Publications by authors named "Barry Paul"

29 Publications

  • Page 1 of 1

Thromboembolism Incidence and Risk Factors in Multiple Myeloma After First Exposure to Immunomodulatory Drug-Based Regimens.

Clin Lymphoma Myeloma Leuk 2021 Mar 28;21(3):188-198.e2. Epub 2020 Nov 28.

Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC.

Background: We evaluated time to thromboembolism (TE) and risk factors in multiple myeloma (MM) patients after first exposure to immunomodulatory therapy, stratified by thromboprophylaxis.

Patients And Methods: We retrospectively analyzed adult MM patients who received immunomodulatory therapy with or without dexamethasone between February 2012 and October 2017. Thromboprophylaxis included aspirin, anticoagulants (low-molecular-weight heparin, direct oral anticoagulants, or warfarin), or none. Primary endpoint was time to on-treatment TE by thromboprophylaxis type. Time to TE using death as a competing risk censored at 12 months was used in univariate and multivariable analyses to identify risk factors.

Results: Of 485 evaluable patients, 57% were white and 36% African American; median age was 66. Most received lenalidomide (97.5%) and dexamethasone (90%). Half presented with ≥ 1 comorbidities. Sixty-nine had no documented receipt of prophylaxis, 357 aspirin, and 59 anticoagulation. More patients receiving anticoagulants had ≥ 1 comorbidities compared to aspirin or no-prophylaxis groups (P < .001). There was no difference in 12-month estimated cumulative incidence of TE (7.3%; 95% confidence interval, 5.2-9.9) between thromboprophylaxis groups (none 4.4%, aspirin 8.5%, anticoagulant 3.4%) (P = .24). In multivariable analyses, male sex (hazard ratio, 2.50; 95% confidence interval, 1.21-5.17; P = .014) and presence of any comorbidity (hazard ratio, 2.35; 95% confidence interval, 1.17-4.73; P = .016) were associated with TE incidence; thromboprophylaxis type was not (P = .12).

Conclusion: Male sex and presence of any comorbidity were associated with time to TE. There were no differences in TE incidence between thromboprophylaxis groups despite a higher proportion of those in the anticoagulant group having ≥ 1 comorbidities.
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http://dx.doi.org/10.1016/j.clml.2020.11.015DOI Listing
March 2021

The Trypanosoma Brucei KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity.

iScience 2020 Aug 20;23(9):101476. Epub 2020 Aug 20.

Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des professeurs Jeener et Brachet, 6041 Gosselies, Belgium. Electronic address:

Human innate immunity to Trypanosoma brucei involves the trypanosome C-terminal kinesin TbKIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that TbKIFC1 preferentially associates with cholesterol-containing membranes and is indispensable for mammalian infectivity. Knockdown of TbKIFC1 did not affect trypanosome growth in vitro but rendered the parasites unable to infect mice unless antibody synthesis was compromised. Surface clearance of Variant Surface Glycoprotein (VSG)-antibody complexes was far slower in these cells, which were more susceptible to capture by macrophages. This phenotype was not due to defects in VSG expression or trafficking but to decreased VSG mobility in a less fluid, stiffer surface membrane. This change can be attributed to increased cholesterol level in the surface membrane in TbKIFC1 knockdown cells. Clearance of surface-bound antibodies by T. brucei is therefore essential for infectivity and depends on high membrane fluidity maintained by the cholesterol-trafficking activity of TbKIFC1.
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http://dx.doi.org/10.1016/j.isci.2020.101476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479354PMC
August 2020

Daratumumab subcutaneous formulation for the treatment of multiple myeloma.

Expert Opin Biol Ther 2020 11 16;20(11):1253-1259. Epub 2020 Aug 16.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: Intravenous daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of daratumumab was approved for use in both the United States and European Union based on data which showed shorter infusion times and decreased rate of infusion reactions while maintaining non-inferior efficacy.

Areas Covered: We cover the physiology behind subcutaneous daratumumab and summarize the relevant clinical data with a particular focus on the pharmacokinetics, pharmacodynamics, safety, and clinical efficacy. Articles used to generate this review were obtained by searching pubmed (https://pubmed.ncbi.nlm.nih.gov/) with the search terms 'subcutaneous daratumumab' and 'daratumumab hyaluronidase'.

Expert Opinion: Subcutaneous daratumumab is associated with lower risk of infusion reactions and decreased administration time while maintaining non-inferior efficacy. We support the use of subcutaneous daratumumab for all approved indications and for investigational use moving forward.
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http://dx.doi.org/10.1080/14712598.2020.1806231DOI Listing
November 2020

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

Clin Lymphoma Myeloma Leuk 2020 10 7;20(10):e777-e781. Epub 2020 Jun 7.

Department of Hematologic Oncology and Blood Disorders, Atrium Health, Levine Cancer Institute, Charlotte, NC.

Background: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs.

Patients And Methods: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion.

Results: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations.

Conclusion: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.
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http://dx.doi.org/10.1016/j.clml.2020.05.024DOI Listing
October 2020

An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma.

Expert Rev Hematol 2020 08 20;13(8):795-802. Epub 2020 Sep 20.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: A subcutaneous formulation of daratumumab, a human immunoglobulin G1 kappa monoclonal antibody targeting CD38, recently achieved FDA approval for both newly diagnosed and relapsed refractory multiple myeloma amid promises to decrease infusion times and rates of infusion reactions in myeloma patients.

Areas Covered: In this article the biology behind subcutaneous administration of oncologic antibody therapies is reviewed and the subcutaneous formulation of daratumumab is covered in depth. The most recent results from the PAVO, COLUMBA, and PLEIADES clinical trials evaluating subcutaneous daratumumab as a single agent, and in combination, in both newly diagnosed, and relapsed and refractory myeloma patients are summarized. The efficacy, safety, and PK data from these trials are reviewed, and the potential of the subcutaneous formulation to improve quality of life in myeloma patients and decrease healthcare resource use is discussed.

Expert Opinion: Subcutaneous daratumumab is non-inferior to conventional intravenous daratumumab with lower risk of infusion-related reactions and decreased administration time. Based on these data, and the recent FDA and European Commission approvalsthe widespread use of the subcutaneous formulation for both conventional and investigational practice is supported.
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http://dx.doi.org/10.1080/17474086.2020.1795829DOI Listing
August 2020

The impact of bone marrow fibrosis and JAK2 expression on clinical outcomes in patients with newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.

Cancer Med 2020 08 6;9(16):5869-5880. Epub 2020 Jul 6.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA.

We determined the impact of bone marrow fibrosis (BMF) on the clinical outcomes of newly diagnosed multiple myeloma (NDMM) patients in the current era of myeloma therapy. A total of 393 MM patients were included in the final analysis. The median followup was 83 months (range: 3.9 to 212 months). BMF was noted in 122 (48.2%) evaluable patients. Median progression free survival (PFS) in patients without BMF was 30.2 (95% CI: 24.7-38.0) months, and 21.1 (95% CI: 18.8-27.5) months in patients with BMF present (P = .024). Median overall survival (OS) was 61.2 (95% CI: 51.5-81.2) months in patients without BMF, and 45.1 (95% CI: 38.7-57.0) months in patients with BMF (P = .0048). A subset of 99 patients had their bone marrow biopsies stained for JAK1 and JAK2 by immunohistochemistry. Of these samples 67 (67.7%) patients had detectable JAK2 expression predominantly noted on bone marrow megakaryocytes. JAK2 expression correlated with myeloma disease stage (P = .0071). Our study represents the largest dataset to date examining the association of BMF with prognosis in the era of novel therapies and widespread use of hematopoietic stem cell transplant (HSCT). Our data suggest that MM patients with BMF (particularly those with extensive BMF) have a poorer prognosis even when treated with immunomodulatory agents and proteasome inhibitors.
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http://dx.doi.org/10.1002/cam4.3265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433821PMC
August 2020

Management of newly diagnosed transplant ineligible multiple myeloma.

Leuk Lymphoma 2020 11 4;61(11):2549-2560. Epub 2020 Jul 4.

Department of Hematologic Oncology & Blood Disorders, Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Multiple myeloma (MM) is a chronically managed blood cancer with a median age of 69 years at the time of diagnosis. Although high dose melphalan and autologous stem cell transplantation (ASCT) remains a standard of care for eligible patients, more than half of the newly diagnosed MM patients are deemed ineligible due to comorbidities or complications of the disease by itself. In this setting, where ASCT is deemed inappropriate, patients could still achieve durable and deep responses if given the appropriate treatment plan. The key concepts of optimizing induction and maintenance strategies while minimizing side-effects are discussed in this review, especially in the context of employing novel agent combinations. It is important to understand the balance between safety and efficacy for each regimen, utilizing maintenance strategy and the best supportive care measures (bone health, infection prevention, and treatment, pain management, etc.). Here, we examine the evidence behind each of those principles and review results from clinical trials for transplant-ineligible (TI) MM.
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http://dx.doi.org/10.1080/10428194.2020.1786558DOI Listing
November 2020

Safety and Cost Benefits of the Rapid Daratumumab Infusion Protocol.

Clin Lymphoma Myeloma Leuk 2020 08 7;20(8):526-532.e1. Epub 2020 Mar 7.

Plasma Cell Disorders Division, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC. Electronic address:

Introduction: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol.

Patients And Methods: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity.

Results: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively.

Conclusion: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.clml.2020.02.014DOI Listing
August 2020

Gamma Gap: A Point-of-Care Test That Correlates With Disease Burden and Treatment Response in Multiple Myeloma.

JCO Oncol Pract 2020 08 2;16(8):e751-e757. Epub 2020 Apr 2.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC.

Purpose: We performed a retrospective chart review on 393 patients with multiple myeloma (MM) to determine the utility of the gamma gap (GG).

Methods: We calculated the difference between a patient's total serum protein and albumin as a point-of-care test for assessing disease status in MM.

Results: GG is highly correlated with the level of M-spike, and the change in GG correlates with myeloma treatment response. In addition, fitted linear models were established that allow for the calculation of M-protein level from the GG within hours from blood draw.

Conclusion: Our study has important implications in the care of MM, particularly in countries/areas with limited resources.
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http://dx.doi.org/10.1200/JOP.19.00517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427420PMC
August 2020

PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.

Adv Sci (Weinh) 2020 Mar 23;7(5):1900860. Epub 2020 Jan 23.

Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center Durham NC 27710 USA.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers and parkin RBR E3 ubiquitin protein ligase ( in CD138 plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide--chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform () transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.
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http://dx.doi.org/10.1002/advs.201900860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055555PMC
March 2020

Secreted Aromatic Ketoacids Activate the Nrf2/HO-1 Pathway and Suppress Pro-inflammatory Responses in Primary Murine Glia and Macrophages.

Front Immunol 2019 11;10:2137. Epub 2019 Sep 11.

School of Biochemistry and Immunology, Trinity College Dublin, University of Dublin, Dublin, Ireland.

African trypanosomes, such as (), are protozoan parasites of the mammalian vasculature and central nervous system that are best known for causing fatal human sleeping sickness. As exclusively extracellular parasites, trypanosomes are subject to constant challenge from host immune defenses but they have developed very effective strategies to evade and modulate these responses to maintain an infection while simultaneously prolonging host survival. Here we investigate host parasite interactions, especially within the CNS context, which are not well-understood. We demonstrate that strongly upregulates the stress response protein, Heme Oxygenase 1 (HO-1), in primary murine glia and macrophages . Furthermore, using a novel AHADH cell line, we demonstrate that specific aromatic ketoacids secreted by bloodstream forms of are potent drivers of HO-1 expression and are capable of inhibiting pro-IL1β induction in both glia and macrophages. Additionally, we found that these ketoacids significantly reduced IL-6 and TNFα production by glia, but not macrophages. Finally, we present data to support Nrf2 activation as the mechanism of action by which these ketoacids upregulate HO-1 expression and mediate their anti-inflammatory activity. This study therefore reports a novel immune evasion mechanism, whereby secretes amino-acid derived metabolites for the purpose of suppressing both the host CNS and peripheral immune response, potentially via induction of the Nrf2/HO-1 pathway.
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http://dx.doi.org/10.3389/fimmu.2019.02137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749089PMC
October 2020

The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.

Cell Immunol 2019 11 13;345:103964. Epub 2019 Aug 13.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

A cure for multiple myeloma (MM), a malignancy of plasma cells, remains elusive. Nearly all myeloma patients will eventually relapse and develop resistance to currently available treatments. There is an unmet medical need to develop novel and effective therapies that can induce sustained responses. Early phase clinical trials using chimeric antigen receptor (CAR) T cell therapy have shown great promise in the treatment of relapsed and/or refractory MM. In this review article, we provide an overview of the CAR constructs, the gene transfer vector systems, and approaches for T cell activation and expansion. We then summarize the outcomes of several early phase clinical trials of CAR T cell therapy in MM and the novel CAR T targets that are under development. Finally, we explore the potential mechanisms that result in disease relapse after CAR T therapy and propose future directions in CAR T therapy in MM.
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http://dx.doi.org/10.1016/j.cellimm.2019.103964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832886PMC
November 2019

Induction Therapy for Newly Diagnosed Multiple Myeloma.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:e176-e186. Epub 2019 May 17.

4 Plasma Cell Disorders Division, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC.

The frontline therapy for newly diagnosed multiple myeloma (MM) has continued to evolve over the last 10 years. There has been a growing emphasis on achieving the best depth of response in the context of minimal residual disease negativity, given its prognostic correlation with superior overall survival. Another important area of emphasis has been to improve prognostication and staging by including information on disease biology. There also a growing appreciation of global differences in drug access and patterns of care. The current review explores each of these areas and how best to incorporate the emerging induction regimens in to schema of MM therapy.
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http://dx.doi.org/10.1200/EDBK_238527DOI Listing
January 2019

Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma.

J Cancer Metastasis Treat 2019 3;5. Epub 2019 Apr 3.

Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA.

Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids; the generation of energy (ATP); and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.
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http://dx.doi.org/10.20517/2394-4722.2019.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476731PMC
April 2019

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy.

Leukemia 2019 09 11;33(9):2266-2275. Epub 2019 Mar 11.

Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T) was 50.1 months. The median overall survival (OS) from T for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T in 249 (90%) patients. Overall response rate to first regimen after T was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.
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http://dx.doi.org/10.1038/s41375-019-0435-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820050PMC
September 2019

The challenges of checkpoint inhibition in the treatment of multiple myeloma.

Cell Immunol 2018 12 13;334:87-98. Epub 2018 Oct 13.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15 years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. While checkpoint inhibitors are effective in prolonging overall survival in some patients with advanced solid cancers and Hodgkin lymphoma, they have not demonstrated significant activity as a single agent in MM. In fact the combination of checkpoint inhibitors with IMiDs was recently found to increase the risk of death in myeloma patients. These challenges highlight the need for a better understanding of immune dysregulation in myeloma patients, and the mechanisms of action of- and resistance to- checkpoint inhibitors. In this review, we summarize immune dysfunction in patients with MM, and review the preclinical and clinical data regarding checkpoint inhibitors in myeloma. We conclude by proposing strategies to improve the efficacy and safety of checkpoint inhibitors in this population.
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http://dx.doi.org/10.1016/j.cellimm.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309858PMC
December 2018

Periosteal Infusion of Local Anesthetics as an Alternative to Bilateral Subpectoral Interfascial Plane Catheters in Patients With Sternal Fractures.

Reg Anesth Pain Med 2017 May/Jun;42(3):415-416

Department of Anaesthesia, Newcastle-upon-Tyne NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.

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http://dx.doi.org/10.1097/AAP.0000000000000524DOI Listing
March 2018

Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion.

Proc Natl Acad Sci U S A 2016 11 15;113(48):E7778-E7787. Epub 2016 Nov 15.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;

The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stage-dependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.
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http://dx.doi.org/10.1073/pnas.1608221113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137691PMC
November 2016

Checkpoint inhibition for colorectal cancer: progress and possibilities.

Immunotherapy 2016 06;8(6):693-704

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

Colorectal cancer (CRC) remains the third most common cause of cancer death in the USA. Despite an increase in the repertoire of treatment options available for CRC, median overall survival has plateaued at approximately 2.5 years. Strategies that engage the patient's native immune system to overcome checkpoint inhibition have proven to be promising in subsets of CRCs, specifically those with mismatch repair deficiency. Further studies are required to determine combinations of standard therapies with immunotherapy drugs and to discover the best biomarkers to predict response. This review provides insight into the progress made in treating patients with advanced CRC with immunotherapeutics and the areas that demand further research to make these drugs more effective in this patient population.
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http://dx.doi.org/10.2217/imt-2016-0013DOI Listing
June 2016

A Descriptive Study of Body Pain and Work-Related Musculoskeletal Disorders Among Latino Farmworkers Working on Sweet Potato Farms in Eastern North Carolina.

J Agromedicine 2016 ;21(3):234-43

a Department of Public Health , Brody School of Medicine, East Carolina University , Greenville , North Carolina , USA.

Agricultural work is a physically demanding occupation. The purpose of this project was to describe the prevalence of work-related musculoskeletal disorders (WMSDs) and self-reported pain among Latino farmworkers who work extensively hand harvesting sweet potatoes. Data were obtained from a cross-sectional survey of farmworkers (N = 120) in eastern North Carolina. Univariate and bivariate analyses were used to describe personal, work characteristics, and self-reported pain associated with musculoskeletal injuries. Overall, 79% of farmworkers reported any type of pain or discomfort. The highest reported areas of pain were in the back (66%) and shoulder areas (31%). Younger participants experienced more shoulder pain (P = .04) than older workers, and working more than 5 years as a farmworker was significantly associated with back pain (P = .01). Interventions aimed at administrative and engineering controls for reducing risk factors that contribute to WMSDs are warranted.
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http://dx.doi.org/10.1080/1059924X.2016.1178613DOI Listing
April 2017

Nine-year change in statistical design, profile, and success rates of Phase II oncology trials.

J Biopharm Stat 2016 ;26(1):141-9

b Department of Medicine , The University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.

We investigated nine-year trends in statistical design and other features of Phase II oncology clinical trials published in 2005, 2010, and 2014 in five leading oncology journals: Cancer, Clinical Cancer Research, Journal of Clinical Oncology, Annals of Oncology, and Lancet Oncology. The features analyzed included cancer type, multicenter vs. single-institution, statistical design, primary endpoint, number of treatment arms, number of patients per treatment arm, whether or not statistical methods were well described, whether the drug was found effective based on rigorous statistical testing of the null hypothesis, and whether the drug was recommended for future studies.
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http://dx.doi.org/10.1080/10543406.2015.1092030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995106PMC
October 2016

On the connection coefficients of the Chebyshev-Boubaker polynomials.

Authors:
Paul Barry

ScientificWorldJournal 2013 4;2013:657806. Epub 2013 Aug 4.

School of Science, Waterford Institute of Technology, Waterford, Ireland.

The Chebyshev-Boubaker polynomials are the orthogonal polynomials whose coefficient arrays are defined by ordinary Riordan arrays. Examples include the Chebyshev polynomials of the second kind and the Boubaker polynomials. We study the connection coefficients of this class of orthogonal polynomials, indicating how Riordan array techniques can lead to closed-form expressions for these connection coefficients as well as recurrence relations that define them.
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http://dx.doi.org/10.1155/2013/657806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748752PMC
February 2014

Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase.

Cancer Res 2006 Aug;66(16):8116-22

Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.

Elevated expression of ornithine decarboxylase (ODC) and increased synthesis of polyamines are hallmarks of epithelial tumorigenesis. The skin and tumors of K6/ODC and ODC/Ras transgenic mice, in which overexpression of ODC has been targeted to hair follicles, were found to exhibit intrinsically high histone acetyltransferase (HAT) activity. We identified Tip60 as a candidate enzyme for contributing significantly to this abnormally high HAT activity. Compared with normal littermate controls, the levels of Tip60 protein and an alternative splice variant Tip53 were found to be greater in K6/ODC mouse skin. Furthermore, skin tumors that spontaneously develop in ODC/Ras bigenic mice typically have substantially more Tip60 protein than adjacent non-tumor-bearing skin and exhibit a unique pattern of Tip60 size variants and chemically modified protein isoforms. Steady-state Tip60 and Tip53 mRNA levels were not affected in ODC-overexpressing skin and tumors, implying novel posttranscriptional regulation by polyamines. Given the diverse roles of Tip60, the overabundance of Tip60 protein is predicted to have biological consequences. Compared with normal littermate skin, we detected altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors in ODC transgenic mouse skin and tumors. E2F1 was shown to be bound in greater amounts to up-regulated target genes in ODC-overexpressing skin. Thus, up-regulation of Tip60 protein, influencing the expression of Tip60-regulated genes, could play a contributing role in polyamine-mediated tumor promotion. (
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http://dx.doi.org/10.1158/0008-5472.CAN-06-0359DOI Listing
August 2006

Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice.

Carcinogenesis 2005 Jan 16;26(1):119-24. Epub 2004 Sep 16.

Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.

Tea polyphenolic constituents induce apoptosis in cancer cells but not in normal cells. To study the mechanism of this selective effect, we used the ornithine decarboxylase (ODC)/Ras double transgenic mouse model that develops spontaneous skin tumors due to over-expression of ODC and a v-Ha-ras transgene. Administration of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the drinking water significantly decreased both tumor number and total tumor burden compared with untreated ODC/Ras mice without decreasing the elevated polyamine levels present in the ODC/Ras mice. EGCG selectively decreased both proliferation and survival of primary cultures of ODC over-expressing transgenic keratinocytes but not keratinocytes from normal littermates nor ras-infected keratinocytes. This decreased survival was due to EGCG-induced apoptosis and not terminal differentiation. Moreover, in skin from EGCG-treated ODC transgenic mice, caspase 3 (active form) was detected only in epidermal cells that possess very high levels of ODC protein. Since most transformed cells and tumor tissue possess higher levels of polyamines compared with normal cells or tissue, our data suggest that the elevated levels of polyamines in tumor cells sensitize them to EGCG-induced apoptosis. These results suggest that EGCG may be an effective chemopreventive agent in individuals with early, pre-neoplastic stages of cancer having higher levels of polyamines.
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http://dx.doi.org/10.1093/carcin/bgh281DOI Listing
January 2005

Time for a new approach for reporting herbal medicine adverse events?

J Altern Complement Med 2003 Oct;9(5):607-9

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http://dx.doi.org/10.1089/107555303322524427DOI Listing
October 2003

Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation.

Exp Cell Res 2003 Nov;290(2):427-36

Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.

Polyamines affect nucleosome oligomerization and DNA conformation in vitro, yet little information exists regarding the influence of naturally synthesized polyamines on mammalian chromatin. Capitalizing on the relative inefficiency of a moderate ionic strength extraction buffer to dissociate histones, we obtained evidence of altered chromatin in transgenic mice that overexpress ornithine decarboxylase (ODC), which catalyzes polyamine synthesis. Dissociation of histones from chromatin in ODC transgenic mouse skin, as well as in tumors that develop spontaneously in ODC/Ras bigenic mice, is dramatically reduced relative to normal littermate skin. This could reflect tighter tethering of nucleosomes to DNA or a more compacted chromatin structure due to elevated intracellular concentrations of polyamines since this effect is reversible upon treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC enzymatic activity. Impeded release of nonhistone chromatin proteins HP-1beta and nucleophosmin, but not Lamin B, HDAC-1, HMGB, HMGN2, or HMGA1, suggests that polyamines exert selective effects on specific chromatin protein complexes. Moreover, overall acetylation, as well as specific methylation, of nucleosomes in ODC mice is unaffected, implying that access by histone modifying enzymes is not generally restricted. The abnormal chromatin environment fostered by elevated levels of polyamines may be a necessary prerequisite for epithelial tumor growth and maintenance.
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http://dx.doi.org/10.1016/s0014-4827(03)00352-5DOI Listing
November 2003

Embracing street culture: fitting health care into the lives of street youth.

J Transcult Nurs 2002 Apr;13(2):145-52

University of Washington, USA.

The purpose of this article is to describe a unique model for the provision of comprehensive primary health care for homeless youth in Seattle, Washington. Through the description of our program, we argue for the use of youth-centric instead of youth-friendly programs. This means a change from using the friendly health program as the central focus to having the young people be the starting point and adapting the health service to meet their needs. We describe how our model of care optimizes chances for homeless youth to establish positive connections with caring adults. We also show how homeless youth have their own street culture, which is of primary importance to them and which has a powerful impact on how they use and view health care.
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http://dx.doi.org/10.1177/104365960201300208DOI Listing
April 2002

Deregulation of polyamine biosynthesis alters intrinsic histone acetyltransferase and deacetylase activities in murine skin and tumors.

Cancer Res 2002 Jan;62(1):67-74

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.

The essential requirement for polyamines for normal cell growth and differentiation may be partly attributed to their influence on gene expression, a process regulated by the acetylation state of nucleosomal histones. We used transgenic mice to examine the effects of constitutive expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on histone acetylation in epithelial cells in skin. As compared with the skin of normal littermate mice, both intrinsic histone acetyltransferase (HAT) and deacetylase activities are elevated in ODC transgenic skin. Skin tumors that form spontaneously in ODC/Ras double transgenic mice exhibit exceptionally high HAT activity having a distinct specificity for Lys-12 in the tail domain of histone H4, which may have implications for gene transcription. However, acetylation of histones by HAT enzymes was impeded in cultured ODC transgenic keratinocytes, and there were only modest changes in levels of acetylated histones in the skin of ODC transgenic mice. Treatment with the ODC enzyme inhibitor alpha-difluoromethylornithine, which results in regression of ODC/Ras tumors, reverses the effects on HAT and deacetylase enzyme function, implicating polyamine biosynthesis in the regulation of histone acetylation. Polyamines do not directly stimulate the enzymatic activity of either p300 or p300/CREB-binding protein (CBP)-associated factor, members of two distinct classes of HAT enzymes, implying that the elevated CBP/p300-associated HAT activity detected in ODC transgenic skin is attributable to indirect influence of polyamines. These results suggest that multiple mechanisms exist by which endogenous polyamines influence chromatin in mammals. Furthermore, they suggest that the elevated polyamine levels inherent in many solid tumors alter chromatin structure, likely affecting gene expression and promoting the neoplastic process.
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January 2002