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Stephen J Galli
IgE-mediated activation of mast cells is a hallmark of an anaphylactic reaction to allergen. In this issue of the JCI, Duan et al. describe an approach for suppressing IgE-dependent mast cell activation, thereby suppressing anaphylaxis. Specifically, the authors show that delivery of liposomes containing both the specific antigen recognized by the mast cell-bound IgE and a high-affinity glycan ligand of the inhibitory receptor CD33 (CD33L) to targeted mast cells inhibits antigen-induced, FcεRI-dependent spleen tyrosine kinase (Syk) phosphorylation and downstream protein tyrosine kinase (PTK) phosphorylation, Ca++ flux, and β-hexosaminidase release (i...
February 18, 2019: Journal of Clinical Investigation
Amanda McQuade, Mathew Blurton-Jones
Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease, the majority of risk loci discovered through genome-wide association-studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of Alzheimer's disease (AD) from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support...
February 7, 2019: Journal of Molecular Biology
Ioannis Papageorgiou, Michael R Loken, Lisa Eidenschink Brodersen, Mohammed Gbadamosi, Geoffrey L Uy, Soheil Meshinchi, Jatinder K Lamba
No abstract text is available yet for this article.
February 5, 2019: Leukemia & Lymphoma
Noelia Dasilva-Freire, Andrea Mayado, Cristina Teodosio, María Jara-Acevedo, Iván Álvarez-Twose, Almudena Matito, Laura Sánchez-Muñoz, Carolina Caldas, Ana Henriques, Javier I Muñoz-González, Andrés C García-Montero, J Ignacio Sánchez-Gallego, Luis Escribano, Alberto Orfao
Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC...
January 28, 2019: International Journal of Molecular Sciences
Jan Philipp Bewersdorf, Maximilian Stahl, Amer M Zeidan
The 5-year overall survival rate of AML patients remains 25-40%. The prognosis is even more dismal for older patients who are ineligible for intensive chemotherapy and patients with secondary or relapsed/refractory AML. In 2017, 4 new drugs were approved by the US Food and Drug Administration for AML treatment: The FLT3 inhibitor midostaurin, the isocitrate dehydrogenase (IDH)-2 inhibitor enasidenib, a liposomal formulation of cytarabine and daunorubicin (CPX-351), and the anti-CD33 antibody gemtuzumab ozogamicin...
January 17, 2019: Leukemia & Lymphoma
Shiteng Duan, Cynthia J Koziol-White, William F Jester, Corwin M Nycholat, Matthew S Macauley, Reynold A Panettieri, James C Paulson
Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medial supervision to monitor and treat IgE-mast cell mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in transgenic mice with mast cells expressing human CD33, and desensitized mice from subsequent allergen challenge for several days...
January 15, 2019: Journal of Clinical Investigation
Tonglin Hu, Jianping Shen, Wenbin Liu, Zhiying Zheng
RATIONALE: Acute lymphoblastic leukemia (ALL) secondary to multiple myeloma (MM) is rare. Here we report a rare case of secondary ALL transformed from MM. PATIENT CONCERNS: A 64-year-old woman was diagnosed as MM IgG light chain type in 2001. She achieved complete remission after 2 cycles of therapy, and received maintenance therapy with thalidomide. The patient suffered from MM relapse in September 2011. Bone marrow examination showed that the percentage of primary lymphocytes was 59%, indicating ALL-L2 (Pre-B-ALL)...
January 2019: Medicine (Baltimore)
Ying Wang, Peng Li, Bo Wang, Shuai Wang, Pinan Liu
PURPOSE: There is no targeted drug therapy for NF2 patients, and surgery or radiosurgery is not always effective. Therefore, the exploration of new therapeutic pathways is urgently needed. METHODS: We analyzed the expression of cytokines in the serum of NF2 patients and determined the percentage of HLA-DR- CD33+ CD11b+ cells in blood and NF2-associated schwannomas. Furthermore, we analyzed the role of HLA-DR- CD33+ CD11b+ cells in inhibiting T-cell proliferation, cytokine production, and transforming growth factor expression...
January 2, 2019: Journal of Cancer Research and Clinical Oncology
Nicola Potter, Farideh Miraki-Moud, Luca Ermini, Ian Titley, Gowri Vijayaraghavan, Elli Papaemmanuil, Peter Campbell, John Gribben, David Taussig, Mel Greaves
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases...
December 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Steven Lehrer
Background: Cancer mortality and Alzheimer's disease (AD) mortality increase with age, but some studies have shown an inverse relationship of the two diseases, that is, older persons with cancer have a reduced risk of AD and vice versa. However, other analyses suggest that AD and brain tumor might be positively correlated. Objective: In the current study, we wished to determine the relationship of AD mortality to malignant brain tumor mortality in US states and counties...
December 14, 2018: JAD Reports
Junko Johansson, Roberta Kiffin, Annica Andersson, Per Lindnér, Peter L Naredi, Roger Olofsson Bagge, Anna Martner
Hyperthermic isolated limb perfusion with melphalan (M-ILP) is a treatment option for melanoma patients with metastases confined to the limbs. This study aimed at defining the role of cellular immunity for the clinical response to M-ILP in melanoma patients. It was observed that patients with enhanced cytotoxic CD8+ T cell reactivity to common antigens (HCMV/EBV/influenza virus) prior to M-ILP were more likely to achieve a complete disappearance of macroscopic tumors (complete response). Following M-ILP treatment, the proportions of CD16+ intermediate and non-classical monocytes in peripheral blood were significantly enhanced along with induction of HLA-DR on CD4+ and CD8+ T cells...
2018: Frontiers in Oncology
Yuxin Liu, Jan Philipp Bewersdorf, Maximilian Stahl, Amer M Zeidan
Immunotherapy has revolutionized therapy in both solid and liquid malignancies. The ability to cure acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an allogeneic hematopoietic stem cell transplant (HSCT) is proof of concept for the application of immunotherapy in AML and MDS. However, outside of HSCT, only the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin is currently approved as an antibody-targeted therapy for AML. Several avenues of immunotherapeutic drugs are currently in different stages of clinical development...
December 5, 2018: Blood Reviews
Lei-Lei Yang, Meng-Jie Zhang, Lei Wu, Liang Mao, Lei Chen, Guang-Tao Yu, Wei-Wei Deng, Wen-Feng Zhang, Bing Liu, Wei-Ke Sun, Zhi-Jun Sun
BACKGROUND: This study aims to investigate the characteristic role of inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) in oral squamous cell carcinoma (OSCC). METHODS: The expressions of LAIR-1 and other immune-related molecules were detected in a human OSCC tissue microarray. LAIR-1 expression difference among different clinicopathological parameters was analyzed. The correlations of LAIR-1 with several immune-related markers were assessed...
December 14, 2018: Head & Neck
Kifayat Ullah, Frank Addai Peprah, Feng Yu, Haifeng Shi
Adoptive cell transfer (ACT) is an emerging immunotherapy technique that restricts tumor growth and invasion in cancer patients. Among the different types of ACT, chimeric antigen receptor (CAR)T‑cell therapy is considered to be the most advanced and a potentially powerful technique for the treatment of cancer in clinical trials. The primary aim of CART‑cell therapy is to destroy cancer cells and therefore, it serves an important role in tumor immunotherapy. CART‑cell therapy has been demonstrated to mainly treat blood cancer by targeting cluster of differentiation (CD)‑19, CD20, CD22, CD33 and CD123...
December 2018: Oncology Reports
Lingzhi Zhao
Alzheimer's disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD...
December 12, 2018: Gerontology
Kentaro Minagawa, Mustafa Al-Obaidi, Antonio Di Stasi
Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID)...
2019: Methods in Molecular Biology
Pamela C Egan, John L Reagan
Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated approval in the United States in 2000 gave way to fear over increased toxicity in the absence of efficacy, which subsequently resulted in the drug manufacturer voluntarily withdrawing GO from the market in 2010. We outline the history of GO in terms of initial drug development and early clinical trials that ultimately led the way to GO frontline use in AML based on a series of Phase III studies...
2018: OncoTargets and Therapy
Alba Gonzalez-Junca, Kyla Driscoll, Ilenia Pellicciotta, Shisuo Du, Chen Hao Lo, Ritu Roy, Renate Parry, Iliana Tenvooren, Diana Marquez, Matthew H Spitzer, Mary Helen Barcellos-Hoff
Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between TGFB1 and genes expressed by myeloid cells, but not granulocytes, in TCGA lung adenocarcinoma data, in which high TGFB1 expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14+ monocytes isolated from peripheral blood of healthy donors...
December 11, 2018: Cancer Immunology Research
Xiaosan Su, Yaodong Fan, Liu Yang, Jie Huang, Fei Qiao, Yu Fang, Jun Wang
BACKGROUND: Dexmedetomidine (DEX) has been reported to promote tumour metastases. However the underlying mechanisms remain unclear. The purpose of this study was to investigate whether DEX promotes tumour metastasis by inducing myeloid-derived suppressor cells (MDSC) in the context of surgery. METHODS: DEX was given to lung cancer patients and its effects on expansion of monocytic MDSC (M-MDSC) were studied in the context of surgery. Spontaneous tumour metastasis was induced in C57BL/6 mice and the effects of DEX on M-MDSC expansion and metastasis formation were assessed...
December 11, 2018: Journal of Translational Medicine
Dina Schneider, Ying Xiong, Peirong Hu, Darong Wu, Weizao Chen, Tianlei Ying, Zhongyu Zhu, Dimiter S Dimitrov, Boro Dropulic, Rimas J Orentas
Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry...
2018: Frontiers in Oncology
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