PubMed Health⌕ Search

Biomedical subjects

Stephen Evans

Publications and source records attributed to Stephen Evans.

At least 19 recordsLinked to original sources
PubMed2006

Inactivation of TGF-beta signaling in lung cancer results in increased CDK4 activity that can be rescued by ELF.

Escape from TGF-beta inhibition of proliferation is a hallmark of multiple cancers including lung cancer. We explored the role of ELF, crucial TGF-beta adaptor protein identified from endodermal progenitor cells, in lung carcinogenesis and cell-cycle regulation. Interestingly, elf-/- mice develop multiple defects that include lung, liver, and cardiac abnormalities. Four out of 6 lung cancer and mesothelioma cell lines displayed deficiency of ELF expression with increased CDK4 expression. Immunohistochemistry and Western blot analysis of primary human lung cancers also showed decreased ELF expression and overexpression of CDK4. Moreover, rescue of ELF in ELF-deficient cell lines decreased the expression of CDK4 and resulted in accumulation of G1/S checkpoint arrested cells. These results suggest that disruption in TGF-beta signaling mediated by loss of ELF in lung cancer leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-beta adaptor protein in suppressing early lung cancer.

Animals↗
PubMed2006

Hormone replacement therapy and acute myocardial infarction: a large observational study exploring the influence of age.

BACKGROUND: We examined whether the discrepancy between observational studies and randomized clinical trials (RCTs) on the effect of hormone replacement therapy (HRT) on myocardial infarction (MI) could be explained by differences in age of participants at the time of either HRT initiation or the MI event. METHODS: A matched case-control study was performed using the General Practice Research Database. Cases (n = 22 225) had a first diagnosis of MI between 1987 and 2001; up to six controls (n = 144 085) were matched to each case based on age, sex, and practice. Conditional logistic regression was performed adjusting for traditional cardiovascular risk factors, as well as, cardiovascular drug use and consultation rate. RESULTS: HRT users had a lower overall risk of MI compared with never users [odds ratio (OR): 0.76; 95% confidence interval (95% CI) 0.68-0.86); results were similar for opposed (OR: 0.73; 95% CI 0.68-0.86) and unopposed (OR: 0.79; 95% CI 0.66-0.96) therapy. This apparent benefit increased with older age at HRT initiation(18-44 years: OR = 0.99; 95% CI 0.74-1.33; 45-54 years: OR = 0.84; 95% CI 0.71-1.00; 55-64 years: OR = 0.67; 95% CI 0.54-0.82; 65-74 years: OR = 0.50; 95% CI 0.34-0.74; >75 years: OR = 0.55; 95% CI 0.23-1.32). Moreover, the cardioprotective effect was greater for MIs occurring at older ages (P-value for interaction = 0.003). CONCLUSION: The effect of HRT on MI becomes more pronounced with older age at initiation and at older ages at the time of an MI event. These findings contradict the hypothesis that the apparent protection seen in observational studies was due to the inclusion of younger participants.

Adolescent↗
PubMed2006

Risk factors for neonatal morbidity and mortality among "healthy," late preterm newborns.

Research about neonatal outcomes among late preterm infants (34 weeks through 36 6/7 weeks of gestation) is limited. Understanding which late preterm infants are at risk for neonatal morbidity or mortality is necessary to improve health outcomes and reduce hospital costs. We conducted a population-based cohort study of "healthy," singleton late preterm infants vaginally delivered in Massachusetts hospitals to Massachusetts residents between 1998 and 2002. We compared the incidence of neonatal morbidity (postdelivery inpatient readmissions, observational stays, or mortality) between "healthy," late preterm infants with and without infant, obstetric, and sociodemographic factors by calculating risk ratios adjusted for confounding. Of the 9552 late preterm, "healthy" infants, 4.8% had an inpatient readmission and 1.3% had an observational stay. Infants with neonatal morbidity were more likely to be firstborn, be breastfed at discharge, have labor and delivery complications, be a recipient of a public payer source at delivery, or have an Asian/Pacific Islander mother. Non-Hispanic blacks had a decreased risk for neonatal morbidity compared to other racial/ethnic groups. Knowledge of risk factors for neonatal morbidity among "healthy" late preterm infants can be used to identify infants needing closer monitoring and earlier follow-up after hospital discharge.

Adolescent↗
PubMed2006

Early discharge among late preterm and term newborns and risk of neonatal morbidity.

Understanding how late preterm infants (34-36 completed weeks' gestation) are affected by discharge policies created for term infants (37-41 completed weeks' gestation) is essential for preventing postdischarge neonatal morbidity among late preterm infants. We analyzed linked birth certificate and hospital discharge data for Massachusetts between 1998 and 2002 to evaluate the risk of neonatal morbidity (defined as hospital readmission, observational stay, or both) between all vaginally delivered, live-born singleton late preterm and term infants. All infants were born at a Massachusetts hospital to a state resident and were discharged home early (<2-night hospital stay). We calculated crude and adjusted risk ratios using a modified Poisson regression and compared the timing and principal discharge diagnoses for those neonates who needed hospital readmission. Of the 1004 late preterm and 24,320 term infants in our study, 4.3% and 2.7% of infants, respectively, were either readmitted or had an observational stay. Late preterm infants were 1.5 times more likely to require hospital-related care and 1.8 times more likely to be readmitted than term infants. Among infants who were breastfed, late preterm infants were 1.8 times more likely than term infants to require hospital-related care and 2.2 times more likely to be readmitted. In contrast, no differences were found between late preterm and term infants who were not breastfed. Jaundice and infection accounted for the majority of readmissions. Our findings suggest that late preterm infants discharged early experience significantly more neonatal morbidity than term infants discharged early; however, this may be true only for breastfed infants. Evidence-based recommendations for appropriate discharge timing and postdischarge follow-up for these late preterm infants are needed to prevent neonatal morbidity.

Adult↗
PubMed2005

Inactivation of ELF/TGF-beta signaling in human gastrointestinal cancer.

TGF-beta/Smads regulate a wide variety of biological responses through transcriptional regulation of target genes. ELF, a beta-spectrin, plays a key role in the transmission of TGF-beta-mediated transcriptional response through Smads. ELF was originally identified as a key protein involved in endodermal stem/progenitor cells committed to foregut lineage. Also, as a major dynamic adaptor and scaffolding protein, ELF is important for the generation of functionally distinct membranes, protein sorting and the development of polarized differentiated epithelial cells. Disruption of elf results in the loss of Smad3/Smad4 activation and, therefore, a disruption of the TGF-beta pathway. These observations led us to pursue the function of ELF in gastrointestinal (GI) epithelial cell-cell adhesion and tumor suppression. Here, we show a significant loss of ELF and reduced Smad4 expression in human gastric cancer tissue samples. Also, of the six human gastric cancer cell lines examined, three show deficient ELF expression. Furthermore, we demonstrate the rescue of E-cadherin-dependent homophilic cell-cell adhesion by ectopic expression of full-length elf. Our results suggest that ELF has an essential role in tumor suppression in GI cancers.

Antibodies, Monoclonal↗
PubMed2005

Are these data real? Statistical methods for the detection of data fabrication in clinical trials.

OBJECTIVES: To test the application of statistical methods to detect data fabrication in a clinical trial. SETTING: Data from two clinical trials: a trial of a dietary intervention for cardiovascular disease and a trial of a drug intervention for the same problem. OUTCOME MEASURES: Baseline comparisons of means and variances of cardiovascular risk factors; digit preference overall and its pattern by group. RESULTS: In the dietary intervention trial, variances for 16 of the 22 variables available at baseline were significantly different, and 10 significant differences were seen in means for these variables. Some of these P values were extraordinarily small. Distributions of the final recorded digit were significantly different between the intervention and the control group at baseline for 14/22 variables in the dietary trial. In the drug trial, only five variables were available, and no significant differences between the groups for baseline values in means or variances or digit preference were seen. CONCLUSIONS: Several statistical features of the data from the dietary trial are so strongly suggestive of data fabrication that no other explanation is likely.

Adult↗
PubMed2005

The role of PRAJA and ELF in TGF-beta signaling and gastric cancer.

Emerging research has shown that the transforming growth factor-beta (TGF-beta) pathway plays a key role in the suppression of gastric carcinoma. Biological signals for TGF-beta are transduced through transmembrane serine/threonine kinase receptors, which in turn signal to Smad proteins. Inactivation of the TGF-beta pathway often occurs in malignancies of the gastrointestinal system, including gastric cancer. Yet, only a fraction of sporadic gastric tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Smad4, a tumor suppressor, is often mutated in human gastrointestinal cancers. The mechanism of Smad4 inactivation, however, remains uncertain and could be mediated through E3-mediated ubiquitination of Smad4/adaptor protein complexes. The regulation of the TGF-beta pathway through a PRAJA, a RING finger (RING-H2) protein, and ELF, a beta-Spectrin adaptor protein, both which were originally identified in endodermal stem/progenitor cells committed to foregut lineage, could play a pivotal role in gastric carcinogenesis. PRAJA, which functions as an E3 ligase, interacts with ELF in a TGF-beta-dependent manner in gastric cancer cell lines. PRAJA is increased five-fold in human gastric cancers, and inactivates ELF. This is particularly significant since ELF, a Smad4 adaptor protein, possesses potent anti-oncogenic activity and is frequently seen to be inactivated in carcinogenic gastric cells. Strikingly, PRAJA manifests substantial E3-dependent ubiquitination of ELF and Smad3, but not Smad4. The alteration of ELF and/or Smad4 expression and function in the TGF-beta signaling pathway may be induced by enhancement of ELF degradation, which is mediated by the high level expression of PRAJA in gastrointestinal cancers. These studies reveal a mechanism for gastric tumorigenesis whereby defects in adaptor proteins for Smads, such as ELF, can undergo degradation by PRAJA, through the ubiquitin-mediated pathway.

Ephrin-A2↗
PubMed2005

Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.

OBJECTIVE: To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. DESIGN: Nested case-control study. SETTING: Primary care in the United Kingdom. PARTICIPANTS: 146,095 individuals with a first prescription of an antidepressant for depression. MAIN OUTCOME MEASURES: Suicide and non-fatal self harm. RESULTS: 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. CONCLUSION: We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.

Adolescent↗
PubMed2005

The effect of scientific misconduct on the results of clinical trials: a Delphi survey.

OBJECTIVES: To discover what types of scientific misconduct are most likely to influence the results of a clinical trial. DESIGN: Delphi survey of expert opinion with three rounds of consultation. SETTING: Non-industry clinical trial "community". PARTICIPANTS: Experts identified from invitees to a previous MRC consultation on clinical trials. 32 out of the 40 experts approached agreed to participate. RESULTS: We identified thirteen forms of scientific misconduct for which there was majority agreement (>50%) that they would be likely or very likely to distort the results and majority agreement (>50%) that they would be likely or very likely to occur. Of these, the over-interpretation of 'significant' findings in small trials, selective reporting and inappropriate subgroup analyses were the main themes. CONCLUSIONS: According to this expert group, the most important forms of scientific misconduct in clinical trials are selective reporting and the opportunistic use of the play of chance. Data fabrication and falsification were not rated highly because it was considered that these were unlikely to occur. Registration and publication of detailed clinical trial protocols could make an important contribution to preventing scientific misconduct.

Bias↗
PubMed2004

Effects of training on quality of peer review: randomised controlled trial.

OBJECTIVE: To determine the effects of training on the quality of peer review. DESIGN: Single blind randomised controlled trial with two intervention groups receiving different types of training plus a control group. SETTING AND PARTICIPANTS: Reviewers at a general medical journal. Interventions Attendance at a training workshop or reception of a self taught training package focusing on what editors want from reviewers and how to critically appraise randomised controlled trials. MAIN OUTCOME MEASURES: Quality of reviews of three manuscripts sent to reviewers at four to six monthly intervals, evaluated using the validated review quality instrument; number of deliberate major errors identified; time taken to review the manuscripts; proportion recommending rejection of the manuscripts. RESULTS: Reviewers in the self taught group scored higher in review quality after training than did the control group (score 2.85 v 2.56; difference 0.29, 95% confidence interval 0.14 to 0.44; P = 0.001), but the difference was not of editorial significance and was not maintained in the long term. Both intervention groups identified significantly more major errors after training than did the control group (3.14 and 2.96 v 2.13; P < 0.001), and this remained significant after the reviewers' performance at baseline assessment was taken into account. The evidence for benefit of training was no longer apparent on further testing six months after the interventions. Training had no impact on the time taken to review the papers but was associated with an increased likelihood of recommending rejection (92% and 84% v 76%; P = 0.002). CONCLUSIONS: Short training packages have only a slight impact on the quality of peer review. The value of longer interventions needs to be assessed.

Education, Professional↗