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Jian-Fei Tu, Ya-Hui Ding, Xi-Hui Ying, Fa-Zong Wu, Xin-Mu Zhou, Deng-Ke Zhang, Hai Zou, Jian-Song Ji
Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3(+), CD4(+), and CD8(+) cytotoxic lymphocytes (CTLs) as well as CD56(+) NK cells and CD68(+) macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3(+) (FOXP3(+)) Tregs were found in intratumoural tissue...
October 11, 2016: Scientific Reports
Gene Kurosawa, Mariko Kondo, Yoshikazu Kurosawa
When the technology for constructing human antibody (Ab) libraries using a phage-display system was developed, many researchers in Ab-related fields anticipated that it would be widely applied to the development of pharmaceutical drugs against various diseases, including cancers. However, successful examples of such applications are very limited. Moreover, researchers who utilize phage-display technology now show divergent ways of thinking about phage Ab libraries. For example, there is debate about what should be the source of VH and VL genes for the construction of libraries to cover the whole repertoire of Abs present in the human body...
October 5, 2016: Biochemical and Biophysical Research Communications
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
Daniel Sevilla-Sanchez, Núria Molist-Brunet, Jordi Amblàs-Novellas, Pere Roura-Poch, Joan Espaulella-Panicot, Carles Codina-Jané
PURPOSE: Adverse drug events (ADEs) lead to adverse clinical outcomes such as hospitalization. There is little information about the characteristics of ADEs in patients with advanced chronic conditions and have a prognosis of limited life expectancy. This study aimed to evaluate (i) the prevalence of ADEs at the time of admission to hospital, (ii) the causality, severity, and preventability of the ADEs, and (iii) the clinical and pharmacological characteristics associated with the ADEs...
October 4, 2016: European Journal of Clinical Pharmacology
Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
Julien Leconte, Sahar Bagherzadeh Yazdchi, Vincent Panneton, Woong-Kyung Suh
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses...
September 29, 2016: Molecular Immunology
Anna Malgorzata White, David C Wraith
The immune system evolved to respond to foreign invaders and prevent autoimmunity to self-antigens. Several types of regulatory T cells facilitate the latter process. These include a subset of Foxp3(-) CD4(+) T cells able to secrete IL-10 in an antigen-specific manner, type 1 regulatory (Tr1) T cells. Although their suppressive function has been confirmed both in vitro and in vivo, their phenotype remains poorly defined. It has been suggested that the surface markers LAG-3 and CD49b are biomarkers for murine and human Tr1 cells...
2016: Frontiers in Immunology
XiaoMei Zhuang, TianHong Zhang, SiJia Yue, Juan Wang, Huan Luo, YunXia Zhang, Zheng Li, JinJing Che, HaiYing Yang, Hua Li, MingShe Zhu, Chuang Lu
Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4...
September 22, 2016: Biochemical Pharmacology
Florian Kälble, Charlotte Mai, Miriam Wagner, Linda Schober, Matthias Schaier, Martin Zeier, Julia Spratte, Herbert Fluhr, Andrea Steinborn
PROBLEM: Recent studies revealed appropriate differentiation of recent thymic emigrant (RTE)-regulatory T cells (Tregs) to be crucial for maintaining healthy pregnancy. Currently, the role of responder T cells (Tresps) is not known. METHOD OF STUDY: Six-color flow cytometric analysis was used to detect differences in the differentiation of highly proliferative inducible co-stimulatory (ICOS)(+) -RTE-Tregs/Tresps and apoptosis-sensitive ICOS(-) -RTE-Tregs/Tresps into mature naïve (MN)-, CD31(+) -memory and CD31(-) -memory Tregs/Tresps in women with spontaneous preterm labor (sPL) compared to healthy pregnancy...
November 2016: American Journal of Reproductive Immunology: AJRI
Chad Tang, James W Welsh, Patricia de Groot, Erminia Massarelli, Joe Y Chang, Kenneth R Hess, Sreyashi Basu, Michael A Curran, Maria E Cabanillas, Vivek Subbiah, Siqing Fu, Apostolia M Tsimberidou, Daniel Karp, Daniel R Gomez, Adi Diab, Ritsuko Komaki, Padmanee Sharma, Aung Naing, David S Hong
PURPOSE: Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab. EXPERIMENTAL DESIGN: SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
J Amblàs-Novellas, S A Murray, J Espaulella, J C Martori, R Oller, M Martinez-Muñoz, N Molist, C Blay, X Gómez-Batiste
OBJECTIVES: 2 innovative concepts have lately been developed to radically improve the care of patients with advanced chronic conditions (PACC): early identification of palliative care (PC) needs and the 3 end-of-life trajectories in chronic illnesses (acute, intermittent and gradual dwindling). It is not clear (1) what indicators work best for this early identification and (2) if specific clinical indicators exist for each of these trajectories. The objectives of this study are to explore these 2 issues...
September 19, 2016: BMJ Open
Edyta Pawlak-Adamska, Irena Frydecka, Marek Bolanowski, Anna Tomkiewicz, Anna Jonkisz, Lidia Karabon, Anna Partyka, Oskar Nowak, Marek Szalinski, Jacek Daroszewski
Graves' disease, an autoimmune disease with heterogeneous symptoms including Graves' orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves' disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves' disease patients...
September 16, 2016: Endocrine
Hu Zeng, Sivan Cohen, Cliff Guy, Sharad Shrestha, Geoffrey Neale, Scott A Brown, Caryn Cloer, Rigel J Kishton, Xia Gao, Ben Youngblood, Mytrang Do, Ming O Li, Jason W Locasale, Jeffrey C Rathmell, Hongbo Chi
Follicular helper T (Tfh) cells are crucial for germinal center (GC) formation and humoral adaptive immunity. Mechanisms underlying Tfh cell differentiation in peripheral and mucosal lymphoid organs are incompletely understood. We report here that mTOR kinase complexes 1 and 2 (mTORC1 and mTORC2) are essential for Tfh cell differentiation and GC reaction under steady state and after antigen immunization and viral infection. Loss of mTORC1 and mTORC2 in T cells exerted distinct effects on Tfh cell signature gene expression, whereas increased mTOR activity promoted Tfh responses...
September 20, 2016: Immunity
Chao Wang, Qingfa Liu, Fangfang Chen, Wenjuan Xu, Caiqing Zhang, Wei Xiao
BACKGROUND: Interleukin-25 (IL-25) is a potent activator of type-2 immune responses, and is responsible for airway inflammation in asthma. Previous reports have shown that IL-25 expressed hyper-reactivity in an experimental mouse-model of asthma. In addition, the production of IL-13/IL-5 promoted by nuocytes induced airway inflammation. Thus, it has been questioned whether blocking IL-25 against its receptor IL-17BR could inhibit the expression of IL-13 and IL-5 via nuocytes, and further protect against inflammation in ovalbumin (OVA) induced mouse-model of asthma...
2016: PloS One
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
Hideki Ueno
Studies with mouse models have established the pathogenic roles of T follicular helper (Tfh) cells in antibody-mediated autoimmune diseases. In contrast, evidence in human autoimmune pathogenesis has been lacking for years. Recent progress in understanding on the biology of human Tfh cells and on the approaches assessing their response has enabled gaining insights into the alterations of Tfh response and the underlying mechanisms. For example, increase of circulating Tfh (cTfh) cells expressing PD-1 and/or ICOS and alterations in the composition of cTfh subsets have emerged as a common feature in a broad range of autoimmune diseases...
August 30, 2016: Current Opinion in Immunology
Tzu-Yu Shao, Ling-Hui Hsu, Chien-Hui Chien, Bor-Luen Chiang
Recent studies have revealed various Foxp3(-) regulatory T (Treg) cell subsets effectively protect mice from colitis. In the present study, we demonstrated that B cells induced a particular subset of regulatory T (Treg-of-B) cells, expressing programmed cell death 1 (PD-1), inducible costimulator (ICOS), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced tumor necrosis factor receptor (GITR), and OX-40, did not express Foxp3. Treg-of-B cells produced abundant levels of IL-10 and low levels of IL-4 and TGF-β...
2016: Scientific Reports
Nizar Saleh Abdelfattah, Ahmed E Radwan, Srinivas R Sadda
PURPOSE: To evaluate the perspective of ophthalmology residents in the US about their residency programs and compare the competency of residency programs to international competency levels set by the International Council of Ophthalmology (ICO). METHODS: A cross-sectional web-based survey extracted from the ICO published competency standards was sent to program directors of ophthalmology residency programs in the US to forward it to current PGY-3, 4 residents, and residency graduates from 2011 to 2014...
September 2016: Journal of Current Ophthalmology
Heather L McArthur, Adi Diab, David B Page, Jianda Yuan, Stephen B Solomon, Virgilio Sacchini, Christopher Comstock, Jeremy C Durack, Majid Maybody, Janice Sung, Arielle Ginsberg, Phillip Wong, Afsar Barlas, Zhiwan Dong, Chunjun Zhao, Brian Blum, Sujata Patil, Deirdre Neville, Elizabeth Comen, Elizabeth A Morris, Alan Kotin, Edi Brogi, Y Hannah Wen, Monica Morrow, Mario E Lacouture, Padmanee Sharma, James P Allision, Clifford A Hudis, Jedd D Wolchok, Larry Norton
PURPOSE: To assess the safety and tolerability of pre-operative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. EXPERIMENTAL DESIGN: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with pre-operative tumor cryoablation (n=7), single-dose ipilimumab at 10mg/kg (n=6), or both (n=6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy...
August 26, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Didem Ozkazanc, Digdem Yoyen-Ermis, Ece Tavukcuoglu, Yahya Buyukasik, Gunes Esendagli
To cope with immune responses, tumor cells implement elaborate strategies such as adaptive resistance and induction of T cell exhaustion. T cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of costimulatory molecules to T cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukemia-derived costimulatory signals on CD4(+) helper T (Th) cell exhaustion which may limit anti-tumor immunity...
August 27, 2016: Immunology
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