tbuckley/cabot-search huggingface dataset:
Cellular immunity induced by a recombinant adenovirus- human dendritic cell vaccine for melanoma
Authors: Hadas Naveh, Lazar Vujanovic, Lisa H Butterfield
Journal: Journal for ImmunoTherapy of Cancer (2013)

Human Adenoviral vectors (HAdV) are immunogenic vectors which have been tested in many vaccination and gene therapy settings. Dendritic cells (DC) transduced by genetically engineered HAdV-5 (HAdV-5/DC), are investigational cancer vaccines being tested clinically. We have previously examined immune responses to HAdV-5 -encoded melanoma tumor antigens. Here, we determined whether the HAdV-5/DC also present immunogenic HAdV-5 vector-derived antigens, and characterized the cellular immune response to the viral as well as encoded melanoma tumor antigens.Both CD4(+) and CD8(+) HAdV-5-specific T cell responses were examined in vitro, with cells from both 8 healthy donors (HD) and 2 melanoma patients. PBMC were stimulated weekly with HAdV-5/DC and responses were examined after each stimulation. We also tested HAdV-5 neutralizing antibody levels and natural killer (NK) cell and regulatory T cell (Treg) activation and expansion in vitro.HAdV-5/DC rapidly induced a high frequency of type 1 cytokine producing HAdV-5-specific CD8(+) and CD4(+) T cells. IFNγ and TNFα-producing T cells predominate. Those with pre-existing cellular memory to HAdV-5 had more robust responses to the HAdV-5 as well as tumor-associated antigens. NK cells are activated while Treg are only minimally and transiently expanded.This study demonstrates that HAdV-5/DC promote strong type I cellular immunity to viral vector-derived antigens as well as to the encoded tumor antigens. The cytokine and chemokine milieu produced by HAdV-5/DC and the activated HAdV-5-specific T cells may enhance responses to encoded tumor antigens as well. These properties make HAdV-5/DC a cancer vaccine capable of activating type 1 virus and tumor antigen-specific immunity in a cooperative way.
Extramedullary Expansion of Hematopoietic Progenitor Cells in Interleukin (IL)-6–sIL-6R Double Transgenic Mice
Authors: Malte Peters, Peter Schirmacher, Jutta Goldschmitt, Margarete Odenthal, Christian Peschel, Elena Fattori, Gennaro Ciliberto, Hans-Peter Dienes, Karl-Hermann Meyer zum Büschenfelde, Stefan Rose-John
Journal: The Journal of Experimental Medicine (1997)

Soluble cytokine receptors modulate the activity of their cognate ligands. Interleukin (IL)-6 in association with the soluble IL-6 receptor (sIL-6R) can activate cells expressing the gp130 signal transducer lacking the specific IL-6R. To investigate the function of the IL-6–sIL-6R complex in vivo and to discriminate the function of the IL-6–sIL-6R complex from the function of IL-6 alone, we have established a transgenic mouse model. Double-transgenic mice coexpressing IL-6 and sIL-6R were generated and compared with IL-6 and sIL-6R single-transgenic mice. The main phenotype found in IL-6–sIL-6R mice was a dramatic increase of extramedullary hematopoietic progenitor cells in liver and spleen but not in the bone marrow. In IL-6 single-transgenic mice and sIL-6R single-transgenic mice no such effects were observed. The high numbers of hematopoietic progenitor cells were reflected by a strong increase of peripheral blood cell numbers. Therefore, activators of the gp130 signal transducer like the IL-6–IL-6R complex may represent most powerful stimulators for extramedullary hematopoietic progenitor cells. gp130 activators may become important for the expansion of hematopoietic progenitor cells in vivo and in vitro.
Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells
Authors: Hisse-Martien van Santen, Christophe Benoist, Diane Mathis
Journal: The Journal of Experimental Medicine (2004)

It has been reported that the differentiation of CD4+CD25+ regulatory T cells (T reg cells) can be induced by agonist peptide/major histocompatibility complex ligands in the thymus. Exploiting a transgenic mouse line wherein expression of a particular T cell epitope can be controlled temporally and quantitatively, we found that diversion of differentiating thymocytes into the FoxP3 T reg cell pathway by this agonist ligand was essentially nonexistent. However, CD4+CD25+ thymocytes were much less sensitive than their CD4+CD25- companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation. To account for these and prior observations, one can propose that differentiation along the CD4+CD25+ pathway is induced by cues other than recognition of self-agonist cues, which are poorly read by thymocytes, whose T cell receptors are conducive to selection toward the conventional CD4+CD25- lineage. Thus, selective survival, rather than induced differentiation, may explain the apparent enrichment observed here and in previous studies.
Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma
Authors: Jun Miyata, Koichi Fukunaga, Ryo Iwamoto, Yosuke Isobe, Kyoko Niimi, Rina Takamiya, Takahisa Takihara, Katsuyoshi Tomomatsu, Yusuke Suzuki, Tsuyoshi Oguma, Koichi Sayama, Hiroyuki Arai, Tomoko Betsuyaku, Makoto Arita, Koichiro Asano
Journal: Journal of Allergy and Clinical Immunology (2012)
Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis
Authors: Julia Bontscho, Adrian Schreiber, Rudolf A. Manz, Wolfgang Schneider, Friedrich C. Luft, Ralph Kettritz
Journal: Journal of the American Society of Nephrology (2011)

Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgG-mediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.
The Unfolded Protein Response Regulator GRP78/BiP as a Novel Target for Increasing Chemosensitivity in Malignant Gliomas
Authors: Peter Pyrko, Axel H. Schönthal, Florence M. Hofman, Thomas C. Chen, Amy S. Lee
Journal: Cancer Research (2007)

Abstract Poor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. GRP78 is a key regulator of the unfolded protein response (UPR). As a Ca2+-binding molecular chaperone in the endoplasmic reticulum (ER), GRP78 maintains ER homeostasis, suppresses stress-induced apoptosis, and controls UPR signaling. We report here that GRP78 is expressed at low levels in normal adult brain, but is significantly elevated in malignant glioma specimens and human malignant glioma cell lines, correlating with their rate of proliferation. Down-regulation of GRP78 by small interfering RNA leads to a slowdown in glioma cell growth. Our studies further reveal that temozolomide, the chemotherapeutic agent of choice for treatment of malignant gliomas, leads to induction of CHOP, a major proapoptotic arm of the UPR. Knockdown of GRP78 in glioblastoma cell lines induces CHOP and activates caspase-7 in temozolomide-treated cells. Colony survival assays further establish that knockdown of GRP78 lowers resistance of glioma cells to temozolomide, and, conversely, overexpression of GRP78 confers higher resistance. Knockdown of GRP78 also sensitizes glioma cells to 5-fluorouracil and CPT-11. Treatment of glioma cells with (−)-epigallocatechin gallate, which targets the ATP-binding domain of GRP78 and blocks its protective function, sensitizes glioma cells to temozolomide. These results identify a novel chemoresistance mechanism in malignant gliomas and show that combination of drugs capable of suppressing GRP78 with conventional agents such as temozolomide might represent a novel approach to eliminate residual tumor cells after surgery and increase the effectiveness of malignant glioma chemotherapy. [Cancer Res 2007;67(20):9809–16]
An assessment of the relationship between vasoconstrictor assay findings, clinical efficacy and skin thinning effects of a variety of undiluted and diluted corticosteroid preparations
Authors: J. R. GIBSON, J. M. KIRSCH, C. R. DARLEY, S. G. HARVEY, C. A. BURKE, M. E. HANSON
Journal: British Journal of Dermatology (1984)

Journal Article An assessment of the relationship between vasoconstrictor assay findings, clinical efficacy and skin thinning effects of a variety of undiluted and diluted corticosteroid preparations Get access J. R. GIBSON, J. R. GIBSON Skin Department, The London Hospital, Whitechapel, London EI IBB Dr John Gibson, The Skin Department, The London Hospital, Whitechapel, London EI IBB, U. K. Search for other works by this author on: Oxford Academic Google Scholar J. M. KIRSCH, J. M. KIRSCH Department of Pharmacy, Chelsea College, London Search for other works by this author on: Oxford Academic Google Scholar C. R. DARLEY, C. R. DARLEY Skin Department, The London Hospital, Whitechapel, London EI IBB Search for other works by this author on: Oxford Academic Google Scholar S. G. HARVEY, S. G. HARVEY Skin Department, The London Hospital, Whitechapel, London EI IBB Search for other works by this author on: Oxford Academic Google Scholar C. A. BURKE, C. A. BURKE Wellcome Research Laboratories, Langley Court, Beckenham, Kent Search for other works by this author on: Oxford Academic Google Scholar M. E. HANSON M. E. HANSON Skin Department, The London Hospital, Whitechapel, London EI IBB Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 111, Issue s27, 1 July 1984, Pages 204–212, https://doi.org/10.1111/j.1365-2133.1984.tb15606.x Published: 01 July 1984
Childhood Myocarditis Associated With Chlamydia trachomatis Infection
Authors: J. Thomas Grayston
Journal: JAMA (1981)

Paired serum samples from six children with mild to fatal myocarditis have been studied in the microimmunofluorescence test for antibodies against<i>Chlamydia trachomatis</i>. Two patients with other known causes of myocarditis had no antibodies. The other four patients each had<i>C trachomatis</i>antibody. Two had high titer rises, and two with onset one to three months before the first serum sample was taken had level antibody titers. The study of serum from myocarditis patients was unplanned; they were part of a group of paired serum samples from children that had been submitted to the laboratory for viral diagnostic studies during a 16-month period. While the association of<i>C trachomatis</i>antibody with myocarditis was unexpected, it is consistent with the known etiologic role of<i>C psittaci</i>in myocarditis and the widening spectrum of systemic diseases caused by<i>C trachomatis</i>. Since<i>Chlamydia</i>can be treated with antibiotics, the possible etiologic association with myocarditis has important therapeutic ramifications. (<i>JAMA</i>1981;246:2823-2827)
Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy
Authors: Joel D. Leverson, Darren C. Phillips, Michael J. Mitten, Erwin R. Boghaert, Dolores Diaz, Stephen K. Tahir, Lisa D. Belmont, Paul Nimmer, Yu Xiao, Xiaoju Max Ma, Kym N. Lowes, Peter Kovar, Jun Chen, Sha Jin, Morey Smith, John Xue, Haichao Zhang, Anatol Oleksijew, Terrance J. Magoc, Kedar S. Vaidya, Daniel H. Albert, Jacqueline M. Tarrant, Nghi La, Le Wang, Zhi-Fu Tao, Michael D. Wendt, Deepak Sampath, Saul H. Rosenberg, Chris Tse, David C. S. Huang, Wayne J. Fairbrother, Steven W. Elmore, Andrew J. Souers
Journal: Science Translational Medicine (2015)

The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.
Telomere Biology and Cardiovascular Disease
Authors: José J. Fuster, Vicente Andrés
Journal: Circulation Research (2006)

Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease.
Transfusion-Related Cytomegalovirus Infection Following Noncardiac Surgery
Authors: W. Lawrence Drew
Journal: JAMA (1982)

Clinically evident cytomegalovirus (CMV) infections developed in five patients after noncardiac surgery. Each of them had received several blood transfusions and had evidence of primary CMV infection. These five cases were identified in a single eight-month period, suggesting that this syndrome must be occurring with greater frequency than is commonly appreciated. Three of the five patients had undergone splenectomy, and review of the literature for documented cases of posttransfusion CMV mononucleosis following non-cardiac-bypass surgery disclosed an additional nine patients, five of whom had had splenectomies. This striking association suggests the possibility that the spleen plays a role in controlling the incidence or clinical manifestations of posttransfusion CMV infections. Alternatively, this association may only reflect the frequent requirement for many blood transfusions in this type of surgery. (<i>JAMA</i>1982;247:2389-2391)
Estimating a Nucleotide Substitution Rate for Maize from Polymorphism at a Major Domestication Locus
Authors: Richard M. Clark, Simon Tavaré, John Doebley
Journal: Molecular Biology and Evolution (2005)

To estimate a rate for single nucleotide substitutions for maize (Zea mays ssp. mays), we have taken advantage of data from genetic and archaeological studies of the domestication of maize from its wild ancestor, teosinte (Z. mays ssp. parviglumis). Genetic studies have shown that the teosinte branched1 (tb1) gene was a major target of human selection during maize domestication, and sequence diversity in the intergenic region 5′ to the tb1-coding sequence is extraordinarily low. We show that polymorphism in this region is consistent with new mutation following fixation for a small number of tb1 haplotypes during domestication. Archeological studies suggest that maize was domesticated ∼6,250–10,000 years ago and subsequently the size of the maize population is thought to have expanded rapidly. Using the observed number of mutations within the region of selection at tb1, the approximate age of maize domestication, and approximations for the maize genealogy, we have derived estimates for the nucleotide substitution rate for the tb1 intergenic region. Using two approaches, one of which is a coalescent approach, we obtain rate estimates of ∼2.9 × 10−8 and 3.3 × 10−8 substitutions per site per year. We also show that the pattern of polymorphism in the tb1 intergenic region appears to have been strongly affected by the mutagenic effect of DNA methylation. Excluding target sites of symmetric DNA methylation (CG and CNG sites) from analysis, the mutation rate estimates are reduced by ∼50%–60%, while the rates for CG and CNG sites are nearly an order of magnitude higher. We use rate estimates from the tb1 region to estimate the timing of expansion of transposable elements in the maize genome and suggest that this expansion occurred primarily within the last million years.
Royal United Kingdom beneficent association
Authors: C. G. Scorer
Journal: BMJ (1969)

The following summer, during the routine examination of school " leavers," a girl aged 15 years was seen with a rash of typical distribution thought to be scabies.She was asked, largely by chance, if there were any starlings' nests at her home, and she replied that the loft was full of them.A visit to the house confirmed that this was so, the birds having gained access to the loft through a missing tile in the roof.The loft communicated directly with the girl's bedroom by an open ventilator in the ceiling.Nesting material was collected, and the presence of Dermanyssus gallinae again confirmed.Similar measures to the loft and bedroom coincided with early and complete recovery of the patient.Though not perhaps common, it is of some importance to identify these creatures cor- rectly, since infestation may recur despite treatment, as it did in two of our patients, if nesting material is not destroyed.Spontaneous recovery, however, should normally occur if the source of the mites is removed.-We are, etc.,
Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
Authors: Sarah V. Holt, Armelle Logie, Barry R. Davies, Denis Alferez, Sarah Runswick, Sarah Fenton, Christine M. Chresta, Yi Gu, Jingchuan Zhang, Yi-Long Wu, Robert W. Wilkinson, Sylvie M. Guichard, Paul D. Smith
Journal: Cancer Research (2012)

The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.
Spatial expression of transcription factors in Drosophila embryonic organ development
Authors: Ann S Hammonds, Christopher A Bristow, William W Fisher, Richard Weiszmann, Siqi Wu, Volker Hartenstein, Manolis Kellis, Bin Yu, Erwin Frise, Susan E Celniker
Journal: Genome biology (2013)

Abstract Background Site-specific transcription factors (TFs) bind DNA regulatory elements to control expression of target genes, forming the core of gene regulatory networks. Despite decades of research, most studies focus on only a small number of TFs and the roles of many remain unknown. Results We present a systematic characterization of spatiotemporal gene expression patterns for all known or predicted Drosophila TFs throughout embryogenesis, the first such comprehensive study for any metazoan animal. We generated RNA expression patterns for all 708 TFs by in situ hybridization, annotated the patterns using an anatomical controlled vocabulary, and analyzed TF expression in the context of organ system development. Nearly all TFs are expressed during embryogenesis and more than half are specifically expressed in the central nervous system. Compared to other genes, TFs are enriched early in the development of most organ systems, and throughout the development of the nervous system. Of the 535 TFs with spatially restricted expression, 79% are dynamically expressed in multiple organ systems while 21% show single-organ specificity. Of those expressed in multiple organ systems, 77 TFs are restricted to a single organ system either early or late in development. Expression patterns for 354 TFs are characterized for the first time in this study. Conclusions We produced a reference TF dataset for the investigation of gene regulatory networks in embryogenesis, and gained insight into the expression dynamics of the full complement of TFs controlling the development of each organ system.