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Anthony Gonçalves, François Bertucci, Arnaud Guille, Severine Garnier, José Adelaide, Nadine Carbuccia, Oliver Cabaud, Pascal Finetti, Serge Brunelle, Gilles Piana, Jeanne Tomassin-Piana, Maria Paciencia, Eric Lambaudie, Cornel Popovici, Renaud Sabatier, Carole Tarpin, Magali Provansal, Jean-Marc Extra, François Eisinger, Hagay Sobol, Patrice Viens, Marc Lopez, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Max Chaffanet, Daniel Birnbaum
BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%)...
October 18, 2016: Oncotarget
Janet Ayello, Jessica Hochberg, Allyson Flower, Yaya Chu, Laxmi V Baxi, William Quish, Carmella van de Ven, Mitchell S Cairo
NK cells play a significant role in reducing relapse in patients with hematological malignancies following allogeneic stem cell transplantation but NK cell number and naturally occurring inhibitory signals limit their capability. IL-15 and 4-1BBL are important modulators of NK expansion and functional activation. With an aim to overcome these limitations, cord blood (CB) mononuclear cells (MNC) were ex-vivo expanded (EvE) for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wildtype K562 (WTK562)...
October 17, 2016: Experimental Hematology
L Faivre, M Chaussard, L Vercellino, V Vanneaux, B Hosten, K Teixera, V Parietti, P Merlet, L Sarda-Mantel, N Rizzo-Padoin, J Larghero
PURPOSE OF THE STUDY: After transplantation, cord blood (CB) hematopoietic stem and progenitor cells (HSPCs) are able to home to the bone marrow niche and to reconstitute the hematopoietic system. PET-CT imaging may be a useful method to monitor this parameter in different conditions. The aim of our study was to set up an efficient method for HSPC radiolabelling with [(18)F] fluorodeoxyglucose ((18)F-FDG) and to follow early HSPC homing through PET-CT in mice. MATERIALS AND METHODS: Purified CB HSPCs were radiolabelled with (18)F-FDG at 37° C with various conditions of cell concentration, incubation time and radioactivity concentration in order to define the in vitro condition that allows both sufficient (18)F-FDG uptake to get high quality PET imaging, and preservation of HSPC viability and functional properties during 3h after radiolabelling...
July 2016: Current Research in Translational Medicine
Charlotte V Cox, Paraskevi Diamanti, John P Moppett, Allison Blair
A significant number of children with T-lineage acute lymphoblastic leukemia (T-ALL) fail to respond to therapy and experience early relapse. CD99 has been shown to be overexpressed on T-ALL cells and is considered to be a reliable detector of the disease. However, the relevance of CD99 overexpression in ALL has not been investigated in a functional context. The aim of this study was to investigate the functional capacity of CD99+ cells in childhood ALL and determine the suitability of CD99 as a therapeutic target...
2016: PloS One
Jill Moser, Joris van Ark, Marcory C van Dijk, Dale L Greiner, Leonard D Shultz, Harry van Goor, Jan-Luuk Hillebrands
Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood. Hence, the aim of the current study was to investigate the role of the human immune system on subsequent neointima formation elicited by vascular injury in a humanized mouse model. Immunodeficient NOD.Cg-Prkdc(scid)IL2rg(tm1Wjl)(NSG) mice were reconstituted with human (h)PBMCs immediately after both carotid wire and femoral cuff injury were induced in order to identify how differences in the severity of injury influenced endothelial regeneration, neointima formation, and homing of human inflammatory and progenitor cells...
October 19, 2016: Scientific Reports
Ashley I Beyer, Marcus O Muench
Immunodeficient mice play a critical role in hematology research as in vivo models of hematopoiesis and immunology. Multiple strains have been developed, but hematopoietic stem cell engraftment and immune reconstitution have not been methodically compared among them. Four mouse strains were transplanted with human fetal bone marrow or adult peripheral blood CD34+ cells: NSG, NSG-3GS, hSCF-Tg-NSG and hSIRPα-DKO. Hematopoietic engraftment in the bone marrow, blood, spleen and liver was evaluated by flow cytometry 12 weeks after transplant...
October 19, 2016: Stem Cells and Development
Maulik Vyas, Ann-Charlott Schneider, Olga Shatnyeva, Katrin S Reiners, Samir Tawadros, Stephan Kloess, Ulrike Köhl, Michael Hallek, Hinrich P Hansen, Elke Pogge von Strandmann
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts...
2016: Oncoimmunology
Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Julian Pulecio, Oriol Alejo-Valle, Sandra Capellera-Garcia, Marianna Vitaloni, Paula Rio, Eva Mejía-Ramírez, Ilaria Caserta, Juan A Bueren, Johan Flygare, Angel Raya
Current sources of platelets for transfusion are insufficient and associated with risk of alloimmunization and blood-borne infection. These limitations could be addressed by the generation of autologous megakaryocytes (MKs) derived in vitro from somatic cells with the ability to engraft and differentiate in vivo. Here, we show that overexpression of a defined set of six transcription factors efficiently converts mouse and human fibroblasts into MK-like progenitors. The transdifferentiated cells are CD41(+), display polylobulated nuclei, have ploidies higher than 4N, form MK colonies, and give rise to platelets in vitro...
October 11, 2016: Cell Reports
Yoann Duffier, Audrey Lorthiois, Pau Cisteró, Florian Dupuy, Grégory Jouvion, Laurence Fiette, Dominique Mazier, Alfredo Mayor, Catherine Lavazec, Alicia Moreno Sabater
The development of new drugs to disrupt malaria transmission requires the establishment of an in vivo model to address the biology of Plasmodium falciparum sexual stages (gametocytes). Herein we show that chemically immune-modulated NSG mice grafted with human erythrocytes support complete sexual development of P. falciparum parasites and generate high gametocytemia. Immunohistochemistry and RT-qPCR analyses indicate an enrichment of immature gametocytes in the bone marrow and the spleen, suggesting a sequestration mechanism reminiscent to that observed in humans...
October 12, 2016: Scientific Reports
Kae Sian Tay, Anupreet Bassi, William Yeo, Wai Mun Yue
BACKGROUND CONTEXT: There is no current literature comparing outcomes of patients with and without lumbar scoliosis having neurological symptoms undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion (MIS TLIF) technique. PURPOSE: To determine whether associated lumbar scoliosis will result in different clinical, radiological and operative outcomes in patients undergoing focal MISTLIF for neurogenic symptoms, without specific correction of the scoliosis...
October 7, 2016: Spine Journal: Official Journal of the North American Spine Society
Diamanda Rigas, Gavin Lewis, Jennifer L Aron, Bowen Wang, Homayon Banie, Ishwarya Sankaranarayanan, Lauriane Galle-Treger, Hadi Maazi, Richard Lo, Gordon J Freeman, Arlene H Sharpe, Pejman Soroosh, Omid Akbari
BACKGROUND: Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function...
October 4, 2016: Journal of Allergy and Clinical Immunology
James F Powers, Karel Pacak, Arthur S Tischler
A major impediment to the development of effective treatments for metastatic or unresectable pheochromocytomas and paragangliomas has been the absence of valid models for pre-clinical testing. Attempts to establish cell lines or xenografts from human pheochromocytomas and paragangliomas have previously been unsuccessful. NOD-scid gamma (NSG) mice are a recently developed strain lacking functional B-cells, T-cells, and NK cells. We report here that xenografts of primary human paragangliomas will take in NSG mice while maintaining their architectural and immunophenotypic characteristics as expressed in the patients...
October 6, 2016: Endocrine Pathology
Bradley J Monk, Andrea Facciabene, William E Brady, Carol Aghajanian, Paula M Fracasso, Joan Walker, Heather A Lankes, Kristi L Manjarrez, Gwenn Danet-Desnoyers, Katherine M Bell-McGuinn, Carolyn K McCourt, Alexander Malykhin, Robert M Hershberg, George Coukos
BACKGROUND: Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod-a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice-with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. METHODS: We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice reconstituted with human CD34+ cells, and cancer patients to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer...
October 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
C Levy, F Fusil, F Amirache, C Costa, A Girard, D Negre, O Bernadin, G Garaulet, A Rodriguez, N Nair, T Vandendriessche, M Chuah, F-L Cosset, E Verhoeyen
BACKGROUND: B cells are attractive targets for gene therapy of diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen presenting cells. OBJECTIVE: Evaluation of human B cells for secretion of clotting factors such as factor IX (IX) as possible treatment for hemophilia. METHODS: We tested here for the first time our newly developed baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) for human (h) B-cell transduction followed their adaptive transfer into NSG mouse...
September 29, 2016: Journal of Thrombosis and Haemostasis: JTH
Dilini C Gunasekara, Mary M Zheng, Tara Mojtahed, James R Woods, Tamer E Fandy, Mark V Riofski, Carlotta A Glackin, Hazem E Hassan, Julia Kirshner, David A Colby
Recent studies suggest that leukemia stem cells (LSCs) play a critical role in the initiation, propagation, and relapse of leukemia. Herein we show that (-)-15-methylene-eburnamonine, a derivative of the alkaloid (-)-eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also decreases primary LSC frequency in vitro. The cytotoxic effects appear to be mediated via the oxidative stress pathways. Furthermore, we show that the compound kills AML, ALL, and CLL stem cells...
September 28, 2016: ChemMedChem
Curtis A Clark, Harshita Gupta, Gangadhara R Sareddy, Srilakshmi Pandeswara, Shunhua Lao, Bin Yuan, Justin M Drerup, Alvaro Padron, Jose R Conejo-Garcia, Kruthi Murthy, Yang Liu, Mary Jo Turk, Kathrin Thedieck, Vincent Hurez, Rong Li, Ratna K Vadlamudi, Tyler J Curiel
PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in understanding of how to rationally leverage the therapeutic activity. PD-L1 is widely expressed in tumor cells but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1...
September 26, 2016: Cancer Research
Andrew Baird, Chenliang Deng, Matthew H Eliceiri, Fatima Haghi, Xitong Dang, Raul Coimbra, Todd W Costantini, Bruce E Torbett, Brian P Eliceiri
Mice engrafted with human CD34(+) hematopoietic stem and progenitor cells (CD34(+) -HSPCs) have been used to study human infection, diabetes, sepsis, and burn, suggesting that they could be highly amenable to characterizing the human inflammatory response to injury. To this end, human leukocytes infiltrating subcutaneous implants of polyvinyl alcohol (PVA) sponges were analyzed in immunodeficient NSG mice reconstituted with CD34(+) -HSPCs. It was reported that human CD45(+) (hCD45(+) ) leukocytes were present in PVA sponges 3 and 7 days postimplantation and could be localized within the sponges by immunohistochemistry...
September 24, 2016: Wound Repair and Regeneration
Madhavi Puchalapalli, Xianke Zeng, Liang Mu, Aubree Anderson, Laura Hix Glickman, Ming Zhang, Megan R Sayyad, Sierra Mosticone Wangensteen, Charles V Clevenger, Jennifer E Koblinski
Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice...
2016: PloS One
Wei-Wei Deng, Lei Wu, Lin-Lin Bu, Jian-Feng Liu, Yi-Cun Li, Si-Rui Ma, Guang-Tao Yu, Liang Mao, Wen-Feng Zhang, Zhi-Jun Sun
P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2...
2016: American Journal of Translational Research
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