Functional loss of IKBE leads to NF-KB deregulation in aggressive chronic lymphocytic leukemia

NF-?B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-?B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I?B?, a negative regulator of NF-?B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I?B? protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I?B? loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-?B deregulation during lymphomagenesis. <br/

The CDIO Syllabus 3.0 : An Updated Statement of Goals

The CDIO Initiative is going through a process of reconsidering and updating the CDIO approach for engineering education development. Previous work resulted in substantial updates of the twelve CDIO standards and the introduction of “optional” CDIO standards. This paper reports on a similar review and update of the CDIO Syllabus to version 3.0. It has been developed by a working group consisting of four sub-groups and iterated and refined guided by feedback from the whole CDIO community. There are mainly three external drivers that 18 Proceedings of the 18th International CDIO Conference, hosted by Reykjavik University, Reykjavik Iceland, June 13-15, 2022. motivate the changes: sustainability, digitalization, and acceleration. There is also an internal driver in the form of lessons learned within the CDIO community, from using the Syllabus in curriculum and course development. Approximately 70 updates are proposed, amongst them three additions on the X.X level, namely 1.4 Knowledge of Social Sciences and Humanities, 3.1 Teamwork and Collaboration, and 5.3 Research.peerReviewe

The CDIO Syllabus 3.0 - An Updated Statement of Goals

The CDIO Initiative is going through a process of reconsidering and updating the CDIO approach for engineering education development. Previous work resulted in substantial updates of the twelve CDIO standards and the introduction of "optionel" standards. This paper reports on a similar review and update of the CDIO Syllabus to version 3.0. It has been developed by a working group consisting of four sub-groups and iterated and refined guidedby feedback from the whole CDIO community. There are mainly three external drivers that motivate the changes: sustainability, digitalization, and acceleration. There is also an internal driver in the form of lessons learned within the CDIO community, from using the Syllabus in curriculum and course development. Approximately 70 updates are proposed, amongst them three additions on the X.X level, namely 1.4 Knowledge of Social Sciences and Humanities,3.1 Teamwork and Collaboration, and 5.3 Research

The CDIO Syllabus 3.0 - An Updated Statement of Goals

The CDIO Initiative is going through a process of reconsidering and updating the CDIO approach for engineering education development. Previous work resulted in substantial updates of the twelve CDIO standards and the introduction of "optionel" standards. This paper reports on a similar review and update of the CDIO Syllabus to version 3.0. It has been developed by a working group consisting of four sub-groups and iterated and refined guidedby feedback from the whole CDIO community. There are mainly three external drivers that motivate the changes: sustainability, digitalization, and acceleration. There is also an internal driver in the form of lessons learned within the CDIO community, from using the Syllabus in curriculum and course development. Approximately 70 updates are proposed, amongst them three additions on the X.X level, namely 1.4 Knowledge of Social Sciences and Humanities,3.1 Teamwork and Collaboration, and 5.3 Research

Positive Effect of Parathyroidectomy Compared to Observation on BMD in a Randomized Controlled Trial of Mild Primary Hyperparathyroidism

Mild or asymptomatic disease is now the dominating presentation of primary hyperparathyroidism (PHPT). However, bone involvement with decreased bone mineral density (BMD) and an increased risk of fractures has been demonstrated. Indications for parathyroidectomy (PTX) in mild PHPT have been debated for years. There is a need of long-term randomized studies comparing PTX with observation without intervention (OBS). Here, we present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS. This study included 191 patients (96 OBS/95 PTX), and 129 patients (64 OBS/65 PTX) were followed for 10 years to the end of study (EOS). BMD was measured with dual-energy X-ray absorptiometry (DXA), peripheral fractures were noted, and spine radiographs were obtained for vertebral fracture assessment. There was a significant treatment effect of PTX on BMD compared with OBS for all analyzed compartments, most explicit for the lumbar spine (LS) and femoral neck (FN) (p &lt; 0.001). The mean changes in T-score from baseline to 10 years were from 0.41 for radius 33% (Rad33) to 0.58 for LS greater in the PTX group than in the OBS group. There was a significant decrease in BMD for all compartments in the OBS group, most pronounced for FN, Rad33, and ultradistal radius (UDR) (p &lt; 0.001). Even though there was a significant treatment effect of PTX compared with OBS, there was only a significant increase in BMD over time for LS (p &lt; 0.001). We found no difference between groups in fracture frequency in the 10-year cohort, neither with modified intention-to-treat (mITT) analysis nor per protocol analysis. Because BMD is only a surrogate endpoint of bone health and PTX did not reduce fracture risk, observation could be considered a safe option for many patients with mild PHPT regarding bone health in a 10-year perspective