Clinicopathologic Implications of Eukaryotic Initiation Factor 3f and Her‐2/neu Expression in Gastric Cancer

Background:

To detect the expression of eIF3f and human epidermal growth factor receptor 2 (Her‐2)/neu in gastric cancer (GC), correlation with their clinicopathological parameters and the relationship of eIF3f and Her‐2/neu in the occurrence and development of GC.

Methods:

A total of 195 gastrectomy specimens with stage I to III were examined for eIF3f expression by immunohistochemistry and for Her‐2/neu expression by fluorescence in situ hybridization (FISH) with the median follow‐up period of 38 months.

Results:

The positive expression rate of eIF3f in GC and adjacent noncancerous tissue were 33.8% and 59.5%, respectively. eIF3f levels were linked to more advanced tumor stages and likelihood of recurrence (all p < 0.05). The Kaplan–Meier survival curves indicated that decreased expression of eIF3f could serve as a prognosis marker for poor outcome of GC patients (p = 0.04). 15.9% of GC specimens were positive for Her‐2/neu, but whose expression was of no correlation with patients’ survival. Patients who were positive for Her‐2/neu also had high eIF3f expression levels (p = 0.0295).

Conclusion:

Results suggest that eIF3f may play an important role in recurrence, thus representing a promising predictive marker for the prognosis of GC. But Her‐2/neu has no relationship with the prognosis of GC. The clinical significance of eIF3f and Her‐2/neu remains to be further investigated.     

Clinical Significance of Vimentin Expression and Her‐2 Status in Patients with Gastric Carcinoma

Objectives

To determine whether vimentin could be used as a marker of gastric carcinomas with more aggressive behavior. To detect the extent of Her‐2 status in gastric carcinoma and explore the correlation between vimentin expression and Her‐2 status.

Methods

Vimentin expression was detected in surgically resected gastric carcinoma tissue specimens from 143 patients by immunohistochemistry. The human epidermal growth factor receptor 2 (Her2) status was evaluated by fluorescence in situ hybridization (FISH). Correlations between vimentin expression, Her‐2 status and clinicopathological factors were evaluated using Kaplan‐Meier method and Cox multivariate survival models.

Results

Vimentin expression was significantly correlated with age, advanced stage, poorly differentiated type, venous invasion, hepatic metastasis, and recurrence (p < 0.05). Her‐2 gene was amplified in 16 (11.2%) out of the 143 gastric carcinoma tissue specimens. Her‐2 status was correlated with advanced cancer, poor differentiation, venous invasion, hepatic metastasis, and recurrence (p < 0.05). The result of multivariate analysis showed that vimentin expression and lymph node metastasis were independent prognostic factors.

Conclusions

Vimentin expression in epithelial cells of the surgically resected gastric adenocarcinoma tissue is an independent predictor of short survival, and Her‐2 status shows a valuable correlation with clinical parameters.     

Different Cellular Localization of NF‐κB p65 Expression as an Indicator of Different Prognoses of Stage I–III Gastric Cancer Patients

Background

Nuclear factor‐κB p65 (NF‐κB p65) may play a significant role as a biomarker in tumor progression and metastasis. However, the correlation between cellular localization of NF‐κB p65 expression and the prognosis of gastric cancer (GC) patients has not been studied. The present study was designed to investigate the location of NF‐κB p65 expression in GC, and evaluate its correlation with clinicopathological parameters of GC patients.

Methods

NF‐κB p65 expressions in GC tissue and corresponding nonmalignant tissue from gastrectomy of 115 stage I–III GC patients were detected by immunohistochemistry. In addition, correlations between the staining results and the clinicopathologic features and survival of the GC patients were analyzed.

Results

The percentage of NF‐κB p65 expression in GC tissue and the corresponding nonmalignant tissue was 73.9% and 46.80%, respectively. No significant correlation was found between NF‐κB p65 expression and the clinicopathologic parameters. Cox univariate analysis indicated that both nuclear staining and cytoplasmic staining of NF‐κB p65 expression correlated with the prognosis of GC patients (log‐rank, p = 0.0182; p = 0.0144, respectively).

Conclusion

High nuclear expression of NF‐κB p65 is an independent prognostic marker predicting a better survival, while high cytoplasmic staining indicates a worse prognosis of GC patients.     

Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path

Context

This study explores the long‐term impact of the Professional Student Mentored Research Fellowship (PSMRF) program at the University of Kentucky College of Medicine (UKCOM) on medical students’ research productivity and career paths.

Methods

Demographic characteristics, academic profiles, number of publications and residency placements from 2007 to 2012 were used to assess 119 PSMRF graduates against a comparison cohort of 898 UKCOM (non‐PSMRF) students.

Results

PSMRF students had higher MCAT scores at admission (31.5 ± 0.6 vs. 30.6 ± 0.2, p = 0.007) and achieved higher USMLE Step 1 scores (228 ± 4.2 vs. 223 ± 1.5, p = 0.03) than comparison group. PSMRF students were more likely to publish PubMed‐indexed papers (36.7% vs. 17.9%, p < 0.0001), achieve AOA status (19.3% vs. 8.5%, p = 0.0002) and match to top 25 US News and World Report residency programs (23.4% vs. 12.1%, p = 0.008). A greater proportion of PSMRF fellows matched to top tier competitive specialties (23% vs. 14.2%, p = 0.07), however this difference was not statistically significant.

Conclusions

The PSMRF program shows a significant increase in enrollment, as well as positive associations with indicators of success in medical school and subsequent quality of residency program.     

Real‐Time RT‐PCR Ct Values for Blood GAPDH Correlate with Measures of Vascular Endothelial Function in Humans

Purpose

To date, there is a wide range of methods in use to assess endothelial function, each with its own advantages and limitations. Here, we tested hypothesis that real‐time RT‐PCR threshold value (Ct), which is reflective of mRNA level, for Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) from whole blood is indicative of endothelial function in humans.

Materials and Methods

To assess vascular function, we measured baseline skin perfusion, postocclusion reactive hyperemia (PORH), and brachial artery flow‐mediated dilatation (FMD) and tested for a possible correlation between vascular responses and blood GAPDH real‐time RT‐PCR Ct value in 75 healthy volunteers.

Results

Tests known to measure, at least in part, endothelial function such as baseline skin perfusion, the 2‐minute recovery PORH, and FMD exhibited significant positive correlations with blood GAPDH Ct values. In contrast, there was no significant correlation between Ct values for blood GAPDH and peak PORH, an endothelium‐independent parameter.

Conclusions

Based on these findings, we report that GAPDH mRNA level in the blood correlates with vascular function in healthy subjects. This suggests that GAPDH mRNA level could be a potential biomarker of vascular endothelial function.     

Research Participant‐Centered Outcomes at NIH‐Supported Clinical Research Centers

Background

Although research participation is essential for clinical investigation, few quantitative outcome measures exist to assess participants’ experiences. To address this, we developed and deployed a survey at 15 NIH‐supported clinical research centers to assess participant‐centered outcomes; we report responses from 4,961 participants.

Methods

Survey questions addressed core aspects of the research participants’ experience, including their overall rating, motivation, trust, and informed consent. We describe participant characteristics, responses to individual questions, and correlations among responses.

Results

Respondents broadly represented the research population in sex, race, and ethnicity. Seventy‐three percent awarded top ratings to their overall research experience and 94% reported no pressure to enroll. Top ratings correlated with feeling treated with respect, listened to, and having access to the research team (R ² = 0.80–0.96). White participants trusted researchers more (88%) than did nonwhite participants collectively (80%; p < 0.0001). Many participants felt fully prepared by the informed consent process (67%) and wanted to receive research results (72%).

Conclusions

Our survey demonstrates that a majority of participants at NIH‐supported clinical research centers rate their research experience very positively and that participant‐centered outcome measures identify actionable items for improvement of participant''s experiences, research protections, and the conduct of clinical investigation.     

Accrual Index: A Real‐Time Measure of the Timeliness of Clinical Study Enrollment

Background

Achieving timely accrual into clinical research studies remains a challenge for clinical translational research. We developed an evaluation measure, the Accrual Index (AI), normalized for sample size and study duration, using data from the protocol and study management databases. We applied the AI retrospectively and prospectively to assess its utility.

Methods

Accrual Target, Projected Time to Accrual Completion (PTAC), Evaluable Subjects, Dates of Recruitment Initiation, Analysis, and Completion were defined. AI is (% Accrual Target accrued/% PTAC elapsed). Changes to recruitment practices were described, and data extracted from study management databases.

Results

December 2014 (or final) AI was analyzed for 101 studies initiating recruitment from 2007 to 2014. Median AI was ≥1 for protocols initiating recruitment in 2011, 2013, and 2014. The AI varied widely for studies pre‐2013. Studies with AI > 4 utilized convenience samples for recruitment. Data‐justified PTAC was refined in 2013–2014 after which the AI range narrowed. Protocol characteristics were not associated with study AI.

Conclusion

Protocol AI reflects the relative agreement between accrual feasibility assessment (PTAC), and accrual performance, and is affected by recruitment practices. The AI may be useful in managing accountability, modeling accrual, allocating recruitment resources, and testing innovations in recruitment practices.     

Community Engagement Strategies in the Original and Renewal Applications for CTSA Grant Funding

Purpose

The Clinical and Translational Science Award (CTSA) program has highlighted community engagement in research by requiring institutions to develop bidirectional relationships with communities to obtain funding. Little is known about how institutions have operationalized that requirement. This study aimed to describe the strategies proposed by the first institutions to receive CTSA funding and to undergo the CTSA renewal process.

Methods

The authors conducted a qualitative document analysis of the community engagement section of 12 original and 10 renewal grant applications of the 12 institutions awarded CTSA funding in 2006 and renewed in 2010.

Results

Institutions employed ‐ and research engagement strategies. Capacity‐building strategies included education, pilot grants, connecting potential partners, and community research centers. Research engagement strategies ranged from those that allowed for very little input from communities, such as announcements, to those that allowed for a high amount of input from communities, such as community‐researcher teams.

Conclusion

CTSA funding has supported capacity‐building for institutions and communities to partner. Engagement strategies employed by the institutions are largely known from prior community‐engaged research. Based on the grants from these institutions, the CTSA funding has largely enabled institutions to develop capacity to engage.     

Building Interdisciplinary Research Models Through Interactive Education

Background

Critical interdisciplinary research skills include effective communication with diverse disciplines and cultivating collaborative relationships. Acquiring these skills during graduate education may foster future interdisciplinary research quality and productivity.

Objective

The project aim was to develop and evaluate an interactive Toolbox workshop approach within an interprofessional graduate level course to enhance student learning and skill in interdisciplinary research. We sought to examine the student experience of integrating the Toolbox workshop in modular format over the duration of a 14‐week course.

Methods

The Toolbox Health Sciences Instrument includes six modules that were introduced in a 110‐minute dialogue session during the first class and then integrated into the course in a series of six individual workshops in three phases over the course of the semester.

Results

Seventeen students participated; the majority were nursing students. Three measures were used to assess project outcomes: pre–post intervention Toolbox survey, competency self‐assessment, and a postcourse survey. All measures indicated the objectives were met by a change in survey responses, improved competencies, and favorable experience of the Toolbox modular intervention.

Conclusion

Our experience indicates that incorporating this Toolbox modular approach into research curricula can enhance individual level scientific capacity, future interdisciplinary research project success, and ultimately impact on practice and policy.     

Access to Investigational Drugs: FDA Expanded Access Programs or “Right‐to‐Try” Legislation?

Purpose

The Food and Drug Administration Expanded Access (EA) program and “Right‐to‐Try” legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access.

Methods

FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared.

Results

The FDA EA program includes Single Patient‐Investigational New Drug (SP‐IND), Emergency SP‐IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. “Right‐to‐Try” legislation bypasses some of these steps, but provides no regulatory or safety oversight.

Conclusion

The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP‐IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements.     

MOR1 Expression in Gastric Cancer: A Biomarker Associated With Poor Outcome

Background

At present, the expression of MOR1 and its function in gastric cancer remains unclear with evidence suggesting that it is to be involved in tumor progression and metastasis. The study was to assess the clinicopathologic relevance and prognostic value of MOR1 expression in gastric cancer.

Methods

Real‐time quantitative RT‐PCR and immunohistochemical staining were used to detect MOR1 expression in primary gastric cancerous surgical specimens and adjacent nontumorous tissues.

Results

High MOR1 expression was detected in cancerous tumor compared with their adjacent nontumorous tissues. In addition, the chi‐square test revealed that high MOR1 expression was significantly correlated with depth of invasion (p = 0.006), lymph node metastasis (p = 0.001), distant metastasis (p = 0.017), and TNM staging (p = 0.027). Moreover, Kaplan–Meier analysis revealed a significant association between MOR1 expression and overall survival. High expression of MOR1 was identified as an independent and significant predictor gene of reduced postoperative survival.

Conclusion

We conclude that MOR1 expression may be a useful biomarker for better prediction of the clinical outcome and management of gastric cancer patients.     

Promotion and Tenure for Community‐Engaged Research: An Examination of Promotion and Tenure Support for Community‐Engaged Research at Three Universities Collaborating through a Clinical and Translational Science Award

Introduction

Community‐engaged health research, an approach to research which includes the participation of communities, promotes the translation of research to address and improve social determinants of health. As a way to encourage community‐engaged research, the National Institutes of Health required applicants to the Clinical and Translational Science Award (CTSA) to include a community engagement component. Although grant‐funding may support an increase in community‐engaged research, faculties also respond to the rewards and demands of university promotion and tenure standards. This paper measures faculty perception of how three institutions funded by a CTSA support community‐engaged research in the promotion and tenure process.

Methods

At three institutions funded by a CTSA, tenure track and nontenure track faculty responded to a survey regarding perceptions of how promotion and tenure committees value community‐engaged research.

Results

Faculty view support for community‐engaged research with some reserve. Only 36% agree that community‐engaged research is valued in the promotion and tenure process.

Discussion

Encouraging community‐engaged scholarship requires changing the culture and values behind promotion and tenure decisions. Institutions will increase community‐engaged research and more faculty will adopt its principles, when it is rewarded by promotion and tenure committees.     

Faculty Perceptions of How Community‐Engaged Research Is Valued in Tenure,Promotion, and Retention Decisions

Purpose

We assessed the perceptions of community core faculty in academic medical center institutions that received Clinical and Translational Science Awards (CTSA) about how these institutions consider community‐engaged scholarship (CES) when tenure, promotion, and retention decisions are made.

Method

An assessment tool was adapted to create an 18‐item survey that was sent during November and December 2011 via the Internet to the 369 members of the community‐engagement core mailing list of the CTSA.

Results

Fifty‐nine responses were received which represented 37 of the possible 60 different funded institutions. The mean score was 48.14 (SD = 11.18); range of 23–74; and Cronbach''s alpha was .91 About half reported that support for CES and its inclusion in the academic decision process increased since the institution was awarded a CTSA. Open‐ended responses indicated some confusion with terminology although a definition of CES had been provided in the instrument instructions.

Conclusion

Respondents overall agreed there was moderate support for CES in tenure, promotion, and retention decisions which may have been influenced by the CTSA application requirements. This survey could be used to identify if there are differences in institutional and departments and measure changes over time.     

Genotyping HLA‐B*5801 for Allopurinol‐Induced Severe Cutaneous Adverse Reactions: An Accurate and Prompt Method

Objectives

A new method of HLA‐B*5801 genotyping was compared with sequence‐based typing (SBT) to find an accurate and prompt method in genotyping HLA‐B*5801.

Methods

Two groups of patients from allopurinol‐induced cutaneous adverse reactions (SCARs) and allopurinol‐tolerant were both genotyped with PG5801 kit and SBT method. The genotyping results of HLA‐B*5801 were compared between the two groups.

Results

The PG5801 detection kit results were 100% (79/79) in agreement with the SBT genotyping results for identifying the HLA‐B*5801 (+) patients. No false‐positive or false‐negative errors were found. The sensitivity, specificity, rate of adherence, positive predictive value (PPV) and negative predictive value (NPV) were 100%.

Conclusion

The potential fast screening method is an ideal tool to rule out the high‐risk allopurinol‐induced SCARs patients.     

Improving the Proficiency of Research Consent Administrators

Objective:

To describe the development and testing of a module to improve consent administrators’ skills when obtaining research consent from culturally and linguistically diverse and low literacy populations.

Design:

Development and psychometric testing of video module including community vignettes.

Methods:

Following initial content, face, and construct validity testing by experts, a field trial was conducted with pre‐ and postknowledge tests and satisfaction surveys completed by 112 consent administrators.

Results:

Mean score out of a possible 10 on pretest was 8.6 (±standard deviation [SD], 1.55) and on posttest was 9.1 (±SD, 1.2; paired t‐test 95% confidence interval of difference: –0.18 to –0.88; two‐tailed p = 0.003). The average years of experience with obtaining consent was 6.42 years (range: 0–35), but years of experience was not significantly associated with either pre‐ or posttest scores (p = 0.82 and 0.44, respectively). Most user evaluations were positive, although suggestions for improvements were made.

Conclusion:

Although pretest scores were relatively high, training needs of research consent administrators for consenting diverse and low literacy populations may be unmet. We urge that institutional review boards, researchers, policymakers, educators, and bioethicists address the training needs of research consent administrators and we offer this training module as one potential resource and adjunct to such training.     

Assessing the Impact of the NIH CTSA Program on Institutionally Sponsored Clinical Trials

Objective

To assess the impact of the NIH CTSA program on patient enrollment in clinical trials sponsored/collaborated by CTSA consortium institutions.

Material and Methods

Using publicly available clinical trial data at ClinicalTrials.gov, we identify positive trend changes in the number of patients enrolled in clinical trials performed at CTSA consortium institutions over the years before and after their respective CTSA award dates. CTSA consortium institutions were matched with similar non‐CTSA institutions.

Results

As compared to matched non‐CTSA institutions CTSA consortium sites noted an increase in patient enrollment after the CTSA awards. In particular, we detected a change‐point, where a new enrollment trend emerged, 338 days after the CTSA award. No such trend was noted over the same period in the non‐CTSA institutions.

Conclusion

Our analysis provides evidence that the NIH CTSA funding program made a positive impact on patient enrollment.     

Homocysteine Metabolism in Children with Idiopathic Nephrotic Syndrome

Background

Homocysteine metabolism is altered in children with idiopathic nephrotic syndrome. Hyperhomocysteinemia is a risk factor of early atherosclerosis and glomerulosclerosis and may occur at time of first occurrence of idiopathic nephrotic syndrome.

Methods

Thirty children with first episode of idiopathic nephrotic syndrome (FENS) aged 1–16 years along with 30 age‐ and sex‐matched healthy controls were enrolled in this study. Homocysteine and cysteine were measured with HPLC; vitamin B₁₂ and folic acid were measured with electro‐chemilumiscence immunoassay. Primary outcome measure was plasma homocysteine level in children with FENS and in controls. Secondary outcome measures were (1) plasma and urine homocysteine and cysteine levels in children with FENS at 12 weeks and 1 year (remission) and (2) plasma and urine levels of vitamin B₁₂ and folic acid in children with FENS, at 12 weeks and 1 year (remission).

Results

Plasma homocysteine and cysteine levels were comparable to controls in children with FENS, at 12 weeks and 1‐year remission. Plasma levels of vitamin B12 and folic acid were significantly decreased compared to controls in FENS due to increased urinary excretion, which normalize during remission at 12 weeks and 1 year. Urinary homocysteine and cysteine levels were significantly raised in FENS compared to controls and continued to be raised even at 12‐week and 1‐year remission.

Conclusion

Homocysteine metabolism is deranged in children with FENS. Renal effects of long‐term raised urinary homocysteine levels need to be studied.     

A Research Mentor Training Curriculum for Clinical and Translational Researchers

Purpose

To design and evaluate a research mentor training curriculum for clinical and translational researchers. The resulting 8‐hour curriculum was implemented as part of a national mentor training trial.

Method

The mentor training curriculum was implemented with 144 mentors at 16 academic institutions. Facilitators of the curriculum participated in a train‐the‐trainer workshop to ensure uniform delivery. The data used for this report were collected from participants during the training sessions through reflective writing, and following the last training session via confidential survey with a 94% response rate.

Results

A total of 88% of respondents reported high levels of satisfaction with the training experience, and 90% noted they would recommend the training to a colleague. Participants also reported significant learning gains across six mentoring competencies as well as specific impacts of the training on their mentoring practice.

Conclusions

The data suggest the described research mentor training curriculum is an effective means of engaging research mentors to reflect upon and improve their research mentoring practices. The training resulted in high satisfaction, self‐reported skill gains as well as behavioral changes of clinical and translational research mentors. Given success across 16 diverse sites, this training may serve as a national model. Clin Trans Sci 2013; Volume 6: 26–33     

Family History of Dilated Cardiomyopathy among Patients with Heart Failure from the HF‐ACTION Genetic Ancillary Study

Background

The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined.

Methods

A genetic ancillary study was created as a component of the HF‐ACTION trial, a multicenter, prospective, randomized clinical trial of exercise in patients with heart failure and an ejection fraction <35%. A FH‐based study using a structured questionnaire mailed to all consenting individuals was incorporated into the genetic ancillary. FH responses were analyzed for dilated cardiomyopathy (DCM) in family members.

Results

Of the 741 individuals with data available, 358 (48.3%) had nonischemic and 383 (51.6%) had ischemic etiology, and of these 164 (45.8%) and 201 (52.4%), respectively, returned evaluable questionnaires. Of those with nonischemic etiology, 14/164 (8.5%) reported at least one first‐degree family member with DCM or an enlarged heart; another 21/164 (12.8%) reported a FH of “cardiomyopathy,” a less specific term to indicate DCM.

Conclusion

At least 8.5% of patients with nonischemic etiology in the HF‐ACTION genetic ancillary study provided FH indicating familial DCM, information important to inform further genetic analyses of this cohort and to plan other studies.