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Sabrina A Hogan, Mitchell P Levesque, Phil F Cheng
The recent emergence of cancer immunotherapies initiated a significant shift in the clinical management of metastatic melanoma. Prior to 2011, melanoma patients only had palliative treatment solutions which offered little to no survival benefit. In 2018, with immunotherapy, melanoma patients can now contemplate durable or even complete remission. Treatment with novel immune checkpoint inhibitors, anti-cytotoxic T-lymphocyte protein 4 and anti-programmed cell death protein 1, clearly result in superior median and long-term survivals compared to standard chemotherapy; however, more than half of the patients do not respond to immune checkpoint blockade...
2018: Frontiers in Oncology
Fathima Zumla Cader, Ron C J Schackmann, Xihao Hu, Kirsty Wienand, Robert Redd, Bjoern Chapuy, Jing Ouyang, Nicole Paul, Evisa Gjini, Mikel Lipschitz, Philippe Armand, David Wu, Jonathan R Fromm, Donna Neuberg, X Shirley Liu, Scott J Rodig, Margaret A Shipp
In classical Hodgkin lymphoma (cHL), the host anti-tumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system including 9p24.1/ CD274(PD-L1) / PDCD1LG2(PD-L2) genetic alterations, overexpression of the PD-1 ligands and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T-effectors (Teff)...
June 7, 2018: Blood
Savneet Kaur, Rashi Sehgal, Saggere M Shastry, Geoffrey McCaughan, Helen M McGuire, Barbara Fazekas St de Groth, Shiv Sarin, Nirupma Trehanpati, Devanshi Seth
Background and Aim: Endothelial progenitor cells (EPCs) have been implicated in liver injury and repair. However, the phenotype and potential of these heterogenous EPCs remain elusive. In particular, their involvement in the pathogenesis of alcoholic liver cirrhosis (ALC) remains unclear. The current study extensively characterized the phenotype and functions of EPCs to understand their role in ALC pathogenesis. Methods: Circulating EPCs were identified as CD34+CD133+CD31+ cells by flow cytometer in ALC patients ( n = 7) and healthy controls (HC, n = 7)...
2018: Frontiers in Physiology
Christine M D Lingblom, Sangeeta Kowli, Nithya Swaminathan, Holden T Maecker, Stacie L Lambert
BACKGROUND: Mass cytometry, or CyTOF (Cytometry by Time-of-Flight), permits the simultaneous detection of over 40 phenotypic and functional immune markers in individual cells without the issues of spectral overlap seen in traditional flow cytometry. METHODS: In this study, we applied CyTOF to comprehensively characterize the circulating immune cell populations in elderly individuals both before and after administration of an investigational adjuvanted protein vaccine against respiratory syncytial virus (RSV) in a Phase 1a trial...
June 5, 2018: Journal of Translational Medicine
Elisabeta Comsa, Kim-Anh Nguyen, Felicia Loghin, Ahcène Boumendjel, Marine Peuchmaur, Thibault Andrieu, Pierre Falson
AIM: Cisplatin resistance in ovarian cancer remains a complex problem as tumors frequently develop resistance against drugs, a mechanism sometimes mediated by ATP-Binding Cassette transporters. Our goal was to find compounds restricting their inhibition capacity to the cisplatin efflux mediated by ABCC2 pump, among previously identified inhibitors, derived from the 2- indolylmethylenebenzofuranones. Results/methodology: An original method setup allows direct quantitation of platinum by employing cyTOF mass cytometry...
May 31, 2018: Future Medicinal Chemistry
Tina Smets, Frederik Stevenaert, Homer Adams, Greet Vanhoof
Mass cytometry has emerged as a new state-of-the-art technology that enables in-depth characterization of cellular populations and functions at a single cell resolution. We describe the application of this technology to deeply phenotype the blood and bone marrow components of multiple myeloma patients in a clinical setting. This technology allows for simultaneous quantification of more than 40 markers, overcoming the challenges of traditional fluorescence-based flow cytometry.
2018: Methods in Molecular Biology
Eric D Morrell, Alice Wiedeman, S Alice Long, Sina A Gharib, T Eoin West, Shawn J Skerrett, Mark M Wurfel, Carmen Mikacenic
Studies in human peripheral blood monocyte-derived macrophages in vitro have shown clear evidence that multiple macrophage polarization states exist. The extent to which different alveolar macrophage (AM) polarization states exist in homeostasis or in the setting of severe injury such as acute respiratory distress syndrome (ARDS) is largely unknown. We applied single-cell cytometry TOF (CyTOF) to simultaneously measure 36 cell-surface markers on CD45+ cells present in bronchoalveolar lavage from healthy volunteers, as well as mechanically ventilated subjects with and without ARDS...
May 17, 2018: JCI Insight
Jennifer E Cole, Inhye Park, David Ahern, Christina Kassiteridi, Dina Danso Abeam, Michael Goddard, Patricia Green, Pasquale Maffia, Claudia Monaco
Aims: Atherosclerosis is characterised by the abundant infiltration of myeloid cells starting at early stages of disease. Myeloid cells are key players in vascular immunity during atherogenesis. However, the subsets of vascular myeloid cells have eluded resolution due to shared marker expression and atypical heterogeneity in vascular tissues. We applied the high-dimensionality of mass cytometry to the study of myeloid cell subsets in atherosclerosis. Methods and Results: Apolipoprotein E-deficient (ApoE-/-) mice were fed a chow or a high fat (western) diet for 12 weeks...
May 2, 2018: Cardiovascular Research
Pei-Yu Kuo, Shashidhar S Jatiani, Adeeb H Rahman, Donna Edwards, Zewei Jiang, Katya Ahr, Deepak Perumal, Violetta V Leshchenko, Joshua Brody, Rita Shaknovich, B Hilda Ye, Samir Parekh
Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal...
May 17, 2018: Blood
Holger Winkels, Erik Ehinger, Melanie Vassallo, Konrad Buscher, Huy Q Dinh, Kouji Kobiyama, Anouk A J Hamers, Clément Cochain, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Alma Zernecke, Akula Bala Pramod, Amlan K Ghosh, Nathaly Anto Michel, Natalie Hoppe, Ingo Hilgendorf, Andreas Zirlik, Catherine C Hedrick, Klaus Ley, Dennis Wolf
RATIONALE: Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is poorly understood. OBJECTIVE: We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single-cell RNA-sequencing and mass cytometry (cytometry by time of flight) to define an atlas of the immune cell landscape in atherosclerosis...
June 8, 2018: Circulation Research
Priyanka B Subrahmanyam, Zhiwan Dong, Daniel Gusenleitner, Anita Giobbie-Hurder, Mariano Severgnini, Jun Zhou, Michael Manos, Lauren M Eastman, Holden T Maecker, F Stephen Hodi
BACKGROUND: While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling. METHODS: We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti-CTLA-4 or anti-PD-1 therapy...
March 6, 2018: Journal for Immunotherapy of Cancer
Bahareh Ajami, Nikolay Samusik, Peter Wieghofer, Peggy P Ho, Andrea Crotti, Zach Bjornson, Marco Prinz, Wendy J Fantl, Garry P Nolan, Lawrence Steinman
Neuroinflammation and neurodegeneration may represent two poles of brain pathology. Brain myeloid cells, particularly microglia, play key roles in these conditions. We employed single-cell mass cytometry (CyTOF) to compare myeloid cell populations in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, the R6/2 model of Huntington's disease (HD) and the mutant superoxide dismutase 1 (mSOD1) model of amyotrophic lateral sclerosis (ALS). We identified three myeloid cell populations exclusive to the CNS and present in each disease model...
April 2018: Nature Neuroscience
Manman Deng, Jie Zha, Zhiwu Jiang, Xian Jia, Yuanfei Shi, Peng Li, Xiao Lei Chen, Zhihong Fang, Zhiqiang Du, Bing Xu
BACKGROUND: Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells...
February 28, 2018: Journal of Translational Medicine
Tess Melinda Brodie, Vinko Tosevski
Mass cytometry (cytometry by time-of-flight, CyTOF) is a high-dimensional single-cell analytical technology that allows for highly multiplexed measurements of protein or nucleic acid abundances by bringing together the detection capacity of atomic mass spectroscopy and the sample preparation workflow typical of regular flow cytometry. In 2014 the mass cytometer was adapted for the acquisition of samples from microscopy slides (termed imaging mass cytometry), greatly increasing the applicability of this technology with the inclusion of spatial information...
2018: Methods in Molecular Biology
Maximilien Evrard, Immanuel W H Kwok, Shu Zhen Chong, Karen W W Teng, Etienne Becht, Jinmiao Chen, Je Lin Sieow, Hweixian Leong Penny, Goh Chi Ching, Sapna Devi, José Maria Adrover, Jackson L Y Li, Ka Hang Liong, Leonard Tan, Zhiyong Poon, Shihui Foo, Jia Wang Chua, I-Hsin Su, Karl Balabanian, Françoise Bachelerie, Subhra K Biswas, Anis Larbi, William Y K Hwang, Vikas Madan, H Phillip Koeffler, Siew Cheng Wong, Evan W Newell, Andrés Hidalgo, Florent Ginhoux, Lai Guan Ng
Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell-cycle-based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non-proliferating immature neutrophils and mature neutrophils...
February 20, 2018: Immunity
Xuejie Jiang, Po Yee Mak, Hong Mu, Wenjing Tao, Duncan H Mak, Steven Kornblau, Qi Zhang, Peter Ruvolo, Jared K Burks, Weiguo Zhang, Teresa McQueen, Rongqing Pan, Hongsheng Zhou, Marina Konopleva, Jorge Cortes, Qifa Liu, Michael Andreeff, Bing Z Carter
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Veronica D Gonzalez, Nikolay Samusik, Tiffany J Chen, Erica S Savig, Nima Aghaeepour, David A Quigley, Ying-Wen Huang, Valeria Giangarrà, Alexander D Borowsky, Neil E Hubbard, Shih-Yu Chen, Guojun Han, Alan Ashworth, Thomas J Kipps, Jonathan S Berek, Garry P Nolan, Wendy J Fantl
We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses...
February 13, 2018: Cell Reports
Ben Korin, Tania Dubovik, Asya Rolls
Immune cells comprise a diverse and dynamic cell population that is responsible for a broad range of immunological activities. They act in concert with other immune and nonimmune cells via cytokine-mediated communication and direct cell-cell interactions. Understanding the complex immune network requires a broad characterization of its individual cellular components. This is especially relevant for the brain compartment, which is an active immunological site, composed of resident and infiltrating immune cells that affect brain development, tissue homeostasis and neuronal activity...
February 2018: Nature Protocols
Carmen Gondhalekar, Bartek Rajwa, Valery Patsekin, Kathy Ragheb, Jennifer Sturgis, J Paul Robinson
Flow cytometry has well-established methods for data analysis based on traditional data collection techniques. These techniques typically involved manual insertion of tube samples into an instrument that, historically, could only measure 1-3 colors. The field has since evolved to incorporate new technologies for faster and highly automated sample preparation and data collection. For example, the use of microwell plates on benchtop instruments is now a standard on virtually every new instrument, and so users can easily accumulate multiple data sets quickly...
February 1, 2018: Methods: a Companion to Methods in Enzymology
Ye Henry Li, Dangna Li, Nikolay Samusik, Xiaowei Wang, Leying Guan, Garry P Nolan, Wing Hung Wong
Mass cytometry (CyTOF) has greatly expanded the capability of cytometry. It is now easy to generate multiple CyTOF samples in a single study, with each sample containing single-cell measurement on 50 markers for more than hundreds of thousands of cells. Current methods do not adequately address the issues concerning combining multiple samples for subpopulation discovery, and these issues can be quickly and dramatically amplified with increasing number of samples. To overcome this limitation, we developed Partition-Assisted Clustering and Multiple Alignments of Networks (PAC-MAN) for the fast automatic identification of cell populations in CyTOF data closely matching that of expert manual-discovery, and for alignments between subpopulations across samples to define dataset-level cellular states...
December 2017: PLoS Computational Biology
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