Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially ...overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.
•Robust subtypes of DLBCL are identified by model-based clustering of genetic mutations in a large (n = 928) population-based cohort.•With full follow-up data available for all sequenced patients, the prognostic significance of these subtypes is identified.
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In the rapidly evolving business environment of 2024, organizational change management (OCM) leaders face unprecedented challenges driven by technological advancements, digital transformation, the ...integration of remote work, and a heightened focus on sustainability. This study examines the efficacy of traditional OCM models in addressing these modern complexities. Through a qualitative methodology employing an extensive literature review, the research identifies vital issues such as resistance to change, digital transformation imperatives, the shift to remote and hybrid work models, and the imperative for sustainable and ethical business practices. The study posits that while classical OCM frameworks offer foundational insights, there is a pressing need for more adaptive, inclusive, and flexible approaches to navigate the nuanced demands of the contemporary and future business landscape. Expected findings suggest the integration of agile methodologies, technology adoption, and a shift towards a culture of continuous change and employee empowerment as critical strategies for effective change management. These insights aim to guide OCM leaders in developing strategies that address the current challenges but also anticipate the dynamics of future organizational change, thus contributing to the broader discourse on evolving OCM practices in a digital and globally interconnected era.
Cybersecurity leaders are not adequately developed to guide the re-engineering of quality customer service (QCS) workflows, designed with automation and AI, that interrelate with people through ...customers' perceptions. Realizing re-engineering processes should be a team effort with well-versed leadership and stakeholders guiding the successful design through a follow-up process. Leaders must shape compelling and straightforward needs to learn and teach employees and chat boxes indispensable customer service skills demonstrating patience, self-discipline, flexibility, and resourcefulness in communication with irritated customers or difficult circumstances. Whether the analysis, design, development, and implementation struggles are vacuums in cybersecurity knowledge, skill, and abilities or a dearth of budget and resource limits, creating thorough QSC workflows and training requires time and purpose. This knowledge must be proactively, not reactively built. QSC re-engineering epitomizes a shift from reactionary behaviors to proactively preparing a well-defined collection of intends, activities, and aims delineating how organizations will contend through products and services. This article should benefit respondents absorbed in the success of updating and implementing QCS actions and workflows, practitioners who guide direct customer services initiatives, enterprise governance strategists, QCS and machine learning trainers, and learners who want to know more about QCS swathed in cybersecurity.
Summary
Cell‐of‐origin subclassification of diffuse large B cell lymphoma (DLBCL) into activated B cell‐like (ABC), germinal centre B cell‐like (GCB) and unclassified (UNC) or type III by gene ...expression profiling is recommended in the latest update of the World Health Organization’s classification of lymphoid neoplasms. There is, however, no accepted gold standard method or dataset for this classification. Here, we compare classification results using gene expression data for 68 formalin‐fixed paraffin‐embedded DLBCL samples measured on four different gene expression platforms (Illumina wG‐DASLTM arrays, Affymetrix PrimeView arrays, Illumina TrueSeq RNA sequencing and the HTG EdgeSeq DLBCL Cell of Origin Assay EU using an established platform agnostic classification algorithm (DAC) and the classifier native to the HTG platform, which is CE marked for in vitro diagnostic use (CE‐IVD). Classification methods and platforms show a high level of concordance, with agreement in at least 80% of cases and rising to much higher levels for classifications of high confidence. Our results demonstrate that cell‐of‐origin classification by gene expression profiling on different platforms is robust, and that the use of the confidence value alongside the classification result is important in clinical applications.
The Problem
After 30+ years of debating the best model for disability, there is a need for a new framework. As the medical model of disability seeks a cure and the social model points to the ...environment, neither model is without its flaws. Human resource development (HRD) professionals and practitioners are in a position to craft a model that reflects the experiences of people with disabilities. This new model will strengthen HRD’s importance in the field and its impact on other disciplines.
The Solution
This article offers consideration to be given for a new model for disability that addresses the complexities of cultural boundaries, gives value to the experiences of people with disabilities, and changes language in how disabilities are described. Using the results of the literature review, a path to the Transculturalized Diversity and Inclusion Model lays the groundwork for further research. This article accesses the perceptions of people with disabilities regarding both models, incorporates the strategies used by HRD scholars and researchers for improving value in a growing population of disabled people, and synthesizes a platform for future discussion and development of the Transculturalized Diversity and Inclusion Model.
The Stakeholders
HRD practitioners, especially those serving populations with disabilities, will benefit greatly from a new model and perspective provided by the Transculturalized Diversity and Inclusion Model. HRD scholars likewise will be provided with a new framework for conducting research on people with disabilities in the workplace.
Many universities require end of course evaluations for all courses taught as tool for academic accreditation purposes. The reality is that often many academic departments either do not do anything ...or have no idea what to do when evaluations continue to be poor. As a result, students have fought back against this process to create their own on-line rating program, Rate My Professor.com, which allows students to give other students insights into who is a quality professor and who is not. This paper explores this use of mock teaching simulations, which are also called Micro-teaching approaches, as a quality management tool to improve the way students are taught in Technology Management, Cybersecurity, and Computer Science degree and certificate programs.
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This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous ...research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.
•Subtypes of follicular lymphoma are identified by model-based clustering of genetic mutations in a large (n = 548) population-based cohort.•These subtypes imply distinct mechanistic subsets of ...follicular lymphoma with implications for patient risk and treatment opportunities.
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Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer’s heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations. We investigated whether molecular subclusters of FL can be identified and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; and FL_Com, with the absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17 of 26 had evidence of branching evolution. Poorer overall survival (OS) in the aSHM group (P = .04) was associated with older age; however, overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies 3 molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.
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This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was ...explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat.
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