Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

Student perceptions of the progress test in two settings and the implications for test deployment.

BACKGROUND: The Progress Test (PT) was developed to assess student learning within integrated curricula. Whilst it is effective in promoting and rewarding deep approaches to learning in some settings, we hypothesised that implementation of the curriculum (design and assessment) may impact on students' preparation for the PT and their learning. Aim To compare students' perceptions of and preparations for the PT at two medical schools. METHOD: Focus groups were used to generate items for a questionnaire. This was piloted, refined, and then delivered at both schools. Exploratory factor analysis identified the main factors underpinning response patterns. ANOVA was used to compare differences in response by school, year group and gender. RESULTS: Response rates were 640 (57%) and 414 (47%) at Schools A and B, respectively. Three major factors were identified: the PT's ability to (1) assess academic learning (2) support clinical learning; (3) the PT's impact on exam preparation. Significant differences were found between settings. In the school with early clinical contact, more frequent PTs and no end of unit tests, students were more likely to appreciate the PT as a support for learning, perceive it as fair and valid, and use a deeper approach to learning-but they also spent longer preparing for the test. CONCLUSION: Different approaches to the delivery of the PT can impact significantly on student study patterns. The learning environment has an important impact on student perceptions of assessment and approach to learning. Careful decisions about PT deployment must be taken to ensure its optimal impact.

Improving progress test score estimation using bayesian statistics.

OBJECTIVES: Progress tests give a continuous measure of a student's growth in knowledge. However, the result at each test instance is subject to measurement error from a variety of sources. Previous tests contain useful information that might be used to reduce this error. A Bayesian statistical approach to using this prior information was investigated. METHODS: We first developed a Bayesian model that used the result from only one preceding test to update both the current estimated test score and its standard error of measurement (SEM). This was then extended to include results from all previous tests. RESULTS: The Bayesian model leads to an exponentially weighted combination of test scores. The results show smoothing of test scores when all previous tests are included in the model. The effective sample size is doubled, leading to a 30% reduction in measurement error. CONCLUSIONS: A Bayesian approach can give improved score estimates and smaller SEMs. The method is simple to use with large cohorts of students and frequent tests. The smoothing of raw scores should give greater consistency in rank ordering of students and hence should better identify both high-performing students and those in need of remediation.

Are multiple choice tests fair to medical students with specific learning disabilities?

The purpose of multiple choice tests of medical knowledge is to estimate as accurately as possible a candidate's level of knowledge. However, concern is sometimes expressed that multiple choice tests may also discriminate in undesirable and irrelevant ways, such as between minority ethnic groups or by sex of candidates. There is little literature to establish whether multiple choice tests may also discriminate against students with specific learning disabilities (SLDs), in particular those with a diagnosis of dyslexia, and whether the commonly-used accommodations allow such students to perform up to their capability. We looked for evidence to help us determine whether multiple choice tests could be relied upon to test all medical students fairly, regardless of disability. We analyzed the mean scores of over 900 undergraduate medical students on eight multiple-choice progress tests containing 1,000 items using a repeated-measures analysis of variance. We included disability, gender and ethnicity as possible explanatory factors, as well as year group. There was no significant difference between mean scores of students with an SLD who had test accommodations and students with no SLD and no test accommodation. Virtually all students were able to complete the tests within the allowed time. There were no significant differences between the mean scores of known minority ethnic groups or between the genders. We conclude that properly-designed multiple-choice tests of medical knowledge do not systematically discriminate against medical students with specific learning disabilities.

Choosing and designing knowledge assessments: experience at a new medical school.

BACKGROUND: Curriculum developers have a wide choice of assessment methods in all aspects of medical education including the specific area of medical knowledge. When selecting the appropriate tool, there is an increasing literature to provide a robust evidence base for developments or decisions. AIM: As a new medical school, we wished to select the most appropriate method for knowledge assessment. METHODS: This article describes how a new medical school came to choose progress testing as its only method of summative assessment of undergraduate medical knowledge. RESULTS: The rationale, implementation, development and performance of the assessment are described. The position after the first cohort of students qualified is evaluated. CONCLUSION: Progress testing has worked well in a new school. Opportunities for further study and development exist. It is to be hoped that our experiences and evidence will assist and inform others as they consider developments for their own schools.

Can we share questions? Performance of questions from different question banks in a single medical school.

BACKGROUND: To use progress testing, a large bank of questions is required, particularly when planning to deliver tests over a long period of time. The questions need not only to be of good quality but also balanced in subject coverage across the curriculum to allow appropriate sampling. Hence as well as creating its own questions, an institution could share questions. Both methods allow ownership and structuring of the test appropriate to the educational requirements of the institution. METHOD: Peninsula Medical School (PMS) has developed a mechanism to validate questions written in house. That mechanism can be adapted to utilise questions from an International question bank International Digital Electronic Access Library (IDEAL) and another UK-based question bank Universities Medical Assessment Partnership (UMAP). These questions have been used in our progress tests and analysed for relative performance. RESULTS: Data are presented to show that questions from differing sources can have comparable performance in a progress testing format. CONCLUSION: There are difficulties in transferring questions from one institution to another. These include problems of curricula and cultural differences. Whilst many of these difficulties exist, our experience suggests that it only requires a relatively small amount of work to adapt questions from external question banks for effective use. The longitudinal aspect of progress testing (albeit summatively) may allow more flexibility in question usage than single high stakes exams.

Beyond assessment: feedback for individuals and institutions based on the progress test.

BACKGROUND: Progress testing is used at Peninsula Medical School to test applied medical knowledge four times a year using a 125-item multiple choice test. Items within each test are classified and matched to the curriculum blueprint. AIM: To examine the use of item classifications as part of a quality assurance process and to examine the range of available feedback provided after each test or group of tests. METHODS: The questions were classified using a single best classification method. These were placed into a simplified version of the progress test assessment blueprint. Average item facilities for individuals and cohorts were used to provide feedback to individual students and curriculum designers. RESULTS: The analysis shows that feedback can be provided at a number of levels, and inferences about various groups can be made. It demonstrates that learning mostly occurs in the early years of the course, but when examined longitudinally, it shows how different patterns of learning exist in different curriculum areas. It also shows that the effect of changes in the curriculum may be monitored through these data. CONCLUSIONS: Used appropriately, progress testing can provide a wide range of feedback to every individual or group of individuals in a medical school.

Adaptation of medical progress testing to a dental setting.

Although progress testing (PT) is well established in several medical schools, it is new to dentistry. Peninsula College of Medicine and Dentistry has recently established a Bachelor of Dental Surgery programme and has been one of the first schools to use PT in a dental setting. Issues associated with its development and of its adaption to the specific needs of the dental curriculum are considered.

Difficult decisions for progress testing: how much and how often?

This article is primarily an opinion piece which aims to encourage debate and future research. There is little theoretical or practical research on how best to design progress tests. We propose that progress test designers should be clear about the primary purpose of their assessment. We provide some empirical evidence about reliability and cost based upon generalisability theory. We suggest that the future research is needed in the areas of educational impact and acceptability.

A plea for the proper use of criterion-referenced tests in medical assessment.

OBJECTIVES: This paper is aimed at assessment teams which are not steeped in the culture of educational measurement, but, rather, are composed of professionals whose jobs primarily require them to work as clinicians, but whose interest in medical education has given them responsibilities for assessment. It reiterates the difference between criterion-referenced tests and norm-referenced tests. It proposes that those who design and use any assessment in medicine should be clear about which of these approaches to testing they are using. METHODS: This paper does not present any new results, but synthesises what is already known about norm-referenced and criterion-referenced tests by reviewing some of the literature. It explains how these two test paradigms lead to different approaches to test design, different measures of reliability and different standard errors of measurement. It shows how these factors may lead to differences in the standards set for some assessments. CONCLUSIONS: Many common medical assessments are assumed to be criterion-referenced but tend to follow norm-referenced practices. Assessment designers should examine the characteristics of each type of assessment to determine which approach is more appropriate and should then apply the correct theories and methods.

Standard setting for progress tests: combining external and internal standards.

OBJECTIVES: There has been little work on standard setting for progress tests and it is common practice to use normative standards. This study aimed to develop a new approach to standard setting for progress tests administered at the point when students approach graduation. METHODS: In this study we obtained performance data from newly qualified doctors and used this information to set the standard for the last progress test in the final year of undergraduate medical education. This external reference was validated against projections of student performance data based upon normative grading, and other published results. A simple linear growth model was used to set pass scores for progress tests earlier in the final year and this was also validated by published data. RESULTS: There was good agreement between standards set using the data from newly qualified doctors, the standard expected from extrapolation of the student progression data, and published performance data from another medical school. CONCLUSIONS: We have demonstrated that a combination of data from independent sources can be used to triangulate standard-setting decisions for progress tests. Performance data from successive cohorts of medical students could provide a fruitful source of information for standard setting for progress tests.

Innovative learning: employing medical students to write formative assessments.

Peninsula Medical School, UK, employed six students to write MCQ items for a formative applied medical knowledge item bank. The students successfully generated 260 quality MCQs in their six-week contracted period. Informal feedback from students and two staff mentors suggests that the exercise provided a very effective learning environment and that students felt they were 'being paid to learn'. Further research is under way to track the progress of the students involved in the exercise, and to formally evaluate the impact on learning.

Developing a "frequent look and rapid remediation" assessment system for a new medical school.

The Peninsula College of Medicine and Dentistry (PCMD) was among the five new medical schools approved in the United Kingdom in 2000. PCMD required a new curriculum and a new outcomes-oriented assessment system based on sound educational theory. The resulting system was designed to use multiple sampling and show increasing authenticity as students progress through the curriculum. A "frequent look and rapid remediation" structure was incorporated to allow faculty to evaluate student competence throughout the year and take immediate action when warranted. Using a recently published framework, the authors retrospectively evaluate the assessment system and share many of the decisions they and their colleagues had to make. They discuss how to support stakeholders in understanding and contributing to the development of an assessment system and how to meet some of the challenges they encountered. They consider indicators of success in terms of the performance of the assessment system as a whole and the ways the system contributes to educational research. They suggest that future research should focus on building greater flexibility into the system so that assessment decisions can be individualized to particular students.

The tumor suppressor gene FBXW7 is disrupted by a constitutional t(3;4)(q21;q31) in a patient with renal cell cancer.

FBXW7 (alias CDC4) is a p53-dependent tumor suppressor gene that exhibits mutations or deletions in a variety of human tumors. Mutation or deletion of the FBXW7 gene has been associated with an increase in chromosomal instability and cell cycle progression. In addition, the FBXW7 protein has been found to act as a component of the ubiquitin proteasome system and to degrade several oncogenic proteins that function in cellular growth regulatory pathways. By using a rapid breakpoint cloning procedure in a case of renal cell cancer (RCC), we found that the FBXW7 gene was disrupted by a constitutional t(3;4)(q21;q31). Subsequent analysis of the tumor tissue revealed the presence of several anomalies, including loss of the derivative chromosome 3. Upon screening of a cohort of 29 independent primary RCCs, we identified one novel pathogenic mutation, suggesting that the FBXW7 gene may also play a role in the development of sporadic RCCs. In addition, we screened a cohort of 48 unrelated familial RCC cases with unknown etiology. Except for several known or benign sequence variants such as single nucleotide polymorphisms (SNPs), no additional pathogenic variants were found. Previous mouse models have suggested that the FBXW7 gene may play a role in the predisposition to tumor development. Here we report that disruption of this gene may predispose to the development of human RCC.

Chromophoric 5'-O-Silyl protection of N-protected 2'-ACE ribonucleosides for solid-phase RNA synthesis.

Recent advances in the understanding of the pivotal roles played by endogenous small RNAs in gene regulation have resulted in a substantial and rapidly growing market for synthetic RNA. 5'-Silyl-2'-ACE chemistry has proven to be a robust and reliable technology for the synthesis of oligoribonucleotides. This unit describes an important improvement to this chemistry, by adding a cycle-to-cycle traceability analogous to that inherent in 5'-dimethoxytrityl-based approaches. This is achieved by first regioselectively introducing a 5'-alkynylsilyl protecting group onto the 2'-ACE-protected nucleosides. The 5'-alkynylsilyl group is then reacted with an azide derivative of the chromophore Disperse Red 1, which enables spectrophotometric interrogation of each coupling step following 5'-deprotection. Finally, the protected nucleosides are elaborated into their 3'-phosphoramidite derivatives for use in solid-phase RNA synthesis.

'I'm pickin' up good regressions': the governance of generalisability analyses.

CONTEXT: Investigators applying generalisability theory to educational research and evaluation have sometimes done so poorly. The main difficulties have related to: inadequate or non-random sampling of effects, dealing with naturalistic data, and interpreting and presenting variance components. METHODS: This paper addresses these areas of difficulty, and articulates an informal consensus amongst medical educators from Europe, Australia and the USA, who are familiar with generalisability theory. RESULTS: We make the following recommendations. Ensure that all relevant factors are sampled, and that the sampling meets the theory's assumption that the conditions represent a random and representative sample of the factor's 'universe'. Research evaluations will require large samples of each factor if they are to generalise adequately. Where feasible, conduct 2 separate studies (pilot and evaluation, or Generalisability and Decision studies). For unbalanced data, use either urgenova, or 1 of the procedures minimum norm quadratic unbiased estimator, (minque), maximum likelihood (ml) or restricted maximum likelihood (reml) in spss or sas if the data are too complex. State which mathematical procedure was used and the degrees of freedom (d.f.) of the effect estimates. If the procedure does not report d.f., re-analyse with type III sum of squares anova (anova ss III) and report these d.f. Describe and justify the regression model used. Present the raw variance components. Describe the effects that they represent in plain, non-statistical language. If standard error of measurement (SEM) or Reliability coefficients are presented, give the equations used to calculate them. Make sure that the method of reporting reliability (precision or discrimination) is appropriate to the purpose of the assessment. This will usually demand a precision indicator such as SEM. Consider a graphical presentation to combine precision and discrimination.

Assessment of progress tests.

BACKGROUND: Progress testing is a form of longitudinal examination which, in principle, samples at regular intervals from the complete domain of knowledge considered a requirement for medical students on completion of the undergraduate programme. Over the course of the programme students improve their scores on the test, enabling them, as well as staff, to monitor their progress. AIM: We aimed to review methods which have been used to assess the results of individual tests, and to make recommendations on best practice. DISCUSSION: In assessing progress tests, there are a variety of choices that must be made. These include whether the test is norm- or criterion-referenced; whether marking is negative or "number-right"; whether the grades are reported on a continuous or a discontinuous scale, and whether the grades are weighted towards the most recent observations, or the entire set of grades is used to determine the final grade. Grade boundary setting in the context of progress tests is also considered, using a mathematical model to predict the consequences of different approaches. The relationships between boundary setting, progression and remediation rules are considered. CONCLUSIONS: We concluded that norm referencing is preferable to criterion referencing, negative marking preferable to number-right marking, a discontinuous scale preferable to a continuous scale and that grades should be weighted to favour the most recent outcomes, although there should still be a degree of persistence (earlier grades should not disappear all together). Grade boundaries should be established with regard to rules on remediation and progression.