical probes for cellular studies. These probes were screened against the National Cancer Institute NCI-60 human cancer cell line panel. Uniform growth inhibition was observed in the leukemia group of cell lines. Growth inhibition in the most sensitive cell lines coincided with high GCN2 mRNA expression levels. Oncomine analysis revealed high GCN2 expression accompanied by lower asparagine synthetase (ASNS) expression in patient-derived acute lymphoblastic leukemias with B-Cell origins (B-ALL) as well. Notably, asparaginase, which depletes amino acids and triggers GCN2 activity, is a licensed, first-line B-ALL treatment. Thus, we hypothesize that leukemias exhibiting high GCN2 expression and low ASNS expression may be susceptible to pharmacologic GCN2 inhibition.

Chemical probes of Skp2-mediated p27 ubiquitylation and degradation.

Skp2 is a member of the F-box family of proteins that serve as substrate-specific adaptors in Skp1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligases. Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCFSkp2 E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation. As p27 is a powerful suppressor of growth in a variety of cells, and as Skp2 is also overexpressed in many human cancers, Skp2 is considered an oncogene and an intriguing drug target. However, despite 20 years of investigation, a valid chemical inhibitor of Skp2-mediated degradation of p27 has not been identified. Recently, an increasing number of compounds designed to have this bioactivity have been reported. Here, we conduct a meta-analysis of the evidence regarding bioactivity, structure, and medicinal chemistry in order to evaluate and compare these Skp2 inhibitor compounds. Despite chemically diverse compounds with a wide array of Skp2-mediated p27 ubiquitylation inhibition properties reported by several independent groups, no current chemical probe formally qualifies as a validated pharmaceutical hit compound. This finding suggests that our knowledge of the structural biochemistry of the Skp2-p27 complex remains incomplete and highlights the need for novel modes of inquiry.

Impact of trained oncology financial navigators on patient out-of-pocket spending.

OBJECTIVES: Patients with cancer often face financial hardships, including loss of productivity, high out-of-pocket (OOP) costs, depletion of savings, and bankruptcy. By providing financial guidance and assistance through specially trained navigators, hospitals and cancer care clinics may be able mitigate the financial burdens to patients and also minimize financial losses for the treating institutions. STUDY DESIGN: Financial navigators at 4 hospitals were trained through The NaVectis Group, an organization that provides training to healthcare staff to increase patient access to care and assist with OOP expenses. Data regarding financial assistance and hospital revenue were collected after instituting these programs. METHODS: Amount and type of assistance (free medication, new insurance enrollment, premium/co-pay assistance) were determined annually for all qualifying patients at the participating hospitals. RESULTS: Of 11,186 new patients with cancer seen across the 4 participating hospitals between 2012 and 2016, 3572 (32%) qualified for financial assistance. They obtained $39 million in total financial assistance, averaging $3.5 million per year in the 11 years under observation. Patients saved an average of $33,265 annually on medication, $12,256 through enrollment in insurance plans, $35,294 with premium assistance, and $3076 with co-pay assistance. The 4 hospitals were able to avoid write-offs and save on charity care by an average of $2.1 million per year. CONCLUSIONS: Providing financial navigation training to staff at hospitals and cancer centers can significantly benefit patients through decreased OOP expenditures and also mitigate financial losses for healthcare institutions.

An ID2-dependent mechanism for VHL inactivation in cancer.

Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.

Adverse Perinatal Outcomes among Immigrant Women from Ethiopia in Israel.

BACKGROUND: Immigration from Ethiopia to Israel started about 30 years ago. We aimed to compare birth outcomes between Israeli women of Ethiopian origin and Israeli-born, non-Ethiopian women. We hypothesized a higher frequency of adverse birth outcomes among Ethiopian women and a trend of improvement among those who were raised in Israel since early childhood. METHODS: This is a descriptive study, comparing birth outcomes of Ethiopian (n = 1,319) and non-Ethiopian women (n = 27,307) who gave birth in a medical center in Central Israel in 2002 to 2009. Ethiopian women were further categorized by age at immigration. Logistic regressions were constructed to compare the incidence of adverse birth outcomes between Ethiopian and non-Ethiopian women, controlling for potential confounders. RESULTS: Ethiopian women had about twice the incidence of very and extremely preterm births, compared with non-Ethiopians. Ethiopian women had twice the odds for neonates who were either small for gestational age or had low 5-minute Apgar scores. Ethiopian women had about threefold increased risk of stillbirths (OR 2.9 [95% CI 1.87-4.49]). No trend of improvement was noted for women who were raised in Israel from early childhood. CONCLUSION: Ethiopian women are at increased risk of adverse birth outcomes. Future research is needed to investigate the underlying causes for the increased risks and lack of improvement among those who were raised in Israel that will lead to effective interventions.

Short and long-term outcome of pregnant women with preexisting dilated cardiomypathy: an NTproBNP and echocardiography-guided study.

BACKGROUND: Little is known of the outcome of pregnant patients with previously diagnosed dilated cardiomyopathy. These patients are usually firmly advised against continuation of the pregnancy. OBJECTIVES: To examine the usefulness of serial echocardiographic follow-up and plasma N-terminal pro-B type natriuretic peptide levels in the management of pregnant women with preexisting DCM. METHODS: We prospectively enrolled pregnant women with DCM either known or diagnosed in the first trimester. Clinical examination and serial echocardiography studies were performed at baseline, at 30 weeks gestation, peripartum, and 3 and 18 months postpartum. Blinded NTproBNP levels were obtained at 30 weeks, at delivery and 3 months postpartum. RESULTS: Between June 2005 and October 2006 we enrolled seven women who fulfilled the study criteria. Delivery and postpartum were complicated in 3 patients (42%): 2 with acute heart failure, which resolved conservatively, and 1 with major pulmonary embolism. The left ventricular ejection fraction was stable throughout the pregnancy (35% +/- 2.8 at baseline, 33% +/- 2.9 at 30 weeks) and postpartum (35% +/- 2.8 at 1 day, 34% +/- 3.1 at 90 days). Similar stable behavior was observed regarding left ventricular dimensions: LV end-systolic diameters 43.3 +/- 2.7 mm and LV end-diastolic diameters 57.3 +/- 3.3 mm at baseline compared with 44.1 +/- 3.1 mm and 58.7 +/- 3.1 mm postpartum, respectively. The NTproBNP levels rose significantly peripartum in all three patients with complications. CONCLUSIONS: Serial NTproBNP levels, as compared to echocardiography, may be a better clinical tool in monitoring and management of pregnant women with preexisting DCM. An early rise in NTproBNP level appears to predict the occurrence of adverse events.

Foley catheter balloon vs locally applied prostaglandins for cervical ripening and labor induction: a systematic review and metaanalysis.

We performed a metaanalysis of publications comparing the efficacy and safety of cervical ripening and labor induction by Foley catheter balloon (FCB) vs locally applied prostaglandins (LAPG) in the third trimester of pregnancy. Twenty-seven randomized controlled trials (1966-2008; 3532 participants) were selected from MEDLINE, EMBASE, and CENTRAL searches. There was no significant difference between FCB and LAPG in cesarean delivery rates. LAPG had a significantly increased risk of excessive uterine activity (P = .001). FCB had a significantly higher risk of oxytocin induction/augmentation during labor (P = .0002). Cervical prostaglandin-E2 was less effective (P = .04), and vaginal prostaglandin-E1 bore a significantly higher risk of excessive uterine activity (P < .0001) and meconium staining (P = .04). We concluded that FCB and LAPG result in similar cesarean delivery rates, that FCB bears a higher risk of oxytocin use for labor induction and/or augmentation, and that LAPG carries a higher risk of contraction abnormalities.

[Analysis of brachial plexus injuries reported to MRM].

Upper-arm weakness (paresis) or paralysis in the newborn (Erb's palsy) usually indicates peripheral-nerve damage to the brachial plexus. Its location lateral to the lower cervical spine (C5-T1) renders it susceptible to injury by pressure or traction during pregnancy, labor or delivery. The Medical Risk Management (MRM), a "Madanes" group company, routinely receives adverse events reports from medical centers covered by its medical malpractice insurance. In the current study, the authors analyzed 536 reports of Erb's palsy in the newborn, with varying degrees of severity, which were reported to MRM during the years 1993-2004. A dedicated questionnaire with approximately 30 relevant variables was formed in order to analyze these reports. Reference values for pregnancies and deliveries in the general population were obtained from the Israeli Central Statistics Bureau, Information Department in the Ministry of Health, the Israeli Society of Maternal-Fetal Medicine, as well as relevant data in the medical literature. It was found that during the analyzed period of time, the reporting rate for Erb's palsy varied between 0.5-1.2 cases per 1,000 newborns. Compared with the general Israeli population, women in the study group were older, overweight, with higher parity and have diabetic traits. The authors noted a systematic error of underestimation of fetal weight, compared to the actual birth weight in our study group. Although, the majority of the Erb cases followed vaginal deliveries at term, 3% of the cases followed Cesarean sections, the majority of which were either elective or in early labor. A quarter of the Erb cases followed instrument delivery, while the rate of instrumental deliveries in the general population averaged only 5% throughout the study period. In half of the Erb cases, difficulty in extraction of the shoulder (shoulder dystocia) of the involved arm was found in the delivery medical record, but reference to shoulder or head extraction was noted in only half of the cases following vaginal deliveries. However, the rate of medical records with adequate reference to shoulder or head extraction increased from 44% in the beginning, to 74% at the end of the analyzed study period. The average birth weight of our study group was 3888+569 grams, which is significantly higher than the average birth weight in the general population. It was also noted that birth weights of Erb cases are of higher percentiles on the Israeli nomogram of gestational age adjusted birth weights. Thus, 53% of the newborns in our study group were above the 90th percentile and 31% above the 97th percentile of the general population nomogram. Various risk factors for brachial plexus injury were found in this large sample of Erb's palsy cases in Israel. However, the relative importance of each of these factors cannot be determined due to lack of an appropriate control group and valid reference data for the general population of pregnancies and deliveries during the analyzed study period. Nonetheless, the dedicated questionnaire, which was developed for this analysis, may assist in compiling real-time data to support the findings of this study.

Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2.

A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.

Synthesis and evaluation of heteroaryl-ketone derivatives as a novel class of VEGFR-2 inhibitors.

We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.

Clinical, sonographic, and epidemiologic features of second- and early third-trimester spontaneous antepartum uterine rupture: a cohort study.

OBJECTIVE: To present prenatal findings and maternal and neonatal outcomes following second- and early third-trimester spontaneous antepartum uterine rupture events in our institute. METHOD: Charts of patients with full-thickness second- or early third-trimester symptomatic uterine ruptures locally treated between 1984 and 2007 were evaluated. RESULTS: There were seven events involving six women, all requiring emergency laparotomy, and cesarean section (CS). During the study period in our institute, there were 120 636 singleton deliveries (> or =22 weeks' gestation), including 5 of our cases, while in 2 cases, the rupture occurred earlier (<22 weeks' gestation). The rupture occurred after > or = 1 previous CSs in five cases. Six events were associated with abnormal placentation: placenta previa (n = 3), placenta percreta (n = 1), or both (n = 2). Other associated events included short, interpregnancy (IP) interval (n = 3) and past uterine rupture (n = 2). Pregnant women at gestational age > or = 22 weeks, who had the combination of placenta previa, and previous CS (n = 3), had a higher chance for spontaneous symptomatic antepartum uterine rupture when compared to women with placenta previa without a previous CS (OR 29.3, 95% CI 1.5-569.3, p = 0.007). There were no maternal deaths. Three of the five viable neonates survived. CONCLUSIONS: Spontaneous symptomatic second- or early third-trimester uterine rupture in nonlaboring women is a very rare, obstetric emergency, which is hard to diagnose. Maternal and neonatal outcomes can be optimized by awareness of risk factors, recognition of clinical signs and symptoms, and availability of ultrasound to assist in establishing diagnosis, and enabling prompt surgical intervention.

Prenatal thrombosis of the inferior vena cava and the renal veins.

OBJECTIVE: This manuscript discusses the clinical presentation, diagnosis, pathophysiology and possible etiologies of prenatal thrombosis of the inferior vena cava and renal veins. METHODS: Eleven cases were identified through a Medline search of the English literature. These cases were reviewed, together with a recent case that was treated in our medical center. RESULTS: Fetal thrombosis in the aforementioned vessels, presented as hydrops fetalis (33%), acute fetal distress (42%), or as an incidental prenatal ultrasound finding (25%). Underlying maternal conditions were present in 58%, and included chronic conditions (hypertension and diabetes mellitus), acute conditions (pyelonephritis and preeclampsia) and thrombophilia. In 42% cases, the prenatal ultrasound scan revealed an enlarged and hyper-echogenic affected kidney. CONCLUSION: Intrauterine fetal venous thrombosis is a rare phenomenon, probably attributed to a multifactorial process. These factors may include inherited thrombophilia as well as prothrombotic clinical conditions.

Antibiotic treatment of intra-amniotic infection with Ureaplasma urealyticum. A case report and literature review.

BACKGROUND: Ureaplasma urealyticum is the most common pathogen cultured from the amniotic cavity of women with preterm labor and intact membranes. However, experience with antibiotic eradication of the pathogen in this setting is limited. CASE: We report a case of U. urealyticum isolation from the amniotic cavity of a woman with preterm labor at 27 weeks gestation. The patient was treated with erythromycin base for 1 week, followed by fluoroquinolones and clindamycin for 10 days. A healthy neonate was delivered after spontaneous labor began at 33 weeks. The cultures obtained from the placenta and membranes were sterile, but the histopathology of the placenta revealed acute chorioamnionitis with acute funisitis. CONCLUSION: We suggest that intra-amniotic colonization with Mycoplasma spp. remote from term may be managed expectantly, and that therapy with fluoroquinolones and/or clindamycin may be an appropriate choice.

Is there an increased rate of anencephaly in twins?

BACKGROUND: The Israeli Ministry of Health reported an increased rate of twin pregnancies among all cases locally diagnosed as having open neural tube defects. The current study aimed to evaluate whether the etiology of this phenomenon could be attributed either to the twinning or to the mode of conception. METHODS: Women admitted to our hospital between January 1997 and July 2004 for termination of pregnancy because of severe fetal abnormality enrolled into this retrospective case series study. They were further subdivided according to mode of conception (spontaneous, in vitro fertilization (IVF) or intracytoplasmic sperm injection (IVF-ICSI) pregnancies). RESULTS: Three-hundred and eighty consecutive pregnancies, of which 340 (89%) were singletons, participated in our study. Anencephaly was diagnosed in 26 cases: 19 singletons and 7 twins. In the entire twin population, they were all dichorionic twins and only one co-twin was affected. Five of the twins were conceived by IVF-ICSI. All the anencephalic IVF-ICSI twins had normal karyotypes. All IVF-ICSI study women had taken folic acid 400 mcg/day 3 months before conception and throughout the first trimester of pregnancy. In order to find out the cause of the high rate of anencephaly found in IVF-ICSI pregnancies (33.3%), either the twinning or the IVF-ICSI process, a logistic regression analysis was used. A significant correlation was found only between anencephaly and twinning (p = 0.001, CI = 1.86-12.63), with a risk ratio of 4.85. CONCLUSIONS: Our case series data suggest a comparatively higher rate of anencephaly in IVF-ICSI pregnancy secondary to twinning and not because of the assisted reproductive technology. It is suggested that larger epidemiologic studies are conducted to validate our preliminary results.

Arylphthalazines: identification of a new phthalazine chemotype as inhibitors of VEGFR kinase.

A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.

Congenital hypofibrinogenemia in pregnancy: report of two cases and review of the literature.

Fibrinogen abnormalities have been implicated in many adverse pregnancy outcomes, mainly spontaneous abortion, placental abruption, and postpartum hemorrhage. Two new cases of congenital hypofibrinogenemia in pregnancy are reported detailing their obstetric course and management. The relevant obstetric and hematologic literature is reviewed, including previous case reports and studies concerning the mechanisms of pregnancy complications. Suggestions for treatment guidelines and management strategies are detailed.

The lateral recumbent head-down position decreases the incidence of epidural venous puncture during catheter insertion in obese parturients.

PURPOSE: The unintentional and unrecognized cannulation of an extradural vein is a potentially serious complication of an epidural anesthetic. The present study was undertaken to assess the incidence of blood vessel puncture related to epidural catheterization in three different body positions, in a cohort of morbidly obese parturients, following the completion of a similar study published in 2001 from which such parturients were excluded. METHODS: The study was conducted in 450 (three groups of 150) morbidly obese, obstetric patients undergoing continuous epidural analgesia during labour. Epidural catheterization was performed on patients randomized to the sitting, lateral recumbent horizontal, or lateral recumbent head-down position. RESULTS: There was a lower incidence of vessel cannulation when this procedure was performed in the lateral recumbent head-down position [1.3%; body mass index (BMI): 37.0] than in the lateral recumbent horizontal [12.9%; BMI: 38.0] and in the sitting position [12.0%; BMI: 38.0]. The incidence of accidental subarachnoid puncture was 2%, 1.3% and 2% respectively, in these same positions. CONCLUSION: Adoption of the lateral recumbent head-down position for the performance of lumbar epidural blockade, in labour at term, reduces the incidence of lumbar epidural venous puncture in these obese parturients.

Chorioangioma and its severe infantile sequelae: case report.

OBJECTIVE: This case report describes a rare clinical presentation of chorioangioma diagnosed prenatally because of raised-maternal serum (MS) alpha-fetoprotein. METHODS: A thirty-year-old woman gravida 2, para 1 was referred to the ultrasound unit at 18 weeks of gestation because of abnormal MS triple-test results. This included AFP level of 14.9 MoM; hCG of 3.42 MoM and uE3 of 1.01 MoM. A detailed anomaly scan revealed a singleton fetus with no sonographically detectable malformations and normal amniotic fluid. The placenta was posterior. A well-circumscribed, rounded, predominantly hypoechoic lesion near the chorionic surface measuring 5 x 5 cm and protruding into the amniotic cavity was detected. Color Doppler sonogram showed no blood flow within the mass, but clear fetal waveforms in its periphery were demonstrated, and the diagnosis of chorioangioma was made. The pregnancy was followed uneventfully until 35 weeks of gestation when polyhydramnios and severe fetal cardiomegaly developed. Labor was therefore induced. RESULTS: A euploid female, who had multiple diffuse cutaneous and liver angiomatosis was born. She died at the age of one month because of cardiac failure and infection. CONCLUSIONS: The present case alerts to the interrelationship between placental and fetal angiomas. This may lead to severe infantile sequelae because of similar lesions.

The onset of p53-dependent apoptosis plays a role in terminal differentiation of human normoblasts.

The p53 tumor suppressor gene was found to play a role in the differentiation of several tissue types. We report here that p53-dependent apoptosis plays a role in the final stages of physiological differentiation of normoblasts, resulting in nuclear condensation and expulsion without cell death. Blood samples of healthy newborns, cord blood as well as bone marrow, were analysed for apoptosis by TUNEL and p53 expression by immunostaining. While some samples exhibited simultaneously several distinct patterns of apoptosis, such as perinuclear, diffused nuclear or nuclear apoptotic bodies, others presented a single defined pattern. Overexpression of p53 protein was detected in normoblasts exhibiting either perinuclear or diffused nuclear p53, corresponding to the nuclear apoptotic pattern in the same sample. Similar results were also evident with colonies cultivated for 12-14 days in culture. Differentiated erythroid colonies exhibited overexpression of p53 and positive TUNEL staining only in the normoblasts. We further examined the state of caspase 3/7 and observed a decrease of this activated enzyme during erythroid differentiation in culture. This study suggests a novel role for apoptosis in normoblast differentiation where nuclear degradation occurs with a delay in the actual cell death. A pivotal role for the p53-dependent apoptosis in the erythroid lineage development is implied. However, this apoptotic process is not fully executed because of the exhaustion in caspase 3/7 and thus cells are diverted towards final stages of differentiation.