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  • 1
    Online Resource
    Online Resource
    CAR T‐Cell Therapy in Hematologic Malignancies: A Voyage in Progress
    Wiley ; 2020
    In:  Clinical Pharmacology & Therapeutics Vol. 107, No. 1 ( 2020-01), p. 112-122
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 107, No. 1 ( 2020-01), p. 112-122
    Abstract: The development of chimeric antigen receptor (CAR) T‐cell therapy for select hematological malignancies represents one of the most remarkable therapeutic advances in the past decade. Currently, CD19‐targeted CAR T‐cell therapy is approved for relapsed/refractory diffuse large B‐cell lymphoma and acute lymphoblastic leukemia. However, there is significant interest in the application of CAR T‐cell therapy to other hematological malignancies, including multiple myeloma, where the current focus is on the development of B‐cell maturation antigen‐directed CAR T‐cell therapy. Despite the successes achieved to date, there remain significant challenges associated with CAR T‐cell therapy and substantial research efforts are underway to develop new targets and approaches. Here, we provide an overview of the rapidly evolving landscape of CAR T‐cell therapy in hematological malignancies and look ahead at the advances that will shape the future of this field.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v107.1
    DOI: 10.1002/cpt.1674
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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    SSG: 15,3
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  • 2
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    Daratumumab plus lenalidomide, bortezomib and dexamethasone in newly diagnosed multiple myeloma: Analysis of vascular thrombotic events in the GRIFFIN study
    Wiley ; 2022
    In:  British Journal of Haematology Vol. 199, No. 3 ( 2022-11), p. 355-365
    Details
    In: British Journal of Haematology, Wiley, Vol. 199, No. 3 ( 2022-11), p. 355-365
    Abstract: Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study ( ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D‐RVd/RVd induction, high‐dose therapy and ASCT, D‐RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D‐RVd, n  = 99; RVd, n  = 102), VTEs occurred in 10.1% of D‐RVd patients and 15.7% of RVd patients; grade 2–4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D‐RVd versus RVd patients (305 days vs 119 days). Anti‐thrombosis prophylaxis use was similar between arms (D‐RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D‐RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti‐thrombotic prophylaxis use was suboptimal.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.v199.3
    DOI: 10.1111/bjh.18432
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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    detail.hit.zdb_id: 1475751-5
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  • 3
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    Drug use and severe outcomes among adults hospitalized with influenza, 2016–2019
    Wiley ; 2023
    In:  Influenza and Other Respiratory Viruses Vol. 17, No. 1 ( 2023-01)
    Details
    In: Influenza and Other Respiratory Viruses, Wiley, Vol. 17, No. 1 ( 2023-01)
    Abstract: Influenza is a persistent public health problem associated with severe morbidity and mortality. Drug use is related to myriad health complications, but the relationship between drug use and severe influenza outcomes is not well understood. The study objective was to evaluate the relationship between drug use and severe influenza‐associated outcomes. Methods Data were collected by the Influenza Hospitalization Surveillance Network (FluSurv‐NET) from the 2016–2017 through 2018–2019 influenza seasons. Among persons hospitalized with influenza, descriptive statistics and logistic regression models were used to analyze differences in demographic characteristics, risk and behavioral factors, and severe outcomes (intensive care unit [ICU] admission, mechanical ventilation, or death) between people who use drugs (PWUD), defined as having documented drug use within the past year, and non‐PWUD. Results Among 48,430 eligible hospitalized influenza cases, 2019 were PWUD and 46,411 were non‐PWUD. PWUD were younger than non‐PWUD and more likely to be male, non‐Hispanic Black or Hispanic/Latino, smoke tobacco, abuse alcohol, and have chronic conditions including asthma, chronic liver disease, chronic lung disease, or immunosuppressive conditions. PWUD had greater odds of ICU admission and mechanical ventilation, but not death compared with non‐PWUD; however, these findings were not statistically significant after adjustment. Opioid use specifically was associated with increased risk of ICU admission and mechanical ventilation. Conclusion These results support targeted initiatives to prevent influenza in this population, including influenza vaccination, which remains one of the most important tools to prevent influenza infection and associated severe outcomes.
    Type of Medium: Online Resource
    ISSN: 1750-2640 , 1750-2659
    URL: Issue
    URL: Article
    DOI: 10.1111/irv.v17.1
    DOI: 10.1111/irv.13052
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 4
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    The Peptide–Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death
    Wiley ; 2022
    In:  HemaSphere Vol. 6, No. 3 ( 2022-02-25), p. e687-
    Details
    In: HemaSphere, Wiley, Vol. 6, No. 3 ( 2022-02-25), p. e687-
    Abstract: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by clonal plasma cell secretion of misfolded light chains that assemble as toxic amyloid fibrils, depositing in vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell–directed therapeutics are expected to reduce production of toxic light chain by eliminating amyloidogenic cells in bone marrow, thereby diminishing amyloid fibril deposition and providing the potential for organ recovery. Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen is highly lipophilic, permitting rapid uptake by cells, where it is enzymatically hydrolyzed by aminopeptidases, resulting in intracellular accumulation of the alkylating agents, including melphalan. Previous data demonstrating sensitivity of myeloma cells to melflufen suggest that the drug might be useful in AL amyloidosis. We describe the effects of melflufen on amyloidogenic plasma cells in vitro and ex vivo, demonstrating enhanced cytotoxic effects in comparison to melphalan, as well as novel mechanisms of action through the unfolded protein response (UPR) pathway. These findings provide evidence that melflufen-mediated cytotoxicity extends to amyloidogenic plasma cells, and support the rationale for the evaluation of melflufen in patients with AL amyloidosis.
    Type of Medium: Online Resource
    ISSN: 2572-9241
    URL: Article
    DOI: 10.1097/HS9.0000000000000687
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2922183-3
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  • 5
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    Isoprenoids: Remarkable diversity of form and function
    Wiley ; 2004
    In:  Lipids Vol. 39, No. 4 ( 2004-04), p. 293-309
    Details
    In: Lipids, Wiley, Vol. 39, No. 4 ( 2004-04), p. 293-309
    Abstract: The isoprenoid biosynthetic pathway is the source of a wide array of products. The pathway has been highly conserved throughout evolution, and isoprenoids are some of the most ancient biomolecules ever identified, playing key roles in many life forms. In this review we focus on C‐10 mono‐, C‐15 sesqui‐, and C‐20 diterpenes. Evidence for interconversion between the pathway intermediates farnesyl pyrophosphate and geranylgeranly pyrophosphate and their respective metabolites is examined. The diverse functions of these molecules are discussed in detail, including their ability to regulate expression of the β‐HMG‐CoA reductase and Ras‐related proteins. Additional topics include the mechanisms underlying the apoptotic effects of select isoprenoids, antiulcer activities, and the disposition and degradation of isoprenoids in the environment. Finally, the significance of pharmacological manipulation of the isoprenoid pathway and clinical correlations are discussed.
    Type of Medium: Online Resource
    ISSN: 0024-4201 , 1558-9307
    URL: Article
    DOI: 10.1007/s11745-004-1233-3
    Language: English
    Publisher: Wiley
    Publication Date: 2004
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    detail.hit.zdb_id: 241539-2
    SSG: 12
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  • 6
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    PB2129: THE MODAKAFUSP ALFA IINNOVATE CLINICAL DEVELOPMENT PROGRAM: RATIONALE AND DESIGN OF 3 PHASE 1/2 TRIALS OF AN INNATE IMMUNITY ENHANCER FOR MULTIPLE MYELOMA (MM)
    Wiley ; 2023
    In:  HemaSphere Vol. 7, No. S3 ( 2023-08), p. e9860835-
    Details
    In: HemaSphere, Wiley, Vol. 7, No. S3 ( 2023-08), p. e9860835-
    Type of Medium: Online Resource
    ISSN: 2572-9241
    URL: Article
    DOI: 10.1097/01.HS9.0000975280.98608.35
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2922183-3
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  • 7
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    Health‐related quality of life in transplant‐eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient‐reported outcomes from GRIFFIN
    Wiley ; 2024
    In:  American Journal of Hematology Vol. 99, No. 7 ( 2024-07), p. 1257-1268
    Details
    In: American Journal of Hematology, Wiley, Vol. 99, No. 7 ( 2024-07), p. 1257-1268
    Abstract: In the phase 2 GRIFFIN trial ( ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D‐RVd) improved depth of response and progression‐free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant‐eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient‐reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30‐item (QLQ‐C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20‐item (QLQ‐MY20), and EuroQol 5‐Dimension 5‐Level (EQ‐5D‐5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D‐RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D‐RVd and RVd. These improvements in health‐related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D‐RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.
    Type of Medium: Online Resource
    ISSN: 0361-8609 , 1096-8652
    URL: Issue
    URL: Article
    DOI: 10.1002/ajh.v99.7
    DOI: 10.1002/ajh.27326
    Language: English
    Publisher: Wiley
    Publication Date: 2024
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  • 8
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    Investigation of the activity of a novel tropolone in osteosarcoma
    Wiley ; 2024
    In:  Drug Development Research Vol. 85, No. 1 ( 2024-02)
    Details
    In: Drug Development Research, Wiley, Vol. 85, No. 1 ( 2024-02)
    Abstract: Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven‐membered non‐benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO‐OH‐Nap is an α‐substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO‐OH‐Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co‐incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO‐OH‐Nap‐treated OS cells. MO‐OH‐Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron‐regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO‐OH‐Nap on iron‐homeostasis pathways in OS cells. Furthermore, MO‐OH‐Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO‐OH‐Nap‐treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO‐OH‐Nap‐induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO‐OH‐Nap as a novel treatment for OS.
    Type of Medium: Online Resource
    ISSN: 0272-4391 , 1098-2299
    URL: Issue
    URL: Article
    DOI: 10.1002/ddr.v85.1
    DOI: 10.1002/ddr.22129
    Language: English
    Publisher: Wiley
    Publication Date: 2024
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    detail.hit.zdb_id: 604587-X
    SSG: 15,3
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  • 9
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    Quantitative Determination of Geranyl Diphosphate Levels in Cultured Human Cells
    Wiley ; 2009
    In:  Lipids Vol. 44, No. 11 ( 2009-11), p. 1055-1062
    Details
    In: Lipids, Wiley, Vol. 44, No. 11 ( 2009-11), p. 1055-1062
    Abstract: Geranyl diphosphate (GPP), a 10‐carbon isoprenoid, is a key intermediate in the isoprenoid biosynthetic pathway. This pathway, in addition to leading to sterol synthesis, results in the synthesis of farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which serve as substrates for protein isoprenylation reactions. Basal levels of GPP in mammalian cells previously have been undetectable. Here we present a novel, sensitive, nonradioactive method which allows for measurement of GPP in mammalian cells. This methodology involves extraction of isoprenoids from cultured cells followed by enzymatic conjugation of GPP to a fluorescent dansylated‐peptide via farnesyl transferase and quantification with high‐performance liquid chromatography (HPLC). The lower limit of detection of GPP is 5 pg, or 0.015 pmol. Basal levels of GPP were determined in three human multiple myeloma cell lines (RPMI‐8226, U266, H929). Treatment of cells with inhibitors of the isoprenoid biosynthetic pathway results in marked changes in GPP levels: the HMG‐CoA reductase inhibitor lovastatin decreases GPP levels by over 50%, while the FPP synthase inhibitor zoledronic acid increases GPP levels 16‐ to 107‐fold. This method also allows for the simultaneous measurement of GPP, FPP, and GGPP, thus leading to improved understanding of the pathway in a multitude of biological systems. Furthermore, as drugs targeting this pathway are developed, their biological activity can be more directly linked to effects on isoprenoid levels.
    Type of Medium: Online Resource
    ISSN: 0024-4201 , 1558-9307
    URL: Article
    DOI: 10.1007/s11745-009-3355-x
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2030265-4
    detail.hit.zdb_id: 241539-2
    SSG: 12
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  • 10
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    Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target
    Wiley ; 2023
    In:  Clinical and Translational Medicine Vol. 13, No. 1 ( 2023-01)
    Details
    In: Clinical and Translational Medicine, Wiley, Vol. 13, No. 1 ( 2023-01)
    Abstract: Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthesis pathway, is responsible for the production of geranylgeranyl pyrophosphate (GGPP). GGPP serves as a substrate for the post‐translational modification (geranylgeranylation) of proteins, including those belonging to the Ras superfamily of small GTPases. These proteins play key roles in signalling pathways, cytoskeletal regulation and intracellular transport, and in the absence of the prenylation modification, cannot properly localise and function. Aberrant expression of GGDPS has been implicated in various human pathologies, including liver disease, type 2 diabetes, pulmonary disease and malignancy. Thus, this enzyme is of particular interest from a therapeutic perspective. Here, we review the physiological function of GGDPS as well as its role in pathophysiological processes. We discuss the current GGDPS inhibitors under development and the therapeutic implications of targeting this enzyme.
    Type of Medium: Online Resource
    ISSN: 2001-1326 , 2001-1326
    URL: Issue
    URL: Article
    DOI: 10.1002/ctm2.v13.1
    DOI: 10.1002/ctm2.1167
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2697013-2
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