tbuckley/cabot-search huggingface dataset:
Genome Editing of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells With Zinc Finger Nucleases for Cellular Imaging
Authors: Yongming Wang, Wendy Y. Zhang, Shijun Hu, Feng Lan, Andrew S. Lee, Bruno Huber, Leszek Lisowski, Ping Liang, Mei Huang, Patricia E. de Almeida, Jong H. Won, Ning Sun, Robert C. Robbins, Mark A. Kay, Fyodor D. Urnov, Joseph C. Wu
Journal: Circulation Research (2012)

Molecular imaging has proven to be a vital tool in the characterization of stem cell behavior in vivo. However, the integration of reporter genes has typically relied on random integration, a method that is associated with unwanted insertional mutagenesis and positional effects on transgene expression.To address this barrier, we used genome editing with zinc finger nuclease (ZFN) technology to integrate reporter genes into a safe harbor gene locus (PPP1R12C, also known as AAVS1) in the genome of human embryonic stem cells and human induced pluripotent stem cells for molecular imaging.We used ZFN technology to integrate a construct containing monomeric red fluorescent protein, firefly luciferase, and herpes simplex virus thymidine kinase reporter genes driven by a constitutive ubiquitin promoter into a safe harbor locus for fluorescence imaging, bioluminescence imaging, and positron emission tomography imaging, respectively. High efficiency of ZFN-mediated targeted integration was achieved in both human embryonic stem cells and induced pluripotent stem cells. ZFN-edited cells maintained both pluripotency and long-term reporter gene expression. Functionally, we successfully tracked the survival of ZFN-edited human embryonic stem cells and their differentiated cardiomyocytes and endothelial cells in murine models, demonstrating the use of ZFN-edited cells for preclinical studies in regenerative medicine.Our study demonstrates a novel application of ZFN technology to the targeted genetic engineering of human pluripotent stem cells and their progeny for molecular imaging in vitro and in vivo.
Tissue culture of isolated glomeruli in experimental crescentic glomerulonephritis.
Authors: S R Holdsworth, N M Thomson, E F Glasgow, J P Dowling, R C Atkins
Journal: The Journal of Experimental Medicine (1978)

As a means of studying mechanisms of response to injury in glomerulonephritis, glomeruli from normal sheep and rabbits and from sheep and rabbits with experimental crescentic glomerulonephritis have been isolated and grown in tissue culture. The cellular outgrowths from the normal and diseased glomeruli have been compared. The outgrowth of glomeruli from normal animals contained only two cell populations whose microscopic and ultrastructural appearances were of epithelial and mesangial cells. The same cells were also observed in the outgrowths of glomeruli from animals with crescenti nephritis but in addition a third population of cells was present in large numbers. These cells were identified as macrophages by their mobility, ultrastructure, phagocytic capacity, and presence of Fc receptors. Glomerular outgrowth from sheep with crescentic glomerulonephritis contained 170 +/- 20 (SEM) macrophages and outgrowths from rabbits with crescentic nephritis contained 64 +/- 6 (SEM) macrophages per glomerulus. We have previously observed large numbers of macrophages in the outgrowth of isolated glomeruli from humans with rapidly progressive crescentic glomerulonephritis. The predominance of the macrophage in cultures of glomeruli from both human and animal crescentic glomerulonephritis suggests that this is an important cell in the inflammatory reaction occurring in crescentic glomerulonephritis and may comprise a substantial proportion of the cells forming the crescent.
Twenty-fifth Annual Pezcoller Symposium: Metabolism and Tumorigenesis
Authors: William Kaelin, David Livingston, Massimo Loda, Karen Vousden, Enrico Mihich
Journal: Cancer Research (2013)

Choking cancer via inhibition of metabolic enzymes essential for tumor but dispensable in normal tissues was discussed as was the altered metabolism in cancer cells related to: tumor suppressor protein (pVHL) function, the histone acetylation dependence upon glucose, the epigenomic reprogramming of acetyl CoA synthesis, the plasticity of aging mechanisms, and the metabolism orchestration in macrophage polarization. The p53 and p73 pathways role in metabolic adaptation, the effects on growth of AMP-dependent kinase, the growth regulation by the mTOR pathways, and the bioenergetics requirements of cancer cells were also discussed. A novel computational model of personalized metabolic changes in cancer was outlined with applications in patients with breast cancer. Imaging metabolic characteristics of tumors by MRI and (13)C-nuclear magnetic resonance was described. The cancer metabolism regulation related to O-linked β-N-acetylglucosame was described. DNA hypermethylation and impaired hematopoietic differentiation in AML after isocitrate dehydrogenase 1/2 mutation and 2-hydroxyglutarate increases were outlined.
Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG)
Authors: D. Garbay, A. Le Cesne, N. Penel, C. Chevreau, P. Marec-Berard, J.-Y. Blay, M. Debled, N. Isambert, A. Thyss, E. Bompas, O. Collard, S. Salas, J.-M. Coindre, B. Bui, A. Italiano
Journal: Annals of Oncology (2011)
Effects of Acyclic Retinoid on Growth, Cell Cycle Control, Epidermal Growth Factor Receptor Signaling, and Gene Expression in Human Squamous Cell Carcinoma Cells
Authors: Masahito Shimizu, Masumi Suzui, Atsuko Deguchi, Jin T. E. Lim, I. Bernard Weinstein
Journal: Clinical Cancer Research (2004)

Abstract We described recently the growth inhibitory effects of the novel compound acyclic retinoid (ACR) in human hepatoma cell lines (M. Suzui et al., Cancer Res., 62: 3997–4006, 2002). In this study we examined the cellular and molecular effects of ACR on human squamous cell carcinoma (SCC) cells. ACR inhibited growth of the esophageal SCC cell line HCE7, and the head and neck SCC cell lines YCU-N861 and YCU-H891, with IC50 values of ∼10, 25, and 40 μm, respectively. Detailed studies were then done with HCE7 cells. Treatment of these cells with 10 μm ACR caused an increase of cells in G0-G1 and induced apoptosis. This was associated with two phases of molecular events. During phase 1, which occurred within 6–12 h, there was an increase in the retinoic acid receptor β (RARβ) and p21CIP1 proteins, and their corresponding mRNAs, and a decrease in the hyperphosphorylated form of the retinoblastoma protein. During phase 2, which occurred at ∼24 h, there was a decrease in the cellular level of transforming growth factor α, and the phosphorylated (i.e., activated) forms of the epidermal growth factor receptor, Stat3, and extracellular signal-regulated kinase proteins, and a decrease in both cyclin D1 protein and mRNA. Reporter assays indicated that ACR inhibited the transcriptional activity of the cyclin D1, c-fos, and activator protein promoters. On the other hand, ACR markedly stimulated the activity of a retinoic acid response element-CAT reporter when the cells were cotransfected with a RARβ expression vector. A hypothetical model explaining these two phases is presented. The diverse effects that we obtained with ACR suggest that this agent might be useful in the chemoprevention and/or therapy of human SCCs.
A randomized multicenter phase II trial on the efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma
Authors: N. Shinohara, N. Nonomura, M. Eto, G. Kimura, H. Minami, S. Tokunaga, S. Naito
Journal: Annals of Oncology (2013)
Suppression of the antistreptolysin O response by cholesterol and by lipid extracts of rabbit skin.
Authors: E L Kaplan, L W Wannamaker
Journal: The Journal of Experimental Medicine (1976)

Lipids extracted from rabbit skin block the hemolytic capacity of SO and also suppress the neutralizing antibody response to this streptococcal extracellular antigen in rabbith immunized intravenosly. The modification in antibody response is specific for SO; the antibody responses to streptococcal DNase B and to streptococcal NADase are not affected. Cholesterol, a lipid present in abundance in skin, has a similar specific effect on the antigenicity of SO and may be the component responsible for the demonstrated effects of these lipid extracts of skin. In vitro experiments indicate that lipid extracts of rabbit skin have a greater capacity to block the hemolytic capacity of SO than do lipid extracts of rabbit heart, kidney, lung, liver, or spleen. These data support the view that the feeble ASO response observed in patients with streptococcal pyoderma is a result of the abundance of a local lipid inhibitor, such as cholesterol, in the skin. They may also bear on the pathogenesis of rheumatic fever, a complication which apparently does not occur following group A streptococcal pyoderma. Two possible explanations for this remarkable epidemiologic observation, both related to the presence of a local inhibitor, are considered: (a) suppression of the ASO response, the magnitude of which has been correlated with the risk of developing rheumatic fever after streptococcal infection of the throat, and (b) inhibition of the toxicity of SO, which has been shown to have a direct toxic effect on the mammalian heart and on isolated beating myocytes.
Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner
Authors: Jianjun Lei, Jiguang Ma, Qingyong Ma, Xuqi Li, Han Liu, Qinhong Xu, Wanxing Duan, Qing Sun, Jun Xu, Zheng Wu, Erxi Wu
Journal: Molecular Cancer (2013)

Hypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion.Pancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay.Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA. In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-β, KRAS or RTK) bypassing SMO to activate GLI1 directly.Our findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.
Molecular Characterization of Waldenstrom's Macroglobulinemia Reveals Frequent Occurrence of Two B-Cell Clones Having Distinct IgH VDJ Sequences
Authors: Jitra Kriangkum, Brian J. Taylor, Steven P. Treon, Michael J. Mant, Tony Reiman, Andrew R. Belch, Linda M. Pilarski
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Malignant B lineage cells in Waldenstrom's macroglobulinemia (WM) express a unique clonotypic IgM VDJ. The occurrence of biclonal B cells and their clonal relationships were characterized. Experimental Design: Bone marrow and blood from 20 WM patients were analyzed for clonotypic VDJ sequences, clonal B-cell frequencies, and the complementary determining region 3 profile. Results: Two different clonotypic VDJ sequences were identified in 4 of 20 WM. In two cases, partner clones had different VDJ rearrangements, with one clonotypic signature in bone marrow and a second in blood. For both cases, the bone marrow clone was hypermutated, whereas the blood clone was germ line or minimally mutated. In two other cases, partner clones shared a common VDJ rearrangement but had different patterns of somatic mutations. They lacked intraclonal diversity and were more abundant in bone marrow than in blood. VDJ mutation profiles suggested they arose from a common IgM progenitor. Single-cell analysis in one case indicated the partner clones were reciprocally expressed, following rules of allelic exclusion. Conclusions: The existence of two B-cell clones having distinct VDJ sequences is common in WM, suggesting that frequent transformation events may occur. In two cases, the partner clones had distinct tissue distributions in either blood or bone marrow, were of different immunoglobulin isotypes, and in one case exhibited differential response to therapy. The contributions of each clone are unknown. Their presence suggests that WM may involve a background of molecular and cellular events leading to emergence of one or more malignant clones.
Highly Active Antiretroviral Therapy and the Epidemic of HIV+ End-Stage Renal Disease
Authors: Elissa J. Schwartz, Lynda A. Szczech, Michael J. Ross, Mary E. Klotman, Jonathan A. Winston, Paul E. Klotman
Journal: Journal of the American Society of Nephrology (2005)

The rise in the number of patients with HIV-associated nephropathy and HIV-infection with end-stage renal disease (HIV+ ESRD) continues to be a substantial concern for the ESRD program. In order to assess the impact of highly active antiretroviral therapy (HAART) on the progression of patients with AIDS to the development of ESRD and to project the prevalence of HIV+ ESRD through 2020, a mathematical model of the dynamics of HIV+ infection in the ESRD population was developed. Epidemiologic data on AIDS and HIV+ ESRD among black individuals in the United States were obtained since 1991 from the Centers for Disease Control and Prevention and US Renal Data System, respectively. The model was constructed to predict the prevalence of HIV+ ESRD incorporating the current rate of growth in AIDS prevalence. Two possible trends were considered: linear AIDS growth and exponential AIDS growth. The likely effectiveness of HAART in slowing progression to HIV+ ESRD was estimated from the best fit of the model to the data after 1995, when HAART was introduced. The model was then used to evaluate recent data and to project the prevalence of HIV+ ESRD through 2020. The model suggested that HAART has reduced the rate of progression from AIDS to HIV+ ESRD by 38%. The model projected an increase in HIV+ ESRD prevalence in the future as a result of the increase in the AIDS population among black individuals. This increase was predicted even assuming a 95% reduction in the progression from AIDS to HIV+ ESRD. Despite the potential benefit of HAART, the prevalence of HIV+ ESRD in the United States is expected to rise in the future as a result of the expansion of the AIDS population among black individuals. It is concluded that prevention of progression to ESRD should focus on early antiretroviral treatment of HIV-infected patients who have evidence of HIV-associated nephropathy.
Effects of IL-4Rα Blockade on Lung Inflammation and Airway Hyperresponsiveness Using Mu317RAXMu, a Murine Surrogate for AMG 317, in a Treatment Model of Cockroach Allergen-Induced Asthma in Mice
Authors: D SWART, P ANDERSBARTHOLO, J TOCKER
Journal: Journal of Allergy and Clinical Immunology (2008)
Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving
Authors: Jessica A Loweth, Andrew F Scheyer, Mike Milovanovic, Amber L LaCrosse, Eden Flores-Barrera, Craig T Werner, Xuan Li, Kerstin A Ford, Tuan Le, M Foster Olive, Karen K Szumlinski, Kuei Y Tseng, Marina E Wolf
Journal: Nature Neuroscience (2013)
Genetic Variation in the Promoter Region of <i>Chitinase 3-Like 1</i> Is Associated with Atopy
Authors: Myung Hyun Sohn, Ji Hyun Lee, Kyung Won Kim, So Won Kim, Sung Hee Lee, Kyu-Earn Kim, Kyung Hwan Kim, Chun Geun Lee, Jack A Elias, Min Goo Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Atopy or atopic syndrome is an allergic hypersensitivity subject to hereditary influences. Aberrant expression of chitinase 3-like 1 (CHI3L1), also known as YKL-40 or HC gp-39, is involved in the pathogenesis of inflammatory and allergic diseases.The genetic contribution of CHI3L1 gene to atopic susceptibility was investigated using an integrated population genetic and molecular analysis.Genetic variations in CHI3L1 were identified and genotyped in 295 unrelated patients with atopy and 180 control subjects. Serum YKL-40 and IgE levels were analyzed according to genotype. The effects of a promoter polymorphism (g.-247C/T) on promoter activity were examined in reporter and protein binding assays.In the case-control association analysis, the g.-247C/T polymorphism at the promoter region (rs10399805; P = 0.0062) and the IVS7+82C/T polymorphism at intron 7 (rs2275353; P = 0.0056) of CHI3L1 showed a significant association with atopy. Subjects with the g.-247T risk allele had significantly higher serum YKL-40 (P < 0.0001) and IgE (P = 0.012) levels. An in vitro promoter assay using THP-1 human monocyte cells revealed that the C to T conversion at g.-247 induced a more than twofold increase of reporter gene expression. Moreover, the g.-247T allele showed an increased affinity for CCAAT enhancer-binding protein, a well known transcriptional activator, by electrophoretic mobility shift assay. Accordingly, subjects with the g.-247TT genotype showed a 2.5-fold increase in CHI3L1 mRNA expression in peripheral blood cells compared with those with the g.-247CC genotype.These results strongly suggest that the g.-247C/T polymorphism in the CHI3L1 promoter region is associated with the risk of atopy.
Angiogenic Role of LYVE-1–Positive Macrophages in Adipose Tissue
Authors: Chung-Hyun Cho, Young Jun Koh, Jinah Han, Hoon-Ki Sung, Hyuek Jong Lee, Tohru Morisada, Reto A. Schwendener, Rolf A. Brekken, Guson Kang, Yuichi Oike, Tae-Saeng Choi, Toshio Suda, Ook-Joon Yoo, Gou Young Koh
Journal: Circulation Research (2007)

Here we report the discovery of a characteristic dense vascular network (DVN) in the tip portion of epididymal adipose tissue in adult mice. The DVN is formed by angiogenesis rather than by vasculogenesis, and has functional blood circulation. This DVN and its subsequent branching may provide a new functional route for adipogenesis. The recruitment, infiltration, and accumulation of bone marrow-derived LYVE-1 + macrophages in the tip region are crucial for the formation of the DVN. Matrix metalloproteinases (MMPs) and the VEGF-VEGFR2 system are responsible not only for the formation of the DVN, but also for the recruitment and infiltration of LYVE-1 + macrophages into the epididymal adipose tissue tip region. SDF-1, but not the MCP-1-CCR2 system, is a critical factor in recruitment and ongoing retention of macrophages in this area. We also demonstrate that the tip region of epididymal adipose tissue is highly hypoxic, and thus provides a microenvironment conducive to the high expression and enhanced activities of VEGF, VEGFR2, MMPs, and SDF-1 in autocrine and paracrine manners, to create an ideal niche for the recruitment, retention, and angiogenic action of macrophages. These findings shed light on the complex interplay between macrophage infiltration, angiogenesis, and adipogenesis in the tip region of adult epididymal adipose tissue, and provide novel insight into the regulation of alternative outgrowth of adipose tissue.
Choosing the programme for an international congress.
Authors: D R Appleton, D N Kerr
Journal: BMJ (1978)

The method of selecting abstracts for an international congress at which only 15% of submitted papers could be accepted entailed a panel of 12 assessors using their specialised knowledge, but presentation of the abstract was also important is selection. There was only a limited agreement between assessors in arranging abstracts in order of merit, so that a single assessor would be unacceptable. Use of the full panel to grade all abstracts was very expensive, but it could be replaced, without unacceptable injustice, by dividing the work randomly among groups of three selectors.
Strong and Selective Glomerular Localization of CD134 Ligand and TNF Receptor-1 in Proliferative Lupus Nephritis
Authors: JAN ATEN, ANJA ROOS, NIKE CLAESSEN, ESTHER J. M. SCHILDER-TOL, INEKE J. M. TEN BERGE, JAN J. WEENING
Journal: Journal of the American Society of Nephrology (2000)

Abstract. CD134 (OX40) is a member of the tumor necrosis factor (TNF) receptor (TNFR) family that can be expressed on activated T lymphocytes. Interaction between CD134 and its ligand (CD134L) is involved in costimulation of T and B lymphocyte activation, and in T cell adhesion to endothelium. To examine the possible role of this interaction in the pathogenesis of systemic lupus erythematosus (SLE), expression of CD134 and CD134L on peripheral blood leukocytes was studied, and no significant differences between SLE patients and control individuals were found. Immunohistology on renal biopsies from patients with lupus nephritis or other renal disorders, using a recombinant human CD134-containing chimeric molecule to detect CD134L, demonstrated the abundant presence of CD134L in all cases of proliferative lupus nephritis in a granular distribution predominantly along the epithelial side of the glomerular capillary wall. Confocal laser scanning microscopy indicated colocalization with subepithelial immune deposits. In none of the other renal disorders examined, including nonproliferative forms of lupus nephritis, was glomerular staining for CD134L detected in a similar pattern. Endothelial CD134L expression was frequently observed in different types of vasculitis. CD134 was detected on perivascular infiltrating leukocytes and on part of the tubular epithelium, but not on glomerular resident cells. Immunohistology for several other TNF(R) family members revealed in proliferative lupus nephritis a similar distribution for TNFR1 as was observed for CD134L. In contrast, glomerular expression of TNFR2 was similar in all cases examined. The glomerular presence of CD134L and TNFR1 in proliferative lupus nephritis in association with subepithelial immune deposits may be of pathogenetic significance and have diagnostic value.