Coordinate Interstitial Deletions Of Retinoblastoma (Rb1) And Neurobeachin (Nbea) Genes On Chromosome 13 In Mgus And Multiple Myeloma

ABSTRACT OF THE DISSERTATION Coordinate interstitial deletions of Retinoblastoma: RB1) and Neurobeachin: NBEA) genes on chromosome 13 in monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma By Julie O\u27Neal Doctor of Philosophy in Biology and Biomedical Sciences: Molecular and Cellular Biology) Washington University in Saint Louis, 2009 Assistant Professor Michael H. Tomasson, Chair Numeric or structural chromosomal abnormalities are detected in nearly all patients with plasma cell dyscrasias, including primary amyloidosis, monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma: MM). Chromosome 13 deletions, most frequently monosomy 13, are detected in 10- 20% of MM cases by routine cytogenetics or metaphase fluorescent in situ hybridization: FISH) and are a significant predictor of shortened survival. Previous efforts to map somatically acquired DNA copy number losses on chromosome 13 have been limited by their low resolution. To identify DNA copy number losses on chromosome 13 at high resolution, we used genomic DNA isolated from CD138 enriched bone marrow cells: tumor) from twenty patients xiv with MM, monoclonal gammopathy of undetermined significance: MGUS) or amyloidosis. We used matched skin biopsy: normal) genomic DNA to control for copy number polymorphisms and a novel aCGH array dedicated to chromosome 13 to map somatic DNA gains and losses at unprecedented resolution: \u3e385,000 probes; median probe spacing 60bp). We identified RB1 and NBEA as being coordinately affected by copy number loss in MGUS and MM. To characterize these genes in the context of myeloma biology, we performed sequence and expression analysis on RB1 and found exonic mutations affecting RB1 were extremely rare, RB1 levels were decreased in patient samples harboring monosomy 13, and RB1 protein phosphorylation was not common. Expression analysis of NBEA revealed most patient samples harboring monosomy 13 had reduced NBEA, but to our surprise, a subset harbored high levels. Analysis of Nbea in hematopoietic tissues revealed although it was detected in thymus and spleen, using a fetal liver transplantation assay, Nbea was dispensable for hematopoietic development. Future studies investigating cooperation of RB1 and NBEA in plasma cell dyscrasias are warranted

Banner News

https://openspace.dmacc.edu/banner_news/1024/thumbnail.jp

Liposomal phytohemagglutinin: In vivo T-cell activator as a novel pan-cancer immunotherapy

Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, we report a liposomal PHA which increased PHA stability, reduced toxicity and performed as an immunotherapeutic that is able to activate T cells for the use in future cancer immunotherapies to circumvent current obstacles in immunosuppression and T-cell exhaustion

Describing the Evidence Linking Interprofessional Education Interventions to Improving the Delivery of Safe and Effective Patient Care: A Scoping Review

Empirical evidence indicates that collaborative interprofessional practice leads to positive health outcomes. Further, there is an abundance of evidence examining student and/or faculty perceptions of learning or satisfaction about the interprofessional education (IPE) learning experience. However, there is a dearth of research linking IPE interventions to patient outcomes. The objective of this scoping review was to describe and summarize the evidence linking IPE interventions to the delivery of effective patient care. A three-step search strategy was utilized for this review with articles that met the following criteria: publications dated 2015–2020 using qualitative, quantitative or mixed methods; the inclusion of healthcare professionals, students, or practitioners who had experienced IPE or training that included at least two collaborators within coursework or other professional education; and at least one of ten Centers for Medicare & Medicaid Services quality measures (length of stay, medication errors, medical errors, patient satisfaction scores, medication adherence, patient and caregiver education, hospice usage, mortality, infection rates, and readmission rates). Overall, n=94 articles were identified, providing overwhelming evidence supporting a positive relationship between IPE interventions and several key quality health measures including length of stay, medical errors, patient satisfaction, patient or caregiver education, and mortality. Findings from this scoping review suggest a critical need for the development, implementation, and evaluation of IPE interventions to improve patient outcomes

Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin

Evaluating Appropriateness and Diagnostic Stewardship Opportunities of Multiplex Polymerase Chain Reaction Gastrointestinal Testing Within a Hospital System

Objective: This single-center, retrospective, observational cohort study evaluates the appropriateness of the BioFire® FilmArray® Gastrointestinal (GI) multiplex PCR panel testing at a community-teaching hospital. Methods: All adult, hospitalized patients at Prisma Health Richland Hospital with a documented GI multiplex PCR panel from 1 April 2015 through 28 February 2018 were included in the analysis. Inappropriate use of the GI panel was defined as a test obtained without documented diarrhea, greater than 2 days of hospitalization, redundant use with other diagnostic tests (e.g. PCR), or laxative use in the preceding 48 h. Antibiotic use and host variables were compared between groups with positive and negative results. Results: During the study period, 442 GI panels were obtained, among which 268 (61%) were deemed inappropriate. Primary reasons for inappropriate testing were lack of documented diarrhea ( = 92), greater than 2 days of hospitalization ( = 116), having a duplicate PCR test ordered ( = 118), or laxative use in the 48 h before testing ( = 36). A total of 141 (32%) GI panels were positive. The most frequently identified pathogens were (51.1%,  = 72), Enteropathogenic (17.7%,  = 25), and Norovirus GI/GII (12.1%,  = 17). Patients with negative GI panel results were initiated on antibiotics significantly less frequently than those with positive GI panels (62.5% 80.2%,  \u3c 0.00001). Conclusion: Stewardship opportunities exist to optimize the diagnostic application of the GI multiplex PCR panel

Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models