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Dawid Walas, Karol Nowicki-Osuch, Dominic Alibhai, Julian Paton
OBJECTIVE: Cerebrovascular remodeling in the SHR may be causative to the known brainstem hypoperfusion. Using RNA sequencing, we examined age-related processes that may govern remodeling of the cerebral arteries in the SHR. DESIGN AND METHOD: In SHR and their progenitor (normotensive) control (Wistar Kyoto, WKY), RNA-seq was performed at three ages: 5, 9, 13 weeks old. Cerebral arteries were flushed and peeled off the brain, stripped of meninges, snap frozen and RNA extracted...
September 2016: Journal of Hypertension
Joshua C Pritchett, Jaime S Green, Angela M Thomm, Konstance K Knox, Michael R Verneris, Troy C Lund
Human herpesvirus-6B (HHV-6B) commonly reactivates after umbilical cord blood transplant (UCBT) and is associated with delayed engraftment, fever, rash, and CNS dysfunction. Recently CD134 (OX40) has been implicated as a potential viral entry receptor. We evaluated CD4(+)CD134(+)/(neg-lo) and CD8(+) CD134(+)/(neg-lo) cells at day +28 after UCBT in 20 subjects with previously documented HHV-6 reactivation and persistent viremia. Analysis of CD4(+)CD134(+) cells compared to CD4(+)CD134(neg-lo) cells showed 0...
October 4, 2016: Journal of Infectious Diseases
Dawid Walas, Karol Nowicki-Osuch, Dominic Alibhai, Julian Paton
OBJECTIVE: Cerebrovascular remodeling in the SHR may be causative to the known brainstem hypoperfusion. Using RNA sequencing, we examined age-related processes that may govern remodeling of the cerebral arteries in the SHR. DESIGN AND METHOD: In SHR and their progenitor (normotensive) control (Wistar Kyoto, WKY), RNA-seq was performed at three ages: 5, 9, 13 weeks old. Cerebral arteries were flushed and peeled off the brain, stripped of meninges, snap frozen and RNA extracted...
September 2016: Journal of Hypertension
Eleonora Timperi, Ilenia Pacella, Valeria Schinzari, Chiara Focaccetti, Luca Sacco, Francesco Farelli, Roberto Caronna, Gabriella Del Bene, Flavia Longo, Antonio Ciardi, Sergio Morelli, Anna Rita Vestri, Piero Chirletti, Vincenzo Barnaba, Silvia Piconese
Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor...
July 2016: Oncoimmunology
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
Vedran Brezar, Véronique Godot, Liang Cheng, Lishan Su, Yves Lévy, Nabila Seddiki
Efficient vaccines are characterized by the establishment of long-lived memory T cells, including T-helper (effectors and follicular) and T-regulatory cells (Tregs). While the former induces cytotoxic or antibody responses, the latter regulates immune responses by maintaining homeostasis. The role of Tregs in inflammatory conditions is ambiguous and their systematic monitoring in vaccination along with effector T-cells is not instinctive. Recent studies from the cancer field clearly showed that Tregs suppress vaccine-induced immune responses and correlate with poor clinical benefit...
September 5, 2016: Vaccines
Elena Lo Presti, Nadia Caccamo, Valentina Orlando, Francesco Dieli, Serena Meraviglia
Vγ9Vδ2 T cells and plasmacytoid dendritic cells (pDCs) are two distinct cell types of innate immunity that participate in early phases of immune response. We investigated whether a close functional relationship exists between these two cell populations using an in vitro co-culture in a human system.pDCs that had been activated by IL-3 and the TLR9 ligand CpG induced substantial activation of Vγ9Vδ2 T cells upon co-culture, which was cell-to-cell contact dependent, as demonstrated in transwell experiments, but that did not involve any of the costimulatory molecules potentially expressed by pDCs or Vγ9V2 T cells, such as ICOS-L, OX40 and CD40L...
August 31, 2016: Oncotarget
Qing-Qing Wu, Yuan Yuan, Xiao-Han Jiang, Yang Xiao, Zheng Yang, Zhen-Guo Ma, Hai-Han Liao, Yuan Liu, Wei Chang, Zhou-Yan Bian, Qi-Zhu Tang
OX40, which belongs to the tumour necrosis factor (TNF)-receptor family, is a costimulatory receptor that can potentiate T-cell receptor signalling on the surface of T-lymphocytes. The role of OX40 in non-immune systems, particularly the cardiovascular system, has not been defined. In the present study, we observed a noticeable increase in OX40 expression during cardiac remodelling in rodent heart. In the present study, cardiac hypertrophy was induced by aortic banding (AB) in OX40 knockout (KO) mice and wild-type (WT) mice...
November 1, 2016: Clinical Science (1979-)
Adrienne H Long, Steven L Highfill, Yongzhi Cui, Jillian P Smith, Alec J Walker, Sneha Ramakrishna, Rana El-Etriby, Susana Galli, Maria G Tsokos, Rimas J Orentas, Crystal L Mackall
Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2...
October 2016: Cancer Immunology Research
Hans Hammers
PURPOSE OF REVIEW: Kidney cancer, in particular clear cell renal cell carcinoma (ccRCC) has long been considered to be sensitive to immunotherapies. With the recent breakthroughs in immunotherapy for solid tumors and the recent approval of the first immune checkpoint inhibitor for ccRCC, we are reviewing the history of immunotherapy in kidney cancer, describing its current state and look into the future of a rapidly evolving landscape in immunotherapy for kidney cancer. RECENT FINDINGS: Systemic treatment options over the past decade have been dominated by targeted therapies inhibiting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways...
November 2016: Current Opinion in Urology
Amy E Moran, Fanny Polesso, Andrew D Weinberg
Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Maria-Luisa Schubert, Angela Gabriele Hückelhoven, Jean-Marc Hoffmann, Anita Schmitt, Patrick Wuchter, Leopold Sellner, Susanne Hofmann, Anthony D Ho, Peter Dreger, Michael Schmitt
Novel therapies with chimeric antigen receptor (CAR) transduced T cells (TCs) sparked new hope for patients with relapsed or refractory CD19-positive leukemia or lymphoma even after stem cell therapies. This review focuses on CARs recognizing the B cell antigen CD19. Both retro- and lentiviral vectors are used encoding the different anti-CD19 CAR constructs comprising costimulatory molecules like CD28, CD137/4-1BB and OX40 either alone (2nd generation CARs) or in combination (3rd generation CARs). Current up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 59 ongoing trials is given...
August 1, 2016: Human Gene Therapy
William L Redmond, Stefanie N Linch
Numerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy. Furthermore, dual CTLA-4/PD-1 checkpoint blockade recently received FDA-approval for patients with metastatic melanoma, becoming the first combination immunotherapy to garner this designation in a rapidly evolving field. Despite this progress, the majority of patients do not respond to treatment, underscoring the critical need for more effective therapies...
July 26, 2016: Human Vaccines & Immunotherapeutics
Marie Kunihiro, Hideki Fujii, Takuya Miyagi, Yoshiaki Takahashi, Reiko Tanaka, Takuya Fukushima, Aftab A Ansari, Yuetsu Tanaka
The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS...
2016: Viruses
Claudia Curci, Fabio Sallustio, Grazia Serino, Giuseppe De Palma, Mirko Trpevski, Marco Fiorentino, Michele Rossini, Marco Quaglia, Marialuisa Valente, Lucrezia Furian, Alessia Toscano, Gianna Mazzucco, Antonella Barreca, Stefania Bussolino, Loreto Gesualdo, Piero Stratta, Paolo Rigotti, Franco Citterio, Luigi Biancone, Francesco P Schena
BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR...
July 1, 2016: Nephrology, Dialysis, Transplantation
George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H Schreiber
T-cell costimulation typically occurs in a defined microenvironment that is not recapitulated by agonistic antibody therapy. To deliver such stimulation under more favorable conditions, we investigated whether an allogeneic cell-based vaccine that secreted Fc-OX40L, Fc-ICOSL, or Fc-4-1BBL would activate and expand T cells comparably with systemically administered agonist antibodies. Among these costimulators, locally secreted Fc-OX40L provided superior priming of antigen-specific CD8(+) T cells, compared with combinations with OX40 antibodies or vaccine alone...
September 2, 2016: Cancer Immunology Research
Jaw-Ji Tsai, Hsin-Chieh Wang, Chih-Liang Chiu, En-Chih Liao
The innate signaling pathway for Th2 immunity activated by inhaled allergens has not been well defined. Dendritic cells (DCs) can use their innate pattern-recognition Toll-like receptors and C-type lectin receptors to generate innate immunity and influence adaptive responses. The aim of this study was to investigate the glycoform of Dermatophagoides pteronyssinus group 7 allergen (Der p 7) and its functional interaction with dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)...
November 2016: Immunobiology
Hai-Mei Zhao, Rong Xu, Xiao-Ying Huang, Shao-Min Cheng, Min-Fang Huang, Hai-Yang Yue, Xin Wang, Yong Zou, Ai-Ping Lu, Duan-Yong Liu
AIM: To explore the probable pathway by which curcumin (Cur) regulates the function of Treg cells by observing the expression of costimulatory molecules of dendritic cells (DCs). METHODS: Experimental colitis was induced by administering 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Forty male C57BL/6 mice were randomly divided into four groups: normal, TNBS + Cur, TNBS + mesalazine (Mes) and TNBS groups. The mice in the TNBS + Cur and TNBS +Mes groups were treated with Cur and Mes, respectively, while those in the TNBS group were treated with physiological saline for 7 d...
June 21, 2016: World Journal of Gastroenterology: WJG
Colin Havenar-Daughton, Samantha M Reiss, Diane G Carnathan, Jennifer E Wu, Kayla Kendric, Alba Torrents de la Peña, Sudhir Pai Kasturi, Jennifer M Dan, Marcella Bothwell, Rogier W Sanders, Bali Pulendran, Guido Silvestri, Shane Crotty
A range of current candidate AIDS vaccine regimens are focused on generating protective HIV-neutralizing Ab responses. Many of these efforts rely on the rhesus macaque animal model. Understanding how protective Ab responses develop and how to increase their efficacy are both major knowledge gaps. Germinal centers (GCs) are the engines of Ab affinity maturation. GC T follicular helper (Tfh) CD4 T cells are required for GCs. Studying vaccine-specific GC Tfh cells after protein immunizations has been challenging, as Ag-specific GC Tfh cells are difficult to identify by conventional intracellular cytokine staining...
August 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Stefanie N Linch, William L Redmond
Mounting an immune response sufficient to eradicate a tumor is the goal of modern immunotherapy. Single agent therapies with checkpoint inhibitors or costimulatory molecule agonists are effective only for a small portion of all treated patients. Combined therapy, e.g., CTLA-4 and PD-1 checkpoint blockade, is a more effective treatment modality, but in preclinical studies OX40 agonism with CTLA-4 blockade using monoclonal antibodies (aOX40/aCTLA-4) failed to induce tumor regression of larger, more established tumors...
2016: Journal for Immunotherapy of Cancer
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