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https://www.readbyqxmd.com/read/28225754/targeting-a-car-to-the-trac-locus-with-crispr-cas9-enhances-tumour-rejection
#1
Justin Eyquem, Jorge Mansilla-Soto, Theodoros Giavridis, Sjoukje J C van der Stegen, Mohamad Hamieh, Kristen M Cunanan, Ashlesha Odak, Mithat Gönen, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing...
February 22, 2017: Nature
https://www.readbyqxmd.com/read/28210081/role-of-lap-cd4-t-cells-in-the-tumor-microenvironment-of-colorectal-cancer
#2
Wu Zhong, Zhi-Yuan Jiang, Lei Zhang, Jia-Hao Huang, Shi-Jun Wang, Cun Liao, Bin Cai, Li-Sheng Chen, Sen Zhang, Yun Guo, Yun-Fei Cao, Feng Gao
AIM: To investigate the abundance and potential functions of LAP(+)CD4(+) T cells in colorectal cancer (CRC). METHODS: Proportions of LAP(+)CD4(+) T cells were examined in peripheral blood and tumor/paratumor tissues of CRC patients and healthy controls using flow cytometry. Expression of phenotypic markers such as forkhead box (Fox)p3, cytotoxic T-lymphocyte-associated protein (CTLA)-4, chemokine CC receptor (CCR)4 and CCR5 was measured using flow cytometry. LAP(-)CD4(+) and LAP(+)CD4(+) T cells were isolated using a magnetic cell-sorting system and cell purity was analyzed by flow cytometry...
January 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28208753/possible-impact-of-190g-a-ccr2-and-%C3%AE-32-ccr5-mutations-on-decrease-of-the-hbv-vaccine-immunogenicity-a-preliminary-report
#3
Maria Ganczak, Karolina Skonieczna-Żydecka, Marzena Drozd-Dąbrowska, Grażyna Adler
Background: Chemokine genetic variations are involved in infectious diseases such as hepatitis B virus (HBV). Several allelic variants might, in theory, affect the outcome of vaccination. Objectives: This study was carried out to examine the associations of Δ32 CCR5 and 190G > A CCR2 polymorphisms with a response to a primary course of three HBV vaccinations. Methods: Between December 2014 and December 2016, patients from three randomly selected primary care clinics in the West Pomeranian region (Poland), 1 month after receiving the third dose of HBV vaccine, were enrolled...
February 8, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28198557/hiv-1-coreceptor-usage-in-perinatally-infected-thai-children
#4
Tanawan Samleerat, Sayamon Hongjaisee, Pattareeya Phiayura, Wasna Sirirungsi
HIV-1 coreceptor usage in children who were born to HIV-1 infected mothers in Thailand is not well characterized. Here, the prevalence of coreceptor usage and genotype among HIV-1 infected children in Thailand were observed. Proviral DNA from 284 HIV-1 infected children who received HIV-1 early infant diagnosis between 2007 and 2013 under the National AIDS Program were studied. Genotypic tropism testing was performed based on amplification of the V3 region in a triplicate nested-PCR following by DNA sequencing...
February 15, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28196473/2-7-million-samples-genotyped-for-hla-by-next-generation-sequencing-lessons-learned
#5
Gerhard Schöfl, Kathrin Lang, Philipp Quenzel, Irina Böhme, Jürgen Sauter, Jan A Hofmann, Julia Pingel, Alexander H Schmidt, Vinzenz Lange
BACKGROUND: At the DKMS Life Science Lab, Next Generation Sequencing (NGS) has been used for ultra-high-volume high-resolution genotyping of HLA loci for the last three and a half years. Here, we report on our experiences in genotyping the HLA, CCR5, ABO, RHD and KIR genes using a direct amplicon sequencing approach on Illumina MiSeq and HiSeq 2500 instruments. RESULTS: Between January 2013 and June 2016, 2,714,110 samples largely from German, Polish and UK-based potential stem cell donors have been processed...
February 14, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28190711/cd8-t-cells-orchestrate-pdc-xcr1-dendritic-cell-spatial-and-functional-cooperativity-to-optimize-priming
#6
Anna Brewitz, Sarah Eickhoff, Sabrina Dähling, Thomas Quast, Sammy Bedoui, Richard A Kroczek, Christian Kurts, Natalio Garbi, Winfried Barchet, Matteo Iannacone, Frederick Klauschen, Waldemar Kolanus, Tsuneyasu Kaisho, Marco Colonna, Ronald N Germain, Wolfgang Kastenmüller
Adaptive cellular immunity is initiated by antigen-specific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8(+) T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8(+) T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine...
February 8, 2017: Immunity
https://www.readbyqxmd.com/read/28186189/performance-comparison-of-next-generation-sequencing-platforms-for-determining-hiv-1-coreceptor-use
#7
Stéphanie Raymond, Florence Nicot, Nicolas Jeanne, Olivier Delfour, Romain Carcenac, Caroline Lefebvre, Michelle Cazabat, Karine Sauné, Pierre Delobel, Jacques Izopet
The coreceptor used by HIV-1 must be determined before a CCR5 antagonist, part of the arsenal of antiretroviral drugs, is prescribed because viruses that enter cells using the CXCR4 coreceptor are responsible for treatment failure. HIV-1 tropism is also correlated with disease progression and so must be determined for virological studies. Tropism can be determined by next-generation sequencing (NGS), but not all of these new technologies have been fully validated for use in clinical practice. The Illumina NGS technology is used in many laboratories but its ability to predict HIV-1 tropism has not been evaluated while the 454 GS-Junior (Roche) is used for routine diagnosis...
February 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28182750/chemoprophylaxis-with-sporozoite-immunization-in-p-knowlesi-rhesus-monkeys-confers-protection-and-elicits-sporozoite-specific-memory-t-cells-in-the-liver
#8
Sathit Pichyangkul, Michele D Spring, Kosol Yongvanitchit, Utaiwan Kum-Arb, Amporn Limsalakpetch, Rawiwan Im-Erbsin, Ratawan Ubalee, Pattaraporn Vanachayangkul, Edmond J Remarque, Evelina Angov, Philip L Smith, David L Saunders
Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses. Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans. We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites. Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half...
2017: PloS One
https://www.readbyqxmd.com/read/28177261/stability-of-5p12-rantes-a-candidate-rectal-microbicide-in-human-rectal-lavage
#9
Fabrice Cerini, Robin E Offord, Ian McGowan, Oliver Hartley
In the absence of an effective vaccine, strategies to prevent HIV transmission are urgently needed. Condomless receptive anal intercourse represents a major route of transmission, and efforts are being made to develop strategies in which potent anti-HIV drugs are formulated for topical application to the rectum prior to sex. 5P12-RANTES is a promising candidate for such a purpose. It is an analogue of the human chemokine RANTES/CCL5, which potently blocks CCR5, the principal coreceptor used by HIV to enter and infect target cells...
February 8, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28177124/acute-exercise-elicits-differential-expression-of-insulin-resistance-genes-in-the-skeletal-muscle-of-patients-with-polycystic-ovary-syndrome
#10
Wagner Silva Dantas, Igor Hisashi Murai, Luiz Augusto Perandini, Hatylas Azevedo, Carlos Alberto Moreira-Filho, Niels Olsen Saraiva Camara, Hamilton Roschel, Bruno Gualano
OBJECTIVE: This study aimed to explore the role of acute exercise on skeletal muscle gene expression related to insulin resistance in patients with polycystic ovary syndrome (PCOS) and controls. METHODS: Four obese women with PCOS and 4 body controls subjects (CTRL) participated in this study. After an overnight fast, the subjects underwent a single 40-minute bout of aerobic exercise. Muscle samples were obtained from vastus lateralis at baseline and 60 minutes after exercise...
February 8, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28168553/ccr2-contributes-to-the-recruitment-of-monocytes-and-leads-to-kidney-inflammation-and-fibrosis-development
#11
Tarcio Teodoro Braga, Matheus Correa-Costa, Reinaldo Correia Silva, Mario Costa Cruz, Meire Ioshie Hiyane, Joao Santana da Silva, Katia Regina Perez, Iolanda Midea Cuccovia, Niels Olsen Saraiva Camara
Chemokines are a large family of proteins that, once associated to its receptor on leukocytes, stimulate their movement and migration from blood to tissues. Once in the tissue, immune cells trigger inflammation that, when uncontrolled, leads to fibrosis development. Among the immune cells, macrophages take a special role in fibrosis formation, since macrophage depletion reflects less collagen deposition. The majority of tissue macrophages is derived from monocytes, especially monocytes expressing the chemokine receptor CCR2...
February 6, 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/28165741/structural-analysis-of-chemokine-receptor-ligand-interactions
#12
Marta Arimont, Shanliang Sun, Rob Leurs, Martine Smit, Iwan J P De Esch, Chris de Graaf
This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9 and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines...
February 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28155603/advances-in-chemistry-and-pharmacology-of-triterpenoid-synthetic-dimers
#13
Barbara Bednarczyk-Cwynar, Andrzej Günther
The publication focuses on advances in chemistry and pharmacology of synthetic triterpenoid dimers, obtained from natural compounds. Synthetic triterpenoid dimers were divided into specific subgroups basing on the structure of main triterpenoid monomeric skeleton. Synthetic triterpenoid derivatives of dimeric structure can be obtained through the covalent linkage of the C-3 hydroxyl or another group, via the C-2 atom or the C-17 carboxyl group (mainly anhydrides, amides or esters). Some triterpenes can undergo chemical transformations leading to the formation of cyclic dimers or other types of dimers...
February 2, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28150777/pathologically-expanded-peripheral-t-helper-cell-subset-drives-b-cells-in-rheumatoid-arthritis
#14
Deepak A Rao, Michael F Gurish, Jennifer L Marshall, Kamil Slowikowski, Chamith Y Fonseka, Yanyan Liu, Laura T Donlin, Lauren A Henderson, Kevin Wei, Fumitaka Mizoguchi, Nikola C Teslovich, Michael E Weinblatt, Elena M Massarotti, Jonathan S Coblyn, Simon M Helfgott, Yvonne C Lee, Derrick J Todd, Vivian P Bykerk, Susan M Goodman, Alessandra B Pernis, Lionel B Ivashkiv, Elizabeth W Karlson, Peter A Nigrovic, Andrew Filer, Christopher D Buckley, James A Lederer, Soumya Raychaudhuri, Michael B Brenner
CD4(+) T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4(+) T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1(hi)CXCR5(-)CD4(+) T cells in synovium of patients with rheumatoid arthritis...
1, 2017: Nature
https://www.readbyqxmd.com/read/28143740/engineering-hiv-resistant-anti-hiv-chimeric-antigen-receptor-t-cells
#15
Malika Hale, Taylor Mesojednik, Guillermo S Romano Ibarra, Jaya Sahni, Alison Bernard, Karen Sommer, Andrew M Scharenberg, David J Rawlings, Thor A Wagner
The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication...
January 28, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28142395/effectiveness-safety-durability-and-immune-recovery-in-a-retrospective-multicentre-observational-cohort-of-art-experienced-hiv-1-infected-patients-receiving-maraviroc
#16
C Dentone, G Sterrantino, A Signori, G Cenderello, M Guerra, P De Leo, V Bartolacci, E Mantia, G Orofino, M Giacomini, B Bruzzone, D Francisci, A Di Biagio
The aim of this retrospective, multicentre, observational study was to assess the durability, safety, immune recovery and effectiveness on viral suppression of antiretroviral therapy (ART) in a maraviroc (MVC)-based cohort. We collected clinical, demographical, immunological and virological parameters of adult HIV patients who were infected by CCR5-tropic virus and started an ART regimen containing MVC from 2005 to 2012. We created a longitudinal mixed model to assess the change over time of data. We enrolled 126 drug-experienced patients; the median duration of MVC treatment was 25 months...
January 1, 2017: International Journal of STD & AIDS
https://www.readbyqxmd.com/read/28140695/ccr5-expression-in-inflammatory-bowel-disease-and-its-correlation-with-inflammatory-cells-and-%C3%AE-arrestin2-expression
#17
Xiaoyan Ye, Sixue Liu, Mei Hu, Yangda Song, Huarong Huang, Yingqiang Zhong
OBJECTIVE: To elucidate the correlation of expression of CC chemokine receptor 5 (CCR5) with degrees of inflammatory cells infiltration and expression of β-arrestin2 in biopsic intestinal mucosa of the patients with inflammatory bowel disease (IBD). METHODS: Paraffin sections were derived from 53 patients with active IBD, 26 patients with remissive IBD and 30 healthy people. Immunohistochemical envision two-step method was used to test the expression of CCR5 and β-arrestin2 in biopsic intestinal mucosa...
January 31, 2017: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/28139906/heteromer-induction-an-approach-to-unique-pharmacology
#18
Philip S Portoghese, Eyup Akgün, Mary M Lunzer
It is proposed that two types of opioid receptor heteromers exist: a) those that are constitutive and b) those that are induced by bivalent ligands. Mu opioid agonists interact with constitutive MOR-DOR heteromer to mediate tolerance and dependence. Bivalent ligand, MDAN21, is devoid of these adverse effects by virtue of its DOR antagonist pharmacophore. We propose that bivalent ligands MMG22 and MCC22 induce colocalized receptors to form heteromers (MOR-mGluR5 and MOR-CCR5, respectively) that do not occur naturally, thereby promoting unique pharmacology...
January 31, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28138150/finding-host-targets-for-hiv-therapy
#19
C Kimberly Tsui, Amita Gupta, Michael C Bassik
A CRISPR screen conducted in a CD4(+) T cell leukemia line has identified host factors required for HIV infection but dispensable for cellular survival. The results highlight sulfation on the HIV co-receptor CCR5 and cellular aggregation as potential targets for therapeutic intervention.
January 31, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28128944/design-and-elaboration-of-a-tractable-tricyclic-scaffold-to-synthesize-druglike-inhibitors-of-dipeptidyl-peptidase-4-dpp-4-antagonists-of-the-c-c-chemokine-receptor-type-5-ccr5-and-highly-potent-and-selective-phosphoinositol-3-kinase-%C3%AE-pi3k%C3%AE-inhibitors
#20
Carolin Schwehm, Barrie Kellam, Aimie E Garces, Stephen J Hill, Nicholas D Kindon, Tracey D Bradshaw, Jin Li, Simon J F Macdonald, James E Rowedder, Leigh A Stoddart, Michael J Stocks
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs...
February 10, 2017: Journal of Medicinal Chemistry
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