Self-Coding of Fidelity as a Potential Active Ingredient of Consultation to Improve Clinicians’ Fidelity

A key goal for implementation science is the identification of evidence-based consultation protocols and the active ingredients within these protocols that drive clinician behavior change. The current study examined clinicians’ self-coding of fidelity as a potential active ingredient of consultation for the Attachment and Biobehavioral Catch-up (ABC) intervention. It also examined two other potential predictors of clinician fidelity in response to consultation: dosage of consultation and working alliance. Twenty-nine clinicians (97% female, 62% White, M age?=?34 years) participated in a year of weekly fidelity-focused ABC consultation sessions, for which clinicians self-coded fidelity and received consultant feedback on both their coding and their fidelity. Data from the ABC fidelity measure were available for 1067 sessions coded by consultants, and clinicians’ self-coding accuracy was calculated from 1044 sessions coded by both clinicians and consultants. Alliance was measured with the Working Alliance Inventory—Trainee and Supervisor Versions. The study was observational, and fidelity and self-coding accuracy were modeled across time using hierarchical linear modeling. Clinicians’ ABC fidelity, as well as their self-coding accuracy, increased over the course of consultation. Clinicians’ self-coding accuracy predicted their initial fidelity and growth in fidelity. Working alliance was also linked to fidelity and self-coding accuracy. These results suggest that clinician self-coding should be further examined as an active ingredient of consultation. The study has important implications for the design of consultation procedures and fidelity assessments.

     

Translational crossroads for biomarkers.

A group of investigators met at a Specialized Programs of Research Excellence Workshop to discuss key issues in the translation of biomarker discovery to the development of useful laboratory tests for cancer care. Development and approval of several new markers and technologies have provided informative examples that include more specific markers for prostate cancer, more sensitive tests for ovarian cancer, more objective analysis of tissue architecture and an earlier indication of response to treatment in breast cancer. Although there is no clear paradigm for biomarker development, several principles are clear. Marker development should be driven by clinical needs, including early cancer detection, accurate pretreatment staging, and prediction of response to treatment, as well as monitoring disease progression and response to therapy. Development of a national repository that uses carefully preserved, well-annotated tissue specimens will facilitate new marker development. Reference standards will be an essential component of this process. Both hospital-based and commercial laboratories can play a role in developing biomarkers from discovery to test validation. Partnering of academe and industry should occur throughout the process of biomarker development. The National Cancer Institute is in a unique position to bring together academe, industry, and the Food and Drug Administration to (a) define clinical needs for biomarkers by tumor type, (b) establish analytic and clinical paradigms for biomarker development, (c) discuss ways in which markers from different companies might be evaluated in combination, (d) establish computational methods to combine data from multiple biomarkers, (e) share information regarding promising markers developed in National Cancer Institute-supported programs, and (f) exchange data regarding new platforms and techniques that can accelerate marker development.     

CTLA-4 is required for the induction of high dose oral tolerance

Mucosal and systemic administrations of high dose antigens induce long- lasting peripheral T cell tolerance. We and others have shown that high dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the present study, we examined the roles of the B7 co-stimulation pathway in the generation of high dose peripheral T cell tolerance. We found that blocking B7:CD28/CTLA-4 interaction at the time of tolerance induction partially prevented T cell tolerance, whereas selective blockade of B7:CTLA-4 interaction completely abrogated peripheral T cell tolerance induced by either oral or i.p. antigens. These results suggest that CTLA-4-mediated feedback regulation plays a crucial role in the induction of high dose peripheral T cell tolerance.      

The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and E-cadherin.

Several studies have reported loss or alteration of expression of E-cadherin in breast cancer and more recently changes in levels of expression of the catenins. We used immunofluorescence to examine E-cadherin, alpha-catenin, beta-catenin, and p120ctn (formerly p120CAS) expression in 91 cases of invasive ductal carcinoma. As expected, all four proteins co-localize to the junctional regions of the cells. Although nuclear localization has been described for beta-catenin in colonic polyps, no examples were found in these breast cancer cases. We found that, although alteration is common in the catenins and E-cadherin, complete loss, as exemplified by E-cadherin in lobular carcinoma (where E-cadherin is frequently mutated), is rarely seen. In contrast, the catenin-related protein p120ctn shows an expression pattern that is significantly unrelated to the other catenins (or E-cadherin), including complete loss of expression in approximately 10% of the cases. No statistically significant correlations with traditional prognostic indicators were observed with any of these proteins. We conclude 1) that expression of E-cadherin and alpha- and beta-catenin are generally retained at the membrane although frequently reduced or altered, 2) that complete loss of p120ctn expression is seen in approximately 10% of the cases, and 3) that there is a significant correlation in the expression of E-cadherin and the catenins but no correlation between these molecules and p120ctn, suggesting an absence of coordinate regulation.     

Alcohol intake in early adulthood and risk of colorectal cancer: three large prospective cohort studies of men and women in the United States

European Journal of Epidemiology - Heavy alcohol consumption in mid-adulthood is an established risk factor of colorectal cancer (CRC). Alcohol use in early adulthood is common, but its association...     

Validation of tissue microarray technology in breast carcinoma

The recent development of tissue microarray technology has potentiated large-scale retrospective cohort studies using archival formalin-fixed, paraffin-embedded tissues. A major obstacle to broad acceptance of microarrays is that they reduce the amount of tissue analyzed from a whole tissue section to a disk, 0.6 mm in diameter, that may not be representative of the protein expression patterns of the entire tumor. In this study, we examine the number to disks required to adequately represent the expression of three common antigens in invasive breast carcinoma--estrogen receptor, progesterone receptor, and the Her2/neu oncogene--in 38 cases of invasive breast carcinoma. We compared the staining of 2 to 10 microarray disks and the whole tissue sections from which they were derived and determined that analysis of two disks is comparable to analysis of a whole tissue section in more than 95% of cases. To evaluate the potential for using archival tissue in such arrays, we created a breast cancer microarray of 8 to 11 cases from each decade beginning in 1932 to the present day and evaluated the antigenicity of these markers and others. This array demonstrates that many proteins retain their antigenicity for more than 60 years, thus validating their study on archival tissues. We conclude that the tissue microarray technique, with 2-fold redundancy, is a valuable and accurate method for analysis of protein expression in large archival cohorts.     

Expression of an ovalbumin-specific V{beta}8.2 TCR transgene inhibits collagen arthritis in B10.Q mice

Previous studies have illustrated the importance of T cellsbearing ß TCRs in the induction and development ofcollagen induced arthritis (CIA) in mice. However, the scopeof TCR usage in CIA has yet to be clearly defined. Given theinherent diversity of the TCR repertoire, the relative flexibilityof the arthritogenic TCR repertoire specific for type II collagen(CII) is not clear. Therefore, we chose to examine the influenceof a highly skewed TCR repertoire on CIA. Arthritis susceptibleB10.Q (H-2^q) mice were mated with C57L (H-2^b) animals expressingan ovalbuminspecific V_ß8.2 TCR transgene (Tg) andTg⁺ offspring were further backcrossed to B10.Q. HomozygousH-2^a/q, V_ß8.2 Tg⁺ mice displayed a high level of V_ß8.2⁺T cells in peripheral blood. However, expression of some endogenousV_ß TCR, such as V_ß14, was still detected.Upon immunization with bovine CII in adjuvant, V_ß8.2Tg⁺ mice were highly resistant to CIA when compared with Tg^–littermates. Analysis of sera demonstrated a marked reductionin antibody specific for homologous mouse CII as well as heterologousbovine CII in Tg⁺ animals. Interestingly, V_ß8.2 Tg⁺mice still mounted good antibody responses following immunizationwith human thyroglobulin, indicating that the skewed TCR repertoireaffected anti-CII but not antithyroglobulin responses. Thus,our findings show that constraints placed on the TCR repertoireInhibit pathogenic responses against CII and suggest that inH-2^q mice the arthritogenlc TCR repertoire bears only limitedflexibility.