Journal Articles

Immunotherapy reviews

Reviews on preclinical or clinical cancer immunotherapy approaches

Blocking "don't eat me" signal of CD47-SIRPalpha in hematological malignancies, an in-depth review

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Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPalpha triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPalpha resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPalpha interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPalpha interaction in leukemia, lymphoma and multiple myeloma.

Author Info: (1) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: aruss@deptofmed.arizona.edu. (2) Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA. Electronic address

Author Info: (1) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: aruss@deptofmed.arizona.edu. (2) Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA. Electronic address: anhhua@email.arizona.edu. (3) Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA. Electronic address: montfort@email.arizona.edu. (4) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: bushra.rahman@bannerhealth.com. (5) Department of Medicine, Hematology Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: riaz.dr@mayo.edu. (6) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: umarkhalid1990@gmail.com. (7) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: jcarew@email.arizona.edu. (8) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: snawrocki@email.arizona.edu. (9) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: dpersky@email.arizona.edu. (10) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: anwerf@email.arizona.edu.

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Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia

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The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in >90% of ALL patients, and inotuzumab ozogamicin has shown excellent clinical activity even among heavily pretreated relapsed/refractory (R/R) B-ALL patients and elderly B-ALL patients. Clinical trials have shown superior survival with the drug over chemotherapy-based approaches in the first- or second-line salvage therapy for relapsed B-ALL as monotherapy. Currently, new trials are evaluating inotuzumab ozogamicin in the frontline setting in combination-based approaches. In this review, we summarize the preclinical and clinical data of inotuzumab ozogamicin in R/R B-ALL and foresee the future use of this drug in the clinic.

Author Info: (1) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (2) Section of Hematology, Department of Internal Medicine, Yale

Author Info: (1) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (2) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (3) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (4) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

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Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054

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BACKGROUND: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. RESULTS: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1lambda monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways. CONCLUSIONS: LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.

Author Info: (1) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. yiwen.li@lilly.com. Eli Lilly and Company, 450 East 29th Street, New York, NY, 10016

Author Info: (1) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. yiwen.li@lilly.com. Eli Lilly and Company, 450 East 29th Street, New York, NY, 10016, USA. yiwen.li@lilly.com. (2) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (3) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (4) Lilly Research Laboratories, Department of Preclinical Pharmacology, New York, NY, USA. (5) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (6) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (7) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (8) Lilly Research Laboratories, Department of Biologics Technology, New York, NY, USA. (9) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (10) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (11) Lilly Research Laboratories, Department of Biologics Technology, New York, NY, USA. (12) Lilly Research Laboratories, Department of Preclinical Pharmacology, New York, NY, USA. (13) Lilly Research Laboratories, Department of Preclinical Pharmacology, New York, NY, USA. (14) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (15) Lilly Research Laboratories, Department of Non-Clinical Safety, Indianapolis, IN, USA. (16) Lilly Research Laboratories, Department of Quantitative Biology, New York, NY, USA. (17) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (18) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (19) Lilly Research Laboratories, Department of Biologics Technology, New York, NY, USA. (20) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. (21) Lilly Research Laboratories, Department of Cancer Immunobiology, New York, NY, USA. MKALOS@ITS.JNJ.COM. Eli Lilly and Company, 450 East 29th Street, New York, NY, 10016, USA. MKALOS@ITS.JNJ.COM. Janssen Pharmaceutical Companies of Johnson and Johnson, Springhouse, PA, USA. MKALOS@ITS.JNJ.COM.

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Correlates of immune and clinical activity of novel cancer vaccines

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Cancer vaccines are solely meant to amplify the pool of type 1 cytokine oriented CD4+ and CD8+ T cells that recognize tumor antigen and ultimately foster control and destruction of a growing tumor. They are not designed to deal with all aspects of immune ignorance, exclusion, suppression and escape that are generally in place in patients with cancer and may prevent the T cells to enter the tumor or to exert their effector function. This simple fact prompted for a reappraisal of the many recent trials in which therapeutic cancer vaccines have been examined as monotherapy. In this review, I focus on trials examining therapeutic cancer vaccines at different stages of existing disease. The analysis of vaccine-induced immune responses and clinical activity of therapeutic cancer vaccines revealed four levels of evidence for vaccine efficacy. The lowest levels, reflect the many trials in which the strength of the tumor-reactive T cell response of vaccinated patients is associated with better clinical outcome or change in tumor marker. The highest levels indicate occasional regressions of tumors and metastases after vaccination or reflect a stronger clinical impact of vaccine in a randomized trial. A whole series of trials in which vaccine-induced tumor immunity correlates with the clinical impact of cancer vaccines in premalignant diseases, settings of low tumor burden or tumor regressions in patients with cancer, form an attest to the fact that cancer vaccines work. While the current number of true clinical responders in each cancer trial is too low for firm conclusions on immune correlates of clinical reactivity in cancer, extrapolation of the results from vaccinated patients with pre-cancers suggest a requirement of broad type 1 T cell reactivity.

Author Info: (1) Department of Medical Oncology, Leiden University Medical Center, Building 1, C7-P, PO box 9600, 2300 RC Leiden, The Netherlands. Electronic address: shvdburg@lumc.nl.

Author Info: (1) Department of Medical Oncology, Leiden University Medical Center, Building 1, C7-P, PO box 9600, 2300 RC Leiden, The Netherlands. Electronic address: shvdburg@lumc.nl.

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Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

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Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (2) Pediatric Translational Research Unit

Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (2) Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. (3) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand. (4) Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.

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Imaging Polarized Secretory Traffic at the Immune Synapse in Living T Lymphocytes

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Immune synapse (IS) formation by T lymphocytes constitutes a crucial event involved in antigen-specific, cellular and humoral immune responses. After IS formation by T lymphocytes and antigen-presenting cells, the convergence of secretory vesicles toward the microtubule-organizing center (MTOC) and MTOC polarization to the IS are involved in polarized secretion at the synaptic cleft. This specialized mechanism appears to specifically provide the immune system with a fine strategy to increase the efficiency of crucial secretory effector functions of T lymphocytes, while minimizing non-specific, cytokine-mediated stimulation of bystander cells, target cell killing and activation-induced cell death. The molecular bases involved in the polarized secretory traffic toward the IS in T lymphocytes have been the focus of interest, thus different models and several imaging strategies have been developed to gain insights into the mechanisms governing directional secretory traffic. In this review, we deal with the most widely used, state-of-the-art approaches to address the molecular mechanisms underlying this crucial, immune secretory response.

Author Info: (1) Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols CSIC-UAM, Madrid, Spain. (2) Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols CSIC-UAM, Madrid, Spain.

Author Info: (1) Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols CSIC-UAM, Madrid, Spain. (2) Departamento de Bioquimica, Instituto de Investigaciones Biomedicas Alberto Sols CSIC-UAM, Madrid, Spain.

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Chimeric Small Antibody Fragments as Strategy to Deliver Therapeutic Payloads

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Antibody-drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue. The clinical success of brentuximab vedotin and trastuzumab emtansine has led to an extensive expansion of the clinical ADC pipeline. Although the concept of an ADC seems simple, designing a successful ADC is complex and requires careful selection of the receptor antigen, antibody, linker, and payload. In this review, we explore insights in the antibody and antigen requirements needed for optimal payload delivery and support the development of novel and improved ADCs for the treatment of cancer and neurological diseases.

Author Info: (1) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (2) Centro de

Author Info: (1) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (2) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (3) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (4) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (5) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (6) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (7) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: joao.goncalves@ff.ul.pt.

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Generalization and representativeness of phase III immune checkpoint blockade trials in non-small cell lung cancer

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BACKGROUND: Strict eligibility criteria for patient enrollment in phase III trials raise questions regarding generalization to ineligible patients. We evaluated whether pivotal phase III trials of immune checkpoint blockades (ICBs) represent the overall population of non-small cell lung cancer (NSCLC) patients. METHODS: We reviewed the inclusion and exclusion criteria of three phase III trials (CheckMate057, CheckMate017, and KEYNOTE-010). Stage IIIB or IV NSCLC patients diagnosed from 2011 to 2013 at Seoul National University Hospital (cohort 1) were reviewed. We also analyzed the criteria in 53 patients with NSCLC who were treated with nivolumab or pembrolizumab as routine practice (cohort 2). RESULTS: Among the 715 patients in cohort 1, 499 (69.9%) were ineligible for the three trials. Reasons for ineligibility included: no prior platinum doublet treatment (23.6%), lack of tissue availability (22.7%), Eastern Cooperative Oncology Group performance status > 1 (14.1%), steroid use (18.2%), active cerebral nervous system metastasis (8.3%), hepatitis B/hepatitis C/human immunodeficiency virus (8.0%), and no measurable lesion (7.3%). EGFR mutations were more common in the ineligible group. In cohort 2, 67.9% of patients were classified as ineligible. Treatment outcomes of ICB in cohort 2 appeared inferior to those in the three pivotal trials, with a response rate of 11.3% and median progression-free survival of 1.67 months. CONCLUSION: Only 30% of NSCLC patients were eligible for ICB phase III trials. The actual efficacy in the 70% of ineligible patients is unknown. These findings suggest a huge gap between practice-changing phase III trials and the overall population of NSCLC patients.

Author Info: (1) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. (2) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Cancer

Author Info: (1) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. (2) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (3) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. (4) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (5) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (6) Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.

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CD4 Helper and CD8 Cytotoxic T Cell Differentiation

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A fundamental question in developmental immunology is how bipotential thymocyte precursors generate both CD4(+) helper and CD8(+) cytotoxic T cell lineages. The MHC specificity of alphabeta T cell receptors (TCRs) on precursors is closely correlated with cell fate-determining processes, prompting studies to characterize how variations in TCR signaling are linked with genetic programs establishing lineage-specific gene expression signatures, such as exclusive CD4 or CD8 expression. The key transcription factors ThPOK and Runx3 have been identified as mediating development of helper and cytotoxic T cell lineages, respectively. Together with increasing knowledge of epigenetic regulators, these findings have advanced our understanding of the transcription factor network regulating the CD4/CD8 dichotomy. It has also become apparent that CD4(+) T cells retain developmental plasticity, allowing them to acquire cytotoxic activity in the periphery. Despite such advances, further studies are necessary to identify the molecular links between TCR signaling and the nuclear machinery regulating expression of ThPOK and Runx3.

Author Info: (1) Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; email: ichiro.taniuchi@riken.jp.

Author Info: (1) Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; email: ichiro.taniuchi@riken.jp.

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Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response

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Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation. In resting lymphocytes, TEC kinases are autoinhibited, and multiple interactions between the regulatory and kinase domains maintain low activity. Following TCR stimulation, newly generated signaling modules compete with the autoinhibited core and shift the conformational ensemble to the fully active kinase. This multidomain control over kinase activation state provides a structural mechanism to account for ITK's ability to tune the TCR signal.

Author Info: (1) Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA; email: amyand@iastate.edu , jraji@iastate.edu. (2) Roy J

Author Info: (1) Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA; email: amyand@iastate.edu , jraji@iastate.edu. (2) Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA; email: amyand@iastate.edu , jraji@iastate.edu. (3) Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; email: leslie.berg@umassmed.edu , james.conley@umassmed.edu. (4) Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112, USA; email: jiwasa@biochem.utah.edu. (5) Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; email: leslie.berg@umassmed.edu , james.conley@umassmed.edu.

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