Eph and Ephrin Signaling in Mammary Gland Morphogenesis and Cancer

The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, play a central role in pattern formation during embryonic development and there is growing evidence that they are also instrumental in the control of tissue dynamics in the adult. The mammary gland is a paradigm for morphogenic processes occurring in the adult, since the gland develops predominantly postnatally and is subjected to continuous cyclic remodeling according to functional demands. Thus, pattern formation and the establishment of a functional organ structure are permanent themes in the mammary gland life cycle. In this paper we summarize the experimental evidence and discuss possible mechanisms by which Ephs and ephrins are modulating mammary epithelial cell adhesion, communication, and migration. Furthermore, we speculate on the different aspects of their influence on normal mammary gland development, function, and carcinogenesi

A Population-Based Study of Peyronie's Disease: Prevalence and Treatment Patterns in the United States

Purpose. To estimate the US prevalence of Peyronie's disease (PD) from patient-reported data and to identify diagnosis and treatment patterns. Methods. 11,420 US males ≥18 years old completed a brief web-based survey regarding the presence of PD, past treatments, and penile symptoms (Phase 1). Phase 1 respondents with PD diagnosis, history of treatment, or PD-related symptoms then completed a disease-specific survey (Phase 2). Results. Estimated prevalence of PD ranged from 0.5% (diagnosis of PD) to 13% (diagnosis, treatment, or penile symptoms). Thirty-six percent of Phase 2 participants reported that penile symptoms interfered with sexual activities. Of participants who sought treatment for penile symptoms (n = 128), 73% initially saw a primary care physician, 74% did not receive treatment from their first doctor, and 92% were not diagnosed with PD. Conclusions. PD may be underdiagnosed/undertreated in the US. Improved awareness is needed of PD symptoms and treatment options among health care professionals

Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma

Background: Members of the Eph family of tyrosine kinases have been implicated in embryonic pattern formation and vascular development; however, little is known about their role in the adult organism. We have observed estrogen-dependent EphB4 expression in the normal breast suggesting its implication in the hormone-controlled homeostasis of this organ. Since the endometrium is a similarly hormone dependent organ and endometrial carcinoma is thought to result from estrogenic stimulation, we have investigated EphB4 expression in normal human endometrium and during its carcinogenesis. Patients and methods: EphB4 expression was analyzed immunohistochemically in 26 normal endometrium specimens, 15 hyperplasias and 102 endometrioid adenocarcinomas and correlated with clinical and prognostic tumor characteristics. Results: In normal endometrial tissue no EphB4 protein was detected. Strikingly, we observed a drastic increase (P <0.0001) in the number of EphB4 protein-expressing glandular epithelial cells in the majority of hyperplasias and carcinomas. Moreover, we found a statistically highly significant positive correlation between EphB4 expression and post-menopausal stage of the patient (P = 0.007). Conclusions: These findings indicate that in the endometrium, EphB4 is an early indicator of malignant development and, thus, EphB4 may represent a potent tool for diagnosis and therapeutic interventio

Educating Dentists about Fissure Sealants: Effects on Knowledge, Attitudes, and Use

This study evaluated the effects of three modes of education on dentists' knowledge, attitudes, and use of pit and fissure sealants. A randomly selected group of dentists was invited to participate in a sealant education initiative. During a 12-month period, a total of 662 dentists either (1) attended continuing education courses, (2) received written materials and videotapes by mail, or (3) received only written materials by mail. A comparison group (n=337) received no materials until after the education phase and evaluation had been completed. Pre-and postintervention surveys were used to measure changes in knowledge, attitudes, and sealant use. Response rates to the two surveys were 62 percent and 76 percent, respectively. Preintervention values for knowledge scores, an attitude scale, and sealant use were similar among the four groups. At followup, the three education groups had significantly higher knowledge scores than the comparison group. Attitude values for all but one group were not significantly different, and sealant use by all groups was identical. The numbers of respondents not using sealants declined slightly between surveys in the three education groups while rising slightly in the No-Education Group. Because program outcomes were similar to those of another sealant initiative, it can probably be concluded that continuing education will increase dentists' knowledge about sealants, but have little effect upon their attitudes or their use of the technique. The changes observed in this investigation maybe due to the particular capacity for cognitive and affective change's of participants, characteristics of the technology being promoted, and external forces in the professional environment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66125/1/j.1752-7325.1991.tb02208.x.pd

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation:A Multinational Population-Based Cohort Study

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG

Global identification of genes and pathways regulated by Akt during activation of T helper cells

We previously demonstrated that Akt differentially modulated a subset of NF-kB target genes during T cell activation. In the current study, we further explored the broader effects of Akt inhibition on T cell gene induction. Global microarray analysis was used to characterize T helper cell transcriptional responses following antigen receptor stimulation in the absence or presence of Akti1/2 (an allosteric inhibitor which targets Akt1 and Akt2), to identify novel targets dependent upon Akt and obtain a more comprehensive view of Akt-sensitive genes in Th2 helper T cells. Pathway analysis of microarray data from a CD4+ Th2 T cell line revealed effects on gene networks involving ribosomal and T cell receptor signaling pathways associated with Akti1/2 treatment. Using real-time PCR analysis, we validated the differential regulation of several genes in these pathways, including Ier3, Il13, Egr1, Ccl1 and Ccl4, among others. Additionally, transcription factor target gene (TFactS) analysis revealed that NF-kB and Myc were the most significantly enriched transcription factors among Akt-dependent genes after T cell receptor and CD28 stimulation. Akt activation elicited increases in the enrichment of NF-kB- and Myc-targeted genes. The present study has identified a diverse set of genes, and possible mechanisms for their regulation, that are dependent on Akt during T cell activation

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 αC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the αC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type