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Purpose: The Royal College of Physicians and Surgeons of Canada (RCPSC) has mandated the transition of postgraduate medical training in Canada to a competency-based medical education (CBME) model divided into 4 stages of training. As part of the Queen's University Fundamental Innovations in Residency Education proposal, Queen's University in Canada is the first institution to transition all of its residency programs simultaneously to this model, including Diagnostic Radiology. The objective of this report is to describe the Queen's Diagnostic Radiology Residency Program's implementation of a CBME curriculum. Methods: At Queen's University, the novel curriculum was developed using the RCPSC's competency continuum and the CanMEDS framework to create radiology-specific entrustable professional activities (EPAs) and milestones. In addition, new committees and assessment strategies were established. As of July 2015, 3 cohorts of residents (n = 9) have been enrolled in this new curriculum. Results: EPAs, milestones, and methods of evaluation for the Transition to Discipline and Foundations of Discipline stages, as well as the opportunities and challenges associated with the implementation of a competency-based curriculum in a Diagnostic Radiology Residency Program, are described. Challenges include the increased frequency of resident assessments, establishing stage-specific learner expectations, and the creation of volumetric guidelines for case reporting and procedures. Conclusions: Development of a novel CBME curriculum requires significant resources and dedicated administrative time within an academic Radiology department. This article highlights challenges and provides guidance for this process. [ABSTRACT FROM AUTHOR]

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-KB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL. [ABSTRACT FROM AUTHOR]

4-1BB is a TNFR family member associated with NF-κB mediated survival signaling. 4-1BB is widely expressed on activated cells of the immune system, including activated T cells, NK cells and dendritic cells. Its ligand, 4-1BBL, is transiently expressed on activated antigen presenting cells and at low levels on activated T cells. Although 4-1BBL-deficient mice clearly demonstrate a role for 4-1BBL in CD8 T cell responses to viruses such as influenza, 4-1BBL can be difficult to detect following infection of mice. Here we provide evidence for a constitutive interaction between endogenous 4-1BB and 4-1BBL on LPS activated bone marrow-derived murine dendritic cells that can mask its detection, with implications for measurement of 4-1BBL expression. The masking of 4-1BBL by its receptor results in loss of reactivity to the anti-4-1BBL antibody TKS-1, whereas the 19H3 antibody binds to 4-1BBL in the presence or absence of 4-1BB. Moreover, 4-1BB/4-1BBL interaction can occur in trans between 4-1BB +/+ and 4-1BB −/− dendritic cells in culture. These data suggest that 19H3 is the preferable antibody to use to detect 4-1BBL in the presence of its receptor. [ABSTRACT FROM AUTHOR]

Lymphocytic choriomeningitis virus clone 13 (LCMV13) infection of mice is a widely used model for investigating the mechanisms driving persistent viral infection in humans. LCMV13 disrupts splenic architecture early during infection, but this returns to normal within a few weeks. However, the long-term effects of LCMV13 infection on splenic structure have not been reported. Here, we report that persistent infection with LCMV13 results in sustained splenic atrophy that persists for at least 500 days following infection, whereas infection with the acutely infecting LCMV Armstrong is associated with a return to preinfection spleen weights. Splenic atrophy is associated with loss of T, B, and non-B non-T cells, with B cells most significantly affected. These effects were partly ameliorated by anti-NK1.1 or anti-CD8 antibody treatment. Antigen presentation was detectable at the time of contraction of the spleen, but no longer detected at late time points, suggesting that continued antigen presentation is not required to maintain splenic atrophy. Immunity to Salmonella infection and influenza vaccination were decreased after the virus was no longer detected. Thus splenic atrophy following LCMV13 infection is irreversible and may contribute to impaired immunity following clearance of LCMV13. [ABSTRACT FROM AUTHOR]

The persistence of memory lymphocytes is a critical feature of adaptive immunity. The TNF family ligand 4-1 BBL supports the antigen-independent survival of CD8+ memory T cells. Here, we show that mice lacking 4-1 BB only on αβ T cells show a similar defect in CD8+ T-cell recall responses, as previously shown in 4-1 BBL-deficient mice. We show that 4-1 BB is selectively expressed on BM CD8+ but not CD4 + memory T cells of unimmunized mice. Its ligand, 4-1 BBL, is found on VCAM-1+ stromal cells, CD11c+ cells, and a Gr1lo myeloid population in unimmunized mice. Adoptive transfer of in vitro generated memory T cells into mice lacking 4-1 BBL only on radioresistant cells recapitulates the defect in CD8 + T-cell survival seen in the complete knockout mice, with smaller effects of 4-1 BBL on hematopoietic cells. In BM, adoptively transferred Ds Red CD8+ memory T cells are most often found in proximity to VCAM-1+ cells or Gr1+ cells, followed by B220+ cells and to a much lesser extent near CD11c+ cells. Thus, a VCAM-1+ CD45− stromal cell is a plausible candidate for the radioresistant cell that provides 4-1 BBL to CD8+ memory T cells in the BM. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gadolinium-based contrast agents are widely used for meningioma imaging; however, concerns exist regarding their side effects, cost, and environmental impact. At the standard gadolinium dose, most meningiomas show avid contrast enhancement, suggesting that administering a smaller dose may be feasible. The purpose of this study was to evaluate the impact of a lower gadolinium dose on the differentiation between meningiomas and adjacent intracranial tissues., Materials and Methods: One hundred eight patients with presumed or confirmed meningiomas who underwent a brain MRI at multiple doses of gadolinium were included in the study. The patients' MRIs were categorized into 3 groups based on the gadolinium dose administered: micro (approximately 25% of the standard dose), low (approximately 62% of the standard dose), and standard dose. Multireader qualitative visual assessment and quantitative relative signal differences calculations were performed to evaluate tumor differentiation from the cortex and from the dural venous sinus. The relative signal differences for each dose were analyzed by using ANOVA for quantitative assessment and the McNemar test for qualitative assessment. Additionally, noninferiority testing was used to compare the low and micro doses to the standard dose., Results: Decreasing the gadolinium dose to a low dose or micro dose resulted in a statistically significant decrease in signal difference between the tumor and the adjacent brain tissue ( P < .02). However, on visual assessment, the low dose was noninferior to the standard dose. The proportion of cases with suboptimal differentiation was significantly higher for the micro dose than for the standard dose, both for the differentiation between the tumor and the cortex ( P  = .041) and the differentiation between the tumor and the sinus ( P < .001)., Conclusions: Reducing the gadolinium dose to 62% of the standard level still allows for sufficient visual delineation of meningiomas from surrounding tissues. However, further reduction to 25% substantially compromises the ability to distinguish the tumor from adjacent structures and is, therefore, not advisable., (© 2024 by American Journal of Neuroradiology.)

TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1 -/- mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.