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https://www.readbyqxmd.com/read/29773754/a-critical-neurodevelopmental-role-for-l-type-voltage-gated-calcium-channels-in-neurite-extension-and-radial-migration
#1
Satoshi Kamijo, Yuichiro Ishii, Shin-Ichiro Horigane, Kanzo Suzuki, Masamichi Ohkura, Junichi Nakai, Hajime Fujii, Sayaka Takemoto-Kimura, Haruhiko Bito
In spite of many association studies linking gene polymorphisms and mutations of L-type Voltage-Gated Ca2+ Channels (VGCC) in neurodevelopmental disorders, such as autism and schizophrenia, specific L-type VGCC roles during brain development remain unclear. Yet, calcium signaling has been shown to be essential for neurodevelopmental processes such as sculpting of neurites, functional wiring and fine tuning of growing networks. To bridge this gap, we performed submembraneous calcium imaging using a membrane-tethered genetically-encoded calcium indicator (GECI) Lck-G-CaMP7...
May 17, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29764444/molecular-and-clinical-characterization-of-ptpn2-expression-from-rna-seq-data-of-996-brain-gliomas
#2
Peng-Fei Wang, Hong-Qing Cai, Chuan-Bao Zhang, Yan-Michael Li, Xiang Liu, Jing-Hai Wan, Tao Jiang, Shou-Wei Li, Chang-Xiang Yan
BACKGROUND: Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling. METHODS: Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas...
May 15, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29752423/strong-homeostatic-tcr-signals-induce-formation-of-self-tolerant-virtual-memory-cd8-t-cells
#3
Ales Drobek, Alena Moudra, Daniel Mueller, Martina Huranova, Veronika Horkova, Michaela Pribikova, Robert Ivanek, Susanne Oberle, Dietmar Zehn, Kathy D McCoy, Peter Draber, Ondrej Stepanek
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells...
May 11, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29748183/aberrant-lck-signal-via-cd28-co-stimulation-augments-antigen-specific-functionality-and-tumor-control-by-redirected-t-cells-with-pd-1-blockade-in-humanized-mice
#4
Pratiksha Gulati, Julia Rühl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna Jozefa Nytko, Martin N Pruschy, Simon Sulser, Mark D Haefner, Shawn M Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Rs Stenger, Roger Stupp, Walter Weder, Christoph Renner, Christian Münz, Ulf Petrausch
PURPOSE: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. EXPERIMENTAL DESIGN: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, Δ-CD28 (lacking lck binding moiety) or 4-1BB were established...
May 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29740445/loss-of-perp-in-t-cells-promotes-resistance-to-apoptosis-of-t-helper-17-cells-and-exacerbates-the-development-of-experimental-autoimmune-encephalomyelitis-in-mice
#5
Yan Zhou, Xiao Leng, Yan He, Yan Li, Yuan Liu, Yang Liu, Qiang Zou, Guixiu Shi, Yantang Wang
T helper 17 (Th17) cells are crucial for the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in animals. High frequency of Th17 cells and low sensitivity to activation-induced cell death (AICD) are detected in MS patients. However, the mechanisms underlying apoptosis resistance of T cells remain unclear. Perp is an apoptosis-associated target of p53 and implicated in the development of cancers. Here, we show that loss of Perp in T cells does not affect Th1, Th17, or Treg cell differentiation, but does significantly increase the resistance of Perp -/- Th17 cells to AICD and anti-Fas in Lck-Cre ×  Perp fl/fl mice by inhibiting the caspase-dependent apoptotic pathway...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29714078/overexpression-of-p21-activated-kinase-2-is-correlated-with-high-grade-oral-squamous-cell-carcinomas
#6
Yao Xiao, Wei-Wei Deng, Lei-Lei Yang, Hao Li, Guang-Tao Yu, Wen-Feng Zhang, Zhi-Jun Sun
AIM: p21-activated kinase 2 (PAK2) is overexpressed in several tumors but the expression of PAK2 in oral squamous cell carcinomas (OSCCs) remains unclear. MATERIALS & METHODS: Immunohistochemistry was performed on human tissue microarrays containing 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa. RESULTS: PAK2 expression was increased in primary OSCC compared with normal mucosa and significantly increased in primary OSCC grade III compared with grade I, but independent of overall survival rate...
May 1, 2018: Future Oncology
https://www.readbyqxmd.com/read/29713904/gene-expression-changes-in-the-retina-after-systemic-administration-of-aldosterone
#7
Aoi Ono, Kazuyuki Hirooka, Yuki Nakano, Eri Nitta, Akira Nishiyama, Akitaka Tsujikawa
PURPOSE: Retinal ganglion cell (RGC) loss associated with thinning of the retinal nerve fiber layer without elevated intraocular pressure (IOP) occurs after the systemic administration of aldosterone. Since it is important to determine the mechanism of cell death independent of the IOP, we examined gene expression changes in the retina after the systemic administration of aldosterone. METHODS: Following subcutaneous implantation of an osmotic minipump into the mid-scapular region of rats, we administered an 80 μg/kg/day dose of aldosterone...
April 30, 2018: Japanese Journal of Ophthalmology
https://www.readbyqxmd.com/read/29706626/long-non-coding-rna-lnc-tim3-exacerbates-cd8-t-cell-exhaustion-via-binding-to-tim-3-and-inducing-nuclear-translocation-of-bat3-in-hcc
#8
Jie Ji, Yin Yin, Huanyu Ju, Xiaoliang Xu, Wei Liu, Qiang Fu, Jiaojiao Hu, Xudong Zhang, Beicheng Sun
Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells...
April 30, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29703908/a-side-effect-free-method-for-identifying-cancer-drug-targets
#9
Md Izhar Ashraf, Seng-Kai Ong, Shama Mujawar, Shrikant Pawar, Pallavi More, Somnath Paul, Chandrajit Lahiri
Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets...
April 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29698062/targeted-deletion-of-t-cell-s1p-receptor-1-ameliorates-cardiac-fibrosis-in-streptozotocin-induced-diabetic-mice
#10
Chowdhury S Abdullah, Zhu-Qiu Jin
Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P1 )-mediated signaling directs T lymphocyte trafficking. Effects of T-cell S1P1 activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P1 knockout (TS1P1 KO) mice generated by crossing S1pr1 loxP/loxP mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy...
April 26, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29692779/rip2-is-a-critical-regulator-for-nlrs-signaling-and-mhc-antigen-presentation-but-not-for-mapk-and-pi3k-akt-pathways
#11
Xiao Man Wu, Wen Qin Chen, Yi Wei Hu, Lu Cao, Pin Nie, Ming Xian Chang
RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout in vitro . Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo . Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29677469/multidomain-control-over-tec-kinase-activation-state-tunes-the-t-cell-response
#12
Amy H Andreotti, Raji E Joseph, James M Conley, Janet Iwasa, Leslie J Berg
Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation...
April 26, 2018: Annual Review of Immunology
https://www.readbyqxmd.com/read/29669754/ectopic-lck-expression-in-cll-demarcates-intratumoral-subpopulations-with-aberrant-b-cell-receptor-signaling
#13
Efthymia Theofani, Spyridon Alexis, Paul Costeas, Christos Andriopoulos, Georgia Feleskoura, Panagiotis Zikos, Anthi Aktypi, Alexandros Spyridonidis, Konstantina Nika
No abstract text is available yet for this article.
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29625466/narrow-spectrum-kinase-inhibitors-demonstrate-promise-for-the-treatment-of-dry-eye-disease-and-other-ocular-inflammatory-disorders
#14
Suzanne Hagan, Matthew C T Fyfe, Boatemaa Ofori-Frimpong, Katherine Oliver, Martyn R Foster, Sameer Sirohi, Yemisi Solanke, Michael Doughty, Adele Rowley, Mike Taylor, Steve Webber, Claire A Walshe
Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29610179/inherited-immunodeficiency-a-new-association-with-early-onset-childhood-panniculitis
#15
Brigitte Bader-Meunier, Frédéric Rieux-Laucat, Fabien Touzot, Marie-Louise Frémond, Isabelle André-Schmutz, Sylvie Fraitag, Christine Bodemer
We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies...
April 2018: Pediatrics
https://www.readbyqxmd.com/read/29596528/apaf1-plays-a-negative-regulatory-role-in-t-cell-responses-by-suppressing-activation-of-antigen-stimulated-t-cells
#16
Honglian Tong, Yasunobu Miyake, Fumika Mi-Ichi, Yoichiro Iwakura, Hiromitsu Hara, Hiroki Yoshida
Apaf1 is a critical component of the apoptosome and initiates apoptosis downstream mitochondrial damages. Although the importance of Apaf1 in embryonic development was shown, the role of Apaf1 in immune responses, especially T cell responses, has yet to be elucidated. We generated T cell-specific Apaf1-deficient mice (Lck-Cre-Apaf1f/f mice) and examined the antigen-specific delayed-type hypersensitivity (DTH). Lck-Cre-Apaf1f/f mice exhibited exacerbation of DTH responses as compared with Apaf1-sufficient control mice...
2018: PloS One
https://www.readbyqxmd.com/read/29588370/intrinsic-properties-and-plasma-membrane-trafficking-route-of-src-family-kinase-sh4-domains-sensitive-to-retargeting-by-hiv-1-nef
#17
Amanda J Chase, Rebecka Wombacher, Oliver T Fackler
The HIV-1 pathogenicity factor Nef enhances viral replication by modulating multiple host cell pathways, including tuning the activation state of infected CD4 T lymphocytes to optimize virus spread. For this, Nef inhibits anterograde transport of the Src family kinase (SFK) Lck toward the plasma membrane (PM). This leads to retargeting of the kinase to the trans-Golgi network (TGN), while the intracellular transport of a related SFK, Fyn, is unaffected by Nef. The 18 amino acid SH4 domain membrane anchor of Lck is necessary and sufficient for Nef-mediated retargeting, but other details of this process are not known...
March 27, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29588208/application-of-htlv-1-tax-transgenic-mice-for-therapeutic-intervention
#18
REVIEW
Hideki Hasegawa, Kaori Sano, Akira Ainai, Tadaki Suzuki
Adult T-cell leukemia-lymphoma (ATL) is a refractory T-cell malignancy caused by infection of human T-cell leukemia virus type I (HTLV-I). Although the pathogenesis of ATL remains unclear, HTLV-1 oncoprotein Tax plays an important role in pathogenesis (Matsuoka, 2003; Jeang et al., 2004). Chemotherapy resistance of ATL leads the poor prognosis of this disease. In order to understand the pathogenesis and establish an animal model useful for therapy attempts, we have generated HTLV-1 Tax transgenic mice using the Lck proximal promoter to restrict the Tax expression in T-cells...
February 13, 2018: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29572701/diacylglycerol-kinase-%C3%AE-inactivation-is-an-integral-component-of-the-costimulatory-pathway-that-amplifies-tcr-signals
#19
Javier Arranz-Nicolás, Jesús Ogando, Denise Soutar, Raquel Arcos-Pérez, Daniel Meraviglia-Crivelli, Santos Mañes, Isabel Mérida, Antonia Ávila-Flores
The arsenal of cancer therapies has evolved to target T lymphocytes and restore their capacity to destroy tumor cells. T cells rely on diacylglycerol (DAG) to carry out their functions. DAG availability and signaling are regulated by the enzymes diacylglycerol kinase (DGK) α and ζ, whose excess function drives T cells into hyporesponsive states. Targeting DGKα is a promising strategy for coping with cancer; its blockade could reinstate T-cell attack on tumors while limiting tumor growth, due to positive DGKα functions in several oncogenic pathways...
March 23, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29563576/phosphoinositides-regulate-the-tcr-cd3-complex-membrane-dynamics-and-activation
#20
Nassima Chouaki-Benmansour, Kilian Ruminski, Anne-Marie Sartre, Marie-Claire Phelipot, Audrey Salles, Elise Bergot, Ambroise Wu, Gaëtan Chicanne, Mathieu Fallet, Sophie Brustlein, Cyrille Billaudeau, Anthony Formisano, Sébastien Mailfert, Bernard Payrastre, Didier Marguet, Sophie Brasselet, Yannick Hamon, Hai-Tao He
Phosphoinositides (PIs) play important roles in numerous membrane-based cellular activities. However, their involvement in the mechanism of T cell receptor (TCR) signal transduction across the plasma membrane (PM) is poorly defined. Here, we investigate their role, and in particular that of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in TCR PM dynamics and activity in a mouse T-cell hybridoma upon ectopic expression of a PM-localized inositol polyphosphate-5-phosphatase (Inp54p). We observed that dephosphorylation of PI(4,5)P2 by the phosphatase increased the TCR/CD3 complex PM lateral mobility prior stimulation...
March 21, 2018: Scientific Reports
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