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Joseph A Trapani, Phillip K Darcy
BACKGROUND: For 50 years, cancer physicians have relied on just three primary treatment modalities: surgery, radiation therapy and chemotherapy. Over that time, enormous progress has been made in understanding cancer biology, targeted anti-cancer drugs have emerged, and thousands of clinical trials have taught us how best to craft treatment combinations that improve clinical outcomes. Only five years ago, a fourth and radically different form of therapy finally emerged: immune‑based cancer therapies...
2017: Australian Family Physician
Jin-Young Choi, Abhinav Seth, Michael Kashgarian, Sonia Terrillon, Emma Fung, Lili Huang, Li Chun Wang, Joe Craft
Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Marc Douaisi, Rachel S Resop, Maho Nagasawa, Joshua Craft, Beth D Jamieson, Bianca Blom, Christel H Uittenbogaart
Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. In this study, we provide a global picture of the evolution of CD31 expression from the CD34(+) hematopoietic precursor to the CD45RA(+) mature CD4(+) and CD8(+) single-positive (SP) T cells. Using nine-color flow cytometry, we show that CD31 is highly expressed on CD34(+) progenitors and stays high until the early double-positive stage (CD3(-)CD4(+)CD8α(+)β(-))...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
P Singh, T Saha, P Mishra, M K Parai, S Ireddy, S Lavanya Kumar M, S Krishna, S K Kumar, V Chaturvedi, S Sinha, M I Siddiqi, G Panda
We earlier reported thiophene-containing trisubstituted methanes (TRSMs) as novel cores carrying anti-tubercular activity, and identified S006-830 as the phenotypic lead with potent bactericidal activity against single- and multi-drug resistant clinical isolates of Mycobacterium tuberculosis (M. tb). In this work, we carried out additional synthesis of several TRSMs. The reaction scheme essentially followed the Grignard reaction and Friedel-Crafts alkylation, followed by insertion of a dialkylaminoethyl chain...
November 2016: SAR and QSAR in Environmental Research
Patrick Cherubin, Maria Camila Garcia, David Curtis, Christopher B T Britt, John W Craft, Helen Burress, Chris Berndt, Srikar Reddy, Jessica Guyette, Tianyu Zheng, Qun Huo, Beatriz Quiñones, James M Briggs, Ken Teter
Cholera toxin (CT) is an AB-type protein toxin that contains a catalytic A1 subunit, an A2 linker, and a cell-binding B homopentamer. The CT holotoxin is released into the extracellular environment, but CTA1 attacks a target within the cytosol of a host cell. We recently reported that grape extract confers substantial resistance to CT. Here, we used a cell culture system to identify twelve individual phenolic compounds from grape extract that inhibit CT. Additional studies determined the mechanism of inhibition for a subset of the compounds: two inhibited CT binding to the cell surface and even stripped CT from the plasma membrane of a target cell; two inhibited the enzymatic activity of CTA1; and four blocked cytosolic toxin activity without directly affecting the enzymatic function of CTA1...
2016: PloS One
Li Ren, Yang Yu, Li Wang, Zhifeng Zhu, Rong Lu, Zhi Yao
Tumor cells craft microenvironment to overcome growth disadvantages and adjust to escape the immunosurveillance during tumorigenesis and metastasis. The evolving adaption to the changing microenvironment is exemplified by the development of strategies to deal with hypoxia resulted from fast proliferation of the tumor cells. In this study, we found that hypoxia hepatocellular carcinoma (HCC) cells recruited Regulatory T cells (Tregs) and expressed more Chemokine (C-C motif) ligand 28 (CCL28). Deletion of CCL28 inhibited Treg recruitment...
November 15, 2016: Oncotarget
Mary F Fontana, Alyssa Baccarella, Joshua F Craft, Michelle J Boyle, Tara I McIntyre, Matthew D Wood, Kurt S Thorn, Chioma Anidi, Aqieda Bayat, Me Ree Chung, Rebecca Hamburger, Chris Y Kim, Emily Pearman, Jennifer Pham, Jia J Tang, Louis Boon, Moses R Kamya, Grant Dorsey, Margaret E Feeney, Charles C Kim
In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype...
2016: PloS One
Jason S Weinstein, Edward I Herman, Begoña Lainez, Paula Licona-Limón, Enric Esplugues, Richard Flavell, Joe Craft
Germinal center (GC) B cells undergo affinity selection, which depends on interactions with CD4(+) follicular helper T cells (TFH cells). We found that TFH cells progressed through transcriptionally and functionally distinct stages and provided differential signals for GC regulation. They initially localized proximally to mutating B cells, secreted interleukin 21 (IL-21), induced expression of the transcription factor Bcl-6 and selected high-affinity B cell clones. As the GC response evolved, TFH cells extinguished IL-21 production and switched to IL-4 production, showed robust expression of the co-stimulatory molecule CD40L, and promoted the development of antibody-secreting B cells via upregulation of the transcription factor Blimp-1...
October 2016: Nature Immunology
Marilia S Santos, Daniara C Fernandes, Manoel T Rodrigues, Thais Regiani, Adriano D Andricopulo, Ana Lúcia T G Ruiz, Débora B Vendramini-Costa, João E de Carvalho, Marcos N Eberlin, Fernando Coelho
The cyclopenta[b]indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta[b]indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita-Baylis-Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding β-hydroxy-esters...
August 5, 2016: Journal of Organic Chemistry
Stephen R F Twigg, Robert B Hufnagel, Kerry A Miller, Yan Zhou, Simon J McGowan, John Taylor, Jude Craft, Jenny C Taylor, Stephanie L Santoro, Taosheng Huang, Robert J Hopkin, Angela F Brady, Jill Clayton-Smith, Carol L Clericuzio, Dorothy K Grange, Leopold Groesser, Christian Hafner, Denise Horn, I Karen Temple, William B Dobyns, Cynthia J Curry, Marilyn C Jones, Andrew O M Wilkie
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling...
June 2, 2016: American Journal of Human Genetics
Rachel S Resop, Marc Douaisi, Joshua Craft, Loes C M Jachimowski, Bianca Blom, Christel H Uittenbogaart
BACKGROUND: The mechanisms that govern the egress of mature thymocytes from the human thymus to the periphery remain understudied yet are of utmost importance to the field of basic immunology, as well as T-cell reconstitution in various immunodeficiencies. We examined the expression and function of sphingosine-1-phosphate (S1P) receptors in human thymocyte egress. OBJECTIVES: We aimed to determine whether S1P receptors (S1P-Rs) play a role in mature human thymocyte egress and to identify the thymocyte population or populations that express S1P-Rs and respond to S1P by migrating across a concentration gradient...
August 2016: Journal of Allergy and Clinical Immunology
Pamela Y Chan, Eugenio A Carrera Silva, Dimitri De Kouchkovsky, Leonel D Joannas, Liming Hao, Donglei Hu, Scott Huntsman, Celeste Eng, Paula Licona-Limón, Jason S Weinstein, De'Broski R Herbert, Joseph E Craft, Richard A Flavell, Silvia Repetto, Jorge Correale, Esteban G Burchard, Dara G Torgerson, Sourav Ghosh, Carla V Rothlin
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4...
April 1, 2016: Science
Brian J Laidlaw, Joseph E Craft, Susan M Kaech
Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4(+) T cells are essential in the formation of protective memory CD8(+) T cells following infection or immunization...
February 2016: Nature Reviews. Immunology
Eric Peatman, Miles Lange, Honggang Zhao, Benjamin H Beck
The mucosal barriers of catfish (Ictalurus spp) constitute the first line of defense against pathogen invasion while simultaneously carrying out a diverse array of other critical physiological processes, including nutrient adsorption, osmoregulation, waste excretion, and environmental sensing. Catfish depend more heavily on mucosal barriers than their terrestrial counterparts as they are continuously interacting with the aquatic microbiota. Our understanding of these barriers, while growing, is still limited relative to that of mammalian model systems...
October 2015: Tissue Barriers
Janise D Deming, Joseph S Pak, Jung-A Shin, Bruce M Brown, Moon K Kim, Moe H Aung, Eun-Jin Lee, Machelle T Pardue, Cheryl Mae Craft
PURPOSE: Previous studies discovered cone phototransduction shutoff occurs normally for Arr1-/- and Arr4-/-; however, it is defective when both visual arrestins are simultaneously not expressed (Arr1-/-Arr4-/-). We investigated the roles of visual arrestins in an all-cone retina (Nrl-/-) since each arrestin has differential effects on visual function, including ARR1 for normal light adaptation, and ARR4 for normal contrast sensitivity and visual acuity. METHODS: We examined Nrl-/-, Nrl-/-Arr1-/-, Nrl-/-Arr4-/-, and Nrl-/-Arr1-/-Arr4-/- mice with photopic electroretinography (ERG) to assess light adaptation and retinal responses, immunoblot and immunohistochemical localization analysis to measure retinal expression levels of M- and S-opsin, and optokinetic tracking (OKT) to measure the visual acuity and contrast sensitivity...
December 2015: Investigative Ophthalmology & Visual Science
Gang Xin, David M Schauder, Begoña Lainez, Jason S Weinstein, Zhengxi Dai, Yuhong Chen, Enric Esplugues, Renren Wen, Demin Wang, Ian A Parish, Allan J Zajac, Joe Craft, Weiguo Cui
Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response; however, the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function and sufficient to rescue "unhelped" CD8 T cells...
November 10, 2015: Cell Reports
Tia Y Brodeur, Tara E Robidoux, Jason S Weinstein, Joseph Craft, Susan L Swain, Ann Marshak-Rothstein
Type 2 effector production of IL-13, a demonstrated requirement in models of fibrosis, is routinely ascribed to CD4(+) Th2 cells. We now demonstrate a major role for CD8(+) T cells in a murine model of sterile lung injury. These pulmonary CD8(+) T cells differentiate into IL-13-producing Tc2 cells and play a major role in a bleomycin-induced model of fibrosis. Differentiation of these Tc2 cells in the lung requires IL-21, and bleomycin treated IL-21- and IL-21R-deficient mice develop inflammation but not fibrosis...
December 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
John P Ray, Matthew M Staron, Justin A Shyer, Ping-Chih Ho, Heather D Marshall, Simon M Gray, Brian J Laidlaw, Koichi Araki, Rafi Ahmed, Susan M Kaech, Joe Craft
The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells...
October 20, 2015: Immunity
Janise D Deming, Joseph S Pak, Bruce M Brown, Moon K Kim, Moe H Aung, Yun Sung Eom, Jung-A Shin, Eun-Jin Lee, Machelle T Pardue, Cheryl Mae Craft
PURPOSE: Visual arrestins (ARR) play a critical role in shutoff of rod and cone phototransduction. When electrophysiological responses are measured for a single mouse cone photoreceptor, ARR1 expression can substitute for ARR4 in cone pigment desensitization; however, each arrestin may also contribute its own, unique role to modulate other cellular functions. METHODS: A combination of ERG, optokinetic tracking, immunohistochemistry, and immunoblot analysis was used to investigate the retinal phenotypes of Arr4 null mice (Arr4-/-) compared with age-matched control, wild-type mice...
August 2015: Investigative Ophthalmology & Visual Science
Brian J Laidlaw, Weiguo Cui, Robert A Amezquita, Simon M Gray, Tianxia Guan, Yisi Lu, Yasushi Kobayashi, Richard A Flavell, Steven H Kleinstein, Joe Craft, Susan M Kaech
Memory CD8(+) T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4(+) regulatory T cells (Treg cells) was necessary for the maturation of memory CD8(+) T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell-derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase 'restored' the maturation of memory CD8(+) T cells in IL-10-deficient mice...
August 2015: Nature Immunology
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