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Yuki Kagoya, Shinya Tanaka, Tingxi Guo, Mark Anczurowski, Chung-Hsi Wang, Kayoko Saso, Marcus O Butler, Mark D Minden, Naoto Hirano
The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions...
March 2018: Nature Medicine
Christiana Kyvelidou, Dimitris Sotiriou, Ioanna Zerva, Irene Athanassakis
Lipopolysaccharide (LPS) is commonly used in murine sepsis models, which are largely associated with immunosuppression and collapse of the immune system. After adapting the LPS treatment to the needs of locally bred BALB/c mice, the present study explored the potential role of IgG and IgM in reversing LPS endotoxemia. The established protocol consisted of five daily intraperitoneal injections of 0.2 μg/g LPS, which was tolerable by half of the manipulated animals. Such a protocol allowed longer survival, necessary in the prospect of therapeutic treatment application...
April 2018: Shock
Alec J Walker, Robbie G Majzner, Ling Zhang, Kelsey Wanhainen, Adrienne H Long, Sang M Nguyen, Paola Lopomo, Marc Vigny, Terry J Fry, Rimas J Orentas, Crystal L Mackall
We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Lucía Fernández, Jean-Yves Metais, Adela Escudero, María Vela, Jaime Valentín, Isabel Vallcorba, Alejandra Leivas, Juan Torres, Antonio Valeri, Ana Patiño-García, Joaquín Martínez, Wing Leung, Antonio Pérez-Martínez
Purpose: NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express NKG2D receptors, including natural killer (NK) cells and CD8+ T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK-cell elimination of osteosarcoma tumor-initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma...
October 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jan Budczies, Gunhild Mechtersheimer, Carsten Denkert, Frederick Klauschen, Sadaf S Mughal, Priya Chudasama, Michael Bockmayr, Korinna Jöhrens, Volker Endris, Amelie Lier, Felix Lasitschka, Roland Penzel, Manfred Dietel, Benedikt Brors, Stefan Gröschel, Hanno Glimm, Peter Schirmacher, Marcus Renner, Stefan Fröhling, Albrecht Stenzinger
Soft-tissue sarcomas (STS) are rare malignancies that account for 1% of adult cancers and comprise more than 50 entities. Current therapeutic options for advanced-stage STS are limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 signaling axis are being explored as new treatment modality in STS; however, the determinants of response to these agents are largely unknown. Using the sarcoma data set of The Cancer Genome Altas (TCGA) and an independent cohort of untreated high-grade STS, we analyzed DNA copy number status and mRNA expression of PD-L1 in a total of 335 STS cases...
2017: Oncoimmunology
Kyeong-Man Hong, Hyun-Kyoung Kim, Seong-Yeol Park, Shiv Poojan, Mi-Kyung Kim, Joohon Sung, Betty P Tsao, Jennifer M Grossman, Ornella J Rullo, Jennifer M P Woo, Deborah K McCurdy, Lisa G Rider, Frederick W Miller, Yeong-Wook Song
Objective: The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods: DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks ( CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls...
March 1, 2017: Rheumatology
Hatem Zayed
Type 1 diabetes (T1D) is a complex autoimmune disorder that results from the T cell-mediated destruction of the pancreatic β cells and is due to interactions between environmental and genetic factors. Although Arabs have one of the highest global incidence and prevalence rates of T1D, unfortunately, there is a dearth of information regarding the genetic epidemiology of T1D in the Arab world. Arabs share several HLA haplotypes with other ethnic groups, which confer either susceptibility or protection to T1D, but they have specific haplotypes that are distinctive from other ethnicities...
May 2016: Current Diabetes Reports
George Pentheroudakis, Georgia Raptou, Vassiliki Kotoula, Ralph M Wirtz, Eleni Vrettou, Vasilios Karavasilis, Georgia Gourgioti, Chryssa Gakou, Konstantinos N Syrigos, Evangelos Bournakis, Grigorios Rallis, Ioannis Varthalitis, Eleni Galani, Georgios Lazaridis, George Papaxoinis, Dimitrios Pectasides, Gerasimos Aravantinos, Thomas Makatsoris, Konstantine T Kalogeras, George Fountzilas
BACKGROUND: Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study. PATIENTS AND METHODS: Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa...
2015: PloS One
Zouidi Ferjeni, D Bouzid, H Fourati, M Stayoussef, O Abida, T Kammoun, M Hachicha, C Penha-Gonçalves, H Masmoudi
Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2...
January 2015: Immunology Letters
John K Wiencke, Paige M Bracci, George Hsuang, Shichun Zheng, Helen Hansen, Margaret R Wrensch, Terri Rice, Melissa Eliot, Karl T Kelsey
Quantitating the copy number of demethylated CpG promoter sites of the CD3Z gene can be used to estimate the numbers and proportions of T cells in human blood and tissue. Quantitative methylation specific PCR (qPCR) is useful for studying T cells but requires extensive calibration and is imprecise at low copy numbers. Here we compared the performance of a new digital PCR platform (droplet digital PCR or ddPCR) to qPCR using bisulfite converted DNA from 157 blood specimens obtained from ambulatory care controls and patients with primary glioma...
October 2014: Epigenetics: Official Journal of the DNA Methylation Society
Evripidis Lanitis, Mathilde Poussin, Alex W Klattenhoff, Degang Song, Raphael Sandaltzopoulos, Carl H June, Daniel J Powell
Adoptive immunotherapy using T lymphocytes genetically modified to express a chimeric antigen receptor (CAR-T) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy, whereby T-cell activation signal 1 (CD3z) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity: mesothelin and a-folate receptor (FRa)...
July 2013: Cancer Immunology Research
John K Wiencke, William P Accomando, Shichun Zheng, Joe Patoka, Xiaoqin Dou, Joanna J Phillips, George Hsuang, Brock C Christensen, E Andres Houseman, Devin C Koestler, Paige Bracci, Joseph L Wiemels, Margaret Wrensch, Heather H Nelson, Karl T Kelsey
Immune factors are thought to influence glioma risk and outcomes, but immune profiling studies to further our understanding of the immune response are limited by current immunodiagnostic methods. We developed a new assay to capture glioma immune biology based on quantitative methylation specific PCR (qMSP) of two T-cell genes (CD3Z: T-cells, and FOXP3: Tregs). Flow cytometry of T-cells correlated well with the CD3Z demethylation assay (r = 0.93; p < 2.2 × 10 (-16) ), demonstrating the validity of the assay...
December 1, 2012: Epigenetics: Official Journal of the DNA Methylation Society
Hao-jie Li, Zhen-bin Shen, Yi-hong Sun, Feng-lin Liu, Hong-shan Wang, Wei-dong Chen
OBJECTIVE: To investigate the association of the expressions of Th1 cytokines in gastric cancer tissue and the prognosis of patients with gastric cancer after radical resection. METHODS: Fifty-eight patients with gastric cancer treated at the Zhongshan Hospital of Fudan University were retrospectively analyzed. The expressions of Th1 cytokines mRNA were detected in tumor tissues by real-time polymerase chain reaction(RT-PCR) method in Th1 cells including TRAV10, IRF1, TBX21, CD3Z, GZMB, GATA3, and IFNG...
June 2012: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
Li-Ping Pan, Wei Zhang, Li Zhang, Xiao-Pan Wu, Xi-Lin Zhu, Bing-Yu Yan, Jing-Yun Li, Ai-Qiang Xu, Ying Liu, Hui Li
Vaccination against hepatitis B virus is an effective and routine practice that can prevent infection. However, vaccine-induced immunity to hepatitis B varies among individuals. CD4(+) T helper cells, which play an important role in both cellular and humoral immunity, are involved in the immune response elicited by vaccination. Polymorphisms in the genes involved in stimulating the activation and proliferation of CD4(+) T helper cells may influence the immune response to hepatitis B vaccination. In the first stage of the present study, a total of 111 single nucleotide polymorphisms (SNPs) in 17 genes were analyzed, using the iPLEX MassARRAY system, among 214 high responders and 107 low responders to hepatitis B vaccination...
2012: PloS One
R Li, W Yang, J Zhang, N Hirankarn, H-F Pan, C C Mok, T M Chan, R W S Wong, M Y Mok, K W Lee, S N Wong, A M H Leung, X-P Li, Y Avihingsanon, T L Lee, M H K Ho, P P W Lee, W H S Wong, C-M Wong, I O L Ng, J Yang, P H Li, Y Zhang, L Zhang, W Li, L Baum, P Kwan, P Rianthavorn, T Deekajorndej, K Suphapeetiporn, V Shotelersuk, M-M Garcia-Barceló, S S Cherny, P K-H Tam, P C Sham, C S Lau, N Shen, Y l Lau, D-Q Ye
OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established...
January 2012: Lupus
Grace P Yu, Kari C Nadeau, David R Berk, Geneviève de Saint Basile, Nathalie Lambert, Perrine Knapnougel, Joseph Roberts, Kristina Kavanau, Elizabeth Dunn, E Richard Stiehm, David B Lewis, Dale T Umetsu, Jennifer M Puck, Morton J Cowan
There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional patient with T-B+NK+ SCID was identified as the sibling of a patient treated at UCSF. Chart reviews were performed. Molecular analyses of IL7R, IL2RG, JAK3, and the genes encoding the CD3 T-cell receptor components δ (CD3D), ε (CD3E), and ζ (CD3Z) were carried out...
November 2011: Pediatric Transplantation
Michel Noutsias, Maria Rohde, Katrin Göldner, Andrea Block, Katja Blunert, Lara Hemaidan, Michael Hummel, Jan-Henrik Blohm, Dirk Lassner, Uwe Kühl, Heinz-Peter Schultheiss, Hans-Dieter Volk, Katja Kotsch
AIMS: To quantify and functionally characterize the intramyocardial T-cells in endomyocardial biopsies (EMBs) from patients presenting with acute myocarditis (AMC) and dilated cardiomyopathy (DCM). METHODS AND RESULTS: Expression of genes characterizing Th1 [interferon (IFN)γ, Tbet-1, Eomesodermin, interleukin (IL)-27], Th2 (IL-4, IL-5, GATA3), Th17 (IL-17), regulatory [regulatory T-cells (Treg); FoxP3, TGFβ, IL-10], anergic (GRAIL), and cytotoxic T-cells (CTLs: Perforin, Granulysin, Granzyme A), as well as of functional T-cell receptor Vbeta (TRBV) families were investigated in EMBs from AMC patients (n= 58) and DCM patients (n= 34) by pre-amplified real-time reverse transcription-polymerase chain reaction...
June 2011: European Journal of Heart Failure
Kristi Kerkel, Nicole Schupf, Kota Hatta, Deborah Pang, Martha Salas, Alexander Kratz, Mark Minden, Vundavalli Murty, Warren B Zigman, Richard P Mayeux, Edmund C Jenkins, Ali Torkamani, Nicholas J Schork, Wayne Silverman, B Anne Croy, Benjamin Tycko
The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0...
November 18, 2010: PLoS Genetics
T Warchoł, P Piotrowski, M Lianeri, D Cieślak, M Wudarski, P Hrycaj, J K Lacki, P P Jagodziński
Recently, a family-based association analysis showed that the haplotype carrying a low expression of the variant CD3Z 844 T>A (rs1052231) polymorphism located in the 3'-untranslated region of CD3Z predisposes to systemic lupus erythematosus (SLE) incidence. We analyzed the prevalence of the CD3Z 844 T>A polymorphism in SLE patients (n = 152) and controls (n = 304) in Poland. We observed that women with the CD3Z AA and CD3Z AT genotypes exhibited a 1.845-fold increased risk of SLE [95% confidence intervals (95% CI) = 1...
July 2009: Tissue Antigens
Claire L Gorman, Andrew I Russell, Zhuoli Zhang, Deborah Cunninghame Graham, Andrew P Cope, Timothy J Vyse
TCRzeta (CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCRzeta-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRzeta expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCRzeta protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRzeta expression in healthy individuals...
January 15, 2008: Journal of Immunology: Official Journal of the American Association of Immunologists
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