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https://www.readbyqxmd.com/read/28231431/enhancing-adoptive-cell-therapy-of-cancer-through-targeted-delivery-of-small-molecule-immunomodulators-to-internalizing-or-non-internalizing-receptors
#1
Yiran Zheng, Li Tang, Llian Mabardi, Sudha Kumari, Darrell J Irvine
Adoptive cell therapy (ACT) has achieved striking efficacy in B-cell leukemias, but less success treating other cancers, in part due to the rapid loss of ACT T-cell effector function in vivo due to immunosuppression in solid tumors. Transforming growth factor-β (TGF-β) signaling is an important mechanism of immune suppression in the tumor microenvironment, but systemic inhibition of TGF-β is toxic. Here we evaluated the potential of targeting a small molecule inhibitor of TGF-β to ACT T-cells using PEGylated immunoliposomes...
February 23, 2017: ACS Nano
https://www.readbyqxmd.com/read/28231426/engineering-of-anti-cd133-tri-specific-molecule-capable-of-inducing-nk-expansion-and-driving-antibody-dependent-cell-mediated-cytotoxicity-adcc
#2
Jörg U Schmohl, Martin Felices, Felix Oh, Alexander J Lenvik, Aaron M Lebeau, Jayanth Panyam, Jeffrey S Miller, Daniel A Vallera
Purpose: The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 BiKE, consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified IL-15 crosslinker capable of stimulating NK effector cells was introduced. Materials and Methods: DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE)...
February 20, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/28231321/argonaute10-promotes-the-degradation-of-mir165-6-through-the-sdn1-and-sdn2-exonucleases-in-arabidopsis
#3
Yu Yu, Lijuan Ji, Brandon H Le, Jixian Zhai, Jiayi Chen, Elizabeth Luscher, Lei Gao, Chunyan Liu, Xiaofeng Cao, Beixin Mo, Jinbiao Ma, Blake C Meyers, Xuemei Chen
The degradation of small RNAs in plants and animals is associated with small RNA 3' truncation and 3' uridylation and thus relies on exonucleases and nucleotidyl transferases. ARGONAUTE (AGO) proteins associate with small RNAs in vivo and are essential for not only the activities but also the stability of small RNAs. AGO1 is the microRNA (miRNA) effector in Arabidopsis, and its closest homolog, AGO10, maintains stem cell homeostasis in meristems by sequestration of miR165/6, a conserved miRNA acting through AGO1...
February 2017: PLoS Biology
https://www.readbyqxmd.com/read/28231312/analysis-of-the-t-cell-response-to-zika-virus-and-identification-of-a-novel-cd8-t-cell-epitope-in-immunocompetent-mice
#4
Ryan D Pardy, Maaran M Rajah, Stephanie A Condotta, Nathan G Taylor, Selena M Sagan, Martin J Richer
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28231307/differential-regulation-of-c5a-receptor-1-in-innate-immune-cells-during-the-allergic-asthma-effector-phase
#5
Fanny Ender, Anna V Wiese, Inken Schmudde, Jing Sun, Tillman Vollbrandt, Peter König, Yves Laumonnier, Jörg Köhl
C5a drives airway constriction and inflammation during the effector phase of allergic asthma, mainly through the activation of C5a receptor 1 (C5aR1). Yet, C5aR1 expression on myeloid and lymphoid cells during the allergic effector phase is ill-defined. Recently, we generated and characterized a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we used this reporter strain to monitor C5aR1 expression in airway, pulmonary and lymph node cells during the effector phase of OVA-driven allergic asthma...
2017: PloS One
https://www.readbyqxmd.com/read/28230866/oridonin-induces-autophagy-via-inhibition-of-glucose-metabolism-in-p53-mutated-colorectal-cancer-cells
#6
Zhuo Yao, Fuhua Xie, Min Li, Zirui Liang, Wenli Xu, Jianhua Yang, Chang Liu, Hongwangwang Li, Hui Zhou, Liang-Hu Qu
The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28230655/lessons-learned-from-human-hiv-vaccine-trials
#7
Justin Pollara, David Easterhoff, Genevieve G Fouda
PURPOSE OF REVIEW: The ability to induce broadly neutralizing antibody (bNAb) responses is likely essential for development of a globally effective HIV vaccine. Unfortunately, human vaccine trials conducted to date have failed to elicit broad plasma neutralization of primary virus isolates. Despite this limitation, in-depth analysis of the vaccine-induced memory B-cell repertoire can provide valuable insights into the presence and function of subdominant B-cell responses, and identify initiation of antibody lineages that may be on a path towards development of neutralization breadth...
February 21, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28230186/glycan-independent-binding-and-internalization-of-human-igm-to-fcmr-its-cognate-cellular-receptor
#8
Katy A Lloyd, Jiabin Wang, Britta C Urban, Daniel M Czajkowsky, Richard J Pleass
IgM is the first antibody to be produced in immune responses and plays an important role in the neutralization of bacteria and viruses. Human IgM is heavily glycosylated, featuring five N-linked glycan sites on the μ chain and one on the J-chain. Glycosylation of IgG is known to modulate the effector functions of Fcγ receptors. In contrast, little is known about the effect of glycosylation on IgM binding to the human Fcμ receptor (hFCMR). In this study, we identify the Cμ4 domain of IgM as the target of hFCMR, and show that binding and internalization of IgM by hFCMR is glycan-independent...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28229904/regulation-of-g-protein-coupled-receptor-signalling-underpinning-neurobiology-of-mood-disorders-and-depression
#9
Dimitris K Grammatopoulos
G-protein coupled receptors (GPCRs) have long been at the centre of investigations of the neurobiology of depression and mood disorders. Different facets of GPCR signalling pathways, including those controlling monoaminergic and neuropeptidergic hormonal systems are believed to be dysregulated in major depressive and bipolar disorders. Although these receptors are key molecular targets for a variety of therapeutic agents and continue to be the focus of intense pharmaceutical development, the molecular mechanisms activated by these GPCRs and underpin the pathological basis of mood disorders remain poorly understood...
February 13, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28229902/impact-of-high-glucose-and-ages-on-cultured-kidney-derived-cells-effects-on-cell-viability-lysosomal-enzymes-and-effectors-of-cell-signaling-pathways
#10
Giovani B Peres, Nestor Schor, Yara M Michelacci
We have previously reported decreased expression and activities of lysosomal cathepsins B and L in diabetic kidney. Relevant morphological changes were observed in proximal tubules, suggesting that these cells are implicated in the early stages of the disease. The aim of the present study was to investigate the mechanisms that lead to these changes. The effects of high glucose (HG) and advanced glycation end products (AGEs) on cell viability, lysosomal enzymes and other effectors of cell signaling of cultured kidney cells were studied...
February 13, 2017: Biochimie
https://www.readbyqxmd.com/read/28229330/the-involvement-of-the-myelin-associated-inhibitors-and-their-receptors-in-cns-plasticity-and-injury
#11
REVIEW
Anthony G Boghdadi, Leon Teo, James A Bourne
The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair...
February 22, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28229217/foxo3-estrogen-receptor-alpha-and-androgen-receptor-impact-tumor-growth-rate-and-infiltration-of-dendritic-cell-subsets-differentially-between-male-and-female-mice
#12
Matthew G Thompson, Daniel S Peiffer, Michelle Larson, Flor Navarro, Stephanie K Watkins
Tumors evade immune recognition and destruction in many ways including the creation of an immune-suppressive tumor microenvironment (TME). Dendritic cells (DC) that infiltrate the TME are tolerogenic, and suppress effector T cells and anti-tumor activity. Previous reports demonstrated that a key regulator of tolerance in DC is the transcription factor FOXO3. Gender disparity has been studied in cancer in relation to incidence, aggressiveness, and prognosis. Few studies have touched on the importance in relation to impact on the immune system...
February 22, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28229086/rb-an-essential-player-in-adult-neurogenesis
#13
Bensun C Fong, Ruth S Slack
The fundamental mechanisms underlying adult neurogenesis remain to be fully clarified. Members of the cell cycle machinery have demonstrated key roles in regulating adult neural stem cell (NSC) quiescence and the size of the adult-born neuronal population. The retinoblastoma protein, Rb, is known to possess CNS-specific requirements that are independent from its classical role as a tumor suppressor. The recent study by Vandenbosch et al. has clarified distinct requirements for Rb during adult neurogenesis, in the restriction of proliferation, as well as long-term adult-born neuronal survival...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28229085/folate-receptor-alpha-is-more-than-just-a-folate-transporter
#14
Vineet Mohanty, M Rizwan Siddiqui, Tadanori Tomita, Chandra Shekhar Mayanil
Until recently folate receptor alpha (FRα) has only been considered as a folate transporter. However, a novel role of FRα as a transcription factor was reported by our lab. More recently our lab showed a novel pleiotropic role of FRα: (a) direct transcriptional activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules. These observations beg a question: "Can a simple molecule such as folate be used to manipulate the production and/or differentiation of endogenous neural stem cells (NSCs), which may hold promise for future therapies?" Conditions such as spinal cord injury, motor neuron diseases, Alzheimer's disease and multiple sclerosis may benefit from increasing stem cell pool and promoting specific pathways of differentiation...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28228759/interleukin-35-producing-cd8%C3%AE-dendritic-cells-acquire-a-tolerogenic-state-and-regulate-t-cell-function
#15
Sergio Haller, Anaïs Duval, Romain Migliorini, Mathias Stevanin, Vanessa Mack, Hans Acha-Orbea
Dendritic cells (DCs) play a central role in shaping immunogenic as well as tolerogenic adaptive immune responses and thereby dictate the outcome of adaptive immunity. Here, we report the generation of a CD8α(+) DC line constitutively secreting the tolerogenic cytokine interleukin (IL)-35. IL-35 secretion led to impaired CD4(+) and CD8(+) T lymphocyte proliferation and interfered with their function in vitro and also in vivo. IL-35 was furthermore found to induce a tolerogenic phenotype on CD8α(+) DCs, characterized by the upregulation of CD11b, downregulation of MHC class II, a reduced costimulatory potential as well as production of the immunomodulatory molecule IL-10...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28228643/a-chemical-probe-toolbox-for-dissecting-the-cancer-epigenome
#16
REVIEW
Jake Shortt, Christopher J Ott, Ricky W Johnstone, James E Bradner
Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients...
February 23, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28228556/activation-and-functional-specialization-of-regulatory-t-cells-lead-to-the-generation-of-foxp3-instability
#17
Zhongmei Zhang, Wei Zhang, Jie Guo, Qianchong Gu, Xueping Zhu, Xuyu Zhou
Accumulating evidence suggests that Foxp3(+) cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprogrammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3(+) cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage...
February 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28228281/dysregulation-of-the-cytokine-gm-csf-induces-spontaneous-phagocyte-invasion-and-immunopathology-in-the-central-nervous-system
#18
Sabine Spath, Juliana Komuczki, Mario Hermann, Pawel Pelczar, Florian Mair, Bettina Schreiner, Burkhard Becher
Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits...
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28228257/t-regulatory-cells-support-plasma-cell-populations-in-the-bone-marrow
#19
Arielle Glatman Zaretsky, Christoph Konradt, Fabien Dépis, James B Wing, Radhika Goenka, Daniela Gomez Atria, Jonathan S Silver, Sunglim Cho, Amaya I Wolf, William J Quinn, Julie B Engiles, Dorothy C Brown, Daniel Beiting, Jan Erikson, David Allman, Michael P Cancro, Shimon Sakaguchi, Li-Fan Lu, Christophe O Benoist, Christopher A Hunter
Long-lived plasma cells (PCs) in the bone marrow (BM) are a critical source of antibodies after infection or vaccination, but questions remain about the factors that control PCs. We found that systemic infection alters the BM, greatly reducing PCs and regulatory T (Treg) cells, a population that contributes to immune privilege in the BM. The use of intravital imaging revealed that BM Treg cells display a distinct behavior characterized by sustained co-localization with PCs and CD11c-YFP(+) cells. Gene expression profiling indicated that BM Treg cells express high levels of Treg effector molecules, and CTLA-4 deletion in these cells resulted in elevated PCs...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28227997/an-autoclavable-wireless-palpation-instrument-for-minimally-invasive-surgery
#20
Anish S Naidu, Abelardo Escoto, Omar Fahmy, Rajni V Patel, Michael D Naish, Anish S Naidu, Abelardo Escoto, Omar Fahmy, Rajni V Patel, Michael D Naish, Abelardo Escoto, Omar Fahmy, Michael D Naish, Anish S Naidu, Rajni V Patel
Minimally invasive surgery prevents surgeons from manually palpating organs to locate subsurface tumors and other structures. One solution is to use ultrasound; however, it is not always reliable. Various minimally invasive surgery instruments that provide tactile feedback have been proposed to augment ultrasound sensing for tumor localization; however, current designs have limitations such as cumbersome wiring, difficulty in manipulation, lack of sterilizability and high cost. This paper presents a novel, autoclavable, wireless, hand-held palpation instrument that uses a custom, low-cost, disposable tactile sensor to provide tactile and kinesthetic force feedback...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
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