CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its ...application for therapy of AML, non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma.
Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice.
BMS-936564/MDX-1338 is a fully human IgG(4) monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC(50) values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition.
BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma.
The American Nurses Association Enterprise (ANA Enterprise) Research Advisory Council plays a vital role in bringing nursing voices together and shaping the dynamic landscape of nursing research. ...Historically, its priorities have revolved around 4 pivotal research priorities: advancing research capacity, promoting interprofessional collaboration, enhancing data structures and governance, and propelling practice-based nursing research. In a remarkable transition, the 2024 Research Priorities of the ANA Enterprise Research Advisory Council align with the vision and strategic goals of the ANA Enterprise. The Council now places emphasis on the intersection of the research priorities with 5 key areas crucial for "elevating the profession of nursing globally": workforce development; advancing nurse well-being practices; deepening understanding of diversity, equity, inclusion, and belonging; expanding scope of practice; and measuring the value of nursing. This approach provides clear guidance for nursing research efforts, demonstrating a dedicated effort to harmonize the diverse voices within the nursing community. The objective is to shape a future where nursing research not only serves to inform practice but also enhances the overall value and impact of the nursing profession globally.
It is imperative that we listen to our nation's nurses, who have a unique vantage point from their clinical environments. Clinical research nurses have greatly contributed to studying the delivery of ...care over the years; however, since 2020, COVID-19 has brought unprecedented changes within the nursing profession. Each wave of the pandemic has created a worrisome landscape where nurse researchers face multiple challenges in implementing and funding practice-based nursing-led research projects. To raise nurses' voices and promote nurse-led research, the American Nurses Credentialing Center (ANCC) Research Council 2022 Research Priorities include the dissemination of a research agenda for practice-based research, promoting interprofessional research, and encouraging equitable and inclusive participation on research teams.
BackgroundNatural Killer (NK) cells have garnered increasing interest as potential cellular therapies or as targets of biotherapeutic agents due to their ability to kill tumor cells in a non-antigen ...dependent manner. Hence, measurement of NK cell proliferation and/or activation following treatment can serve as a useful biomarker for assessing the efficacy of immunomodulatory therapies.MethodsWe developed a novel 13-parameter flow cytometry panel incorporating cell differentiation (CD) markers important for identification of NK cell subsets (CD56, CD16), their proliferation (Ki-67), activation (CD25, CD335, NKG2D) and inhibition (CD159a) status. Additionally, CD markers that identify other cellular subsets known to be amenable to cytokine modulation (e.g., CD3 and CD14) were included for concurrent monitoring of T cell proliferation and monocyte activation. Method validation focused on analytical sensitivity, specificity and precision as key criteria of assay performance using peripheral blood mononuclear cells (PBMCs) stimulated with NK cell-activating cytokines and resting PBMCs from healthy donors.ResultsThe assay design allowed for robust quantitation of NK cell, T cell and monocyte functionalities. Lower limit of quantification (LLOQ) of target biomarker population was determined to be 1.0% of the parent population, based upon an analysis of 110 key target populations that displayed a co-efficient of variation (CV) of ≤25% and their frequencies ranged from 0.1% to 97.8% of the parent population. Additionally, ≤25% CV was observed in precision assessments, confirming the repeatability and reproducibility of the assay. Clinical trial utility of the assay was verified on cryopreserved PBMCs from patients with a variety of solid tumor malignancies. In these patients, the assay could clearly identify proliferating and activated NK cells, as well as proliferating T cells and activated monocytes, thus demonstrating its suitability for clinical trial applications.ConclusionsWe developed and validated a novel multiparameter flow cytometry assay that allows for simultaneous measurement of proliferation, activation and inhibitory status of key immune cell subsets. Thus, this assay can help shed light on the mode of efficacy of novel therapeutic agents that modulate the immune system, aimed at treatment of cancer and autoimmune diseases.
To raise nurses' voices and promote nurse-led research, the American Nurses Credentialing Center's Research Council 2022 Research Priorities included disseminating a research agenda for ...practice-based research, promoting interprofessional research, and encouraging equitable and inclusive participation on research teams. Expressions of nurses from around the world, however, described how organizational constraints and financial barriers are real challenges that nurse researchers must face, along with forming interdisciplinary teams to work with human subjects. Entities doing research seem to have a heavy focus on academic research where clinical bedside nurses feel separated from nursing research. Including all frontline nurses in research is a must; therefore, nurses' voices are loud and clear when asking for global efforts to be reoriented toward nurse-led, practice-based research and to turn the research priorities into easy-to-carry-forward and achievable actionable items.
The aim of this study was to develop research priorities for positive practice environments identified by Pathway to Excellence® (Pathway) leaders and appraisers.
Identifying research priorities ...achieves 2 goals: 1) advancing research agendas that impact improving practice environments, and nurse and patient outcomes; and 2) informing nursing leaders, researchers, and funders of potential research projects to conduct and support.
Research topics related to the 6 Pathway standards were developed and then rated for importance through 3 rounds of a Delphi survey by leaders at Pathway-designated organizations and Pathway appraisers.
Twenty research priorities were identified from the initial 54 research topics. The top 2 priorities were building and maintaining shared governance participation (91.9%) and nurse participation in performance improvement and evidence-based practice activities (90.7%).
Establishing a Pathway research agenda will guide nursing leadership, researchers, and funders in selecting impactful research priorities to help bolster positive practice environments that engage and empower nurses.
Abstract 1543
BMS-936564/MDX-1338 is a fully human monoclonal antibody that specifically recognizes human CXCR4 and is currently in phase 1 studies in patients with relapsed/refractory acute myeloid ...leukemia (AML) and multiple myeloma (MM). CXCR4 has been identified as a prognostic indicator for AML and other malignancies, in which greater expression of CXCR4 correlates with disease severity. CXCR4 is a seven-transmembrane, G-protein-coupled receptor in the CXC chemokine receptor family. In response to stimulation by its ligand, the chemokine CXCL12, CXCR4 activates calcium flux, chemotaxis and mediates directional migration of hematopoietic cells. In healthy adults, the receptor is predominantly expressed on B and T cells, monocytes, macrophages, NK and dendritic cells, as well as lymphoid and myeloid precursor cells. Expression of CXCR4 is elevated in a variety of cancers and the interaction of CXCR4 on tumor cells with CXCL12 in the bone marrow promotes tumor cell survival and growth. An antagonist of this pathway is predicted to be efficacious in a variety of hematologic malignancies. In vitro studies demonstrate that BMS-936564/MDX-1338 binds to CXCR4expressing cells with low nanomolar affinity. The antibody blocks CXCL12 binding to CXCR4 expressing cells and inhibits CXCL12 induced migration and calcium flux with low nanomolar EC50 values. When given as monotherapy on established tumors, the antibody exhibits anti-tumor activity in multiple AML, NHL and MM xenograft models. BMS-936564/MDX-1338 is an IgG4 and thus does not elicit complement dependent cytotoxicity (CDC) or antibody dependent cell mediated cytotoxicity (ADCC). In vitro and in vivo studies suggest that BMS-936564/MDX-1338 induces apoptosis as one mechanism of tumor growth inhibition. Here we describe the in vitro and in vivo characterization and activities of BMS-936564/MDX-1338.
Kuhne:Bristol-Myers Squibb: Employment. Mulvey:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Pan:Bristol-Myers Squibb: Employment. Chong:Bristol-Myers Squibb: Employment. Niekro:Bristol-Myers Squibb: Employment. Kempe:Bristol-Myers Squibb: Employment. Henning:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Korman:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment.
This collection of newly commissioned essays brings together major scholars in the field of Gothic studies in order to re-think the topic of 'Women and the Gothic'.
Practitioners and researchers in geoscience education embrace collaboration applying ICON (Integrated, Coordinated, Open science, and Networked) principles and approaches which have been used to ...create and share large collections of educational resources, to move forward collective priorities, and to foster peer‐learning among educators. These strategies can also support the advancement of coproduction between geoscientists and diverse communities. For this reason, many authors from the geoscience education community have co‐created three commentaries on the use and future of ICON in geoscience education. We envision that sharing our expertise with ICON practice will be useful to other geoscience communities seeking to strengthen collaboration. Geoscience education brings substantial expertise in social science research and its application to building individual and collective capacity to address earth sustainability and equity issues at local to global scales The geoscience education community has expanded its own ICON capacity through access to and use of shared resources and research findings, enhancing data sharing and publication, and leadership development. We prioritize continued use of ICON principles to develop effective and inclusive communities that increase equity in geoscience education and beyond, support leadership and full participation of systemically non‐dominant groups and enable global discussions and collaborations.
Plain Language Summary
The Geoscience Education community describes the value, use, and future of ICON collaboration through three independent, community‐produced commentaries focused on the practice of geoscience education; geoscience education research; and diversity, equity, inclusion, and justice. Each commentary offers ideas important to building inclusive and effective communities. These ideas apply to science‐community collaboration broadly and inform coproduction and network building activities within and across geoscience‐public boundaries. The expansion of inclusive and effective networks is needed for equitable outcomes.
Key Points
Integrated, Coordinated, Open science, and Networked (ICON) principles and practices are widely used in geoscience education to improve both research and practice
Strengthened capacity for ICON practices is needed to advance current educational priorities
A priority must be placed on full participation by that are systemically non‐dominant groups and improving global interactions
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