tbuckley/cabot-search huggingface dataset:
Aging and epigenetic drift: a vicious cycle
Authors: Jean-Pierre Issa
Journal: Journal of Clinical Investigation (2014)

The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome - a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.
Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease
Authors: Fala El Machhour, Zela Keuylian, Panagiotis Kavvadas, Jean-Claude Dussaule, Christos Chatziantoniou
Journal: Journal of the American Society of Nephrology (2014)

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN.
Dexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation
Authors: Fotini Debonera, Alyssa M. Krasinkas, Andrew E. Gelman, Xavier Aldeguer, Xingye Que, Abraham Shaked, Kim M. Olthoff
Journal: Hepatology (2003)

Regeneration is crucial for the recovery of hepatic mass following liver transplantation. Glucocorticoids, immunosuppressive and antiinflammatory agents commonly used in transplantation, are known to inhibit the expression of specific cytokines and growth factors. Some of these proteins, namely tumor necrosis factor α (TNF–α) and interleukin 6 (IL–6), play a critical role in the initiation of liver regeneration. Following cold preservation and reperfusion of the transplanted liver, the normal recovery process is marked by increased expression of TNF–α and IL–6, followed by activation of cytokine–responsive transcription factors and progression of the cell cycle resulting in hepatocyte proliferation. We hypothesized that glucocorticoids may influence the repair mechanisms initiated after extended cold preservation and transplantation. Using a rat orthotopic liver transplant model, recipient animals were treated with dexamethasone at the time of transplantation of liver grafts with prolonged cold storage (16 hours). Treatment with dexamethasone suppressed and delayed the expression of TNF–α and IL–6 compared with animals receiving no treatment and attenuated downstream nuclear factor κB (NF–κB), signal transduction and activator of transcription 3 (STAT3), and activation protein 1 (AP–1) activation. This suppression was accompanied by poor cell–cycle progression, delayed cyclin D1 nuclear transposition, and impaired hepatocyte proliferation by BrdU uptake. Histologically, the liver grafts in treated animals demonstrated more injury than controls, which appeared to be necrosis, rather than apoptosis. In conclusion, these data provide evidence that the administration of glucocorticoids at the time of transplantation inhibits the initiation of the regenerative process and may have a deleterious effect on the recovery of liver grafts requiring significant regeneration. This may be particularly relevant for transplantation of partial liver grafts in the living donor setting.
Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels
Authors: Johannes-Peter Stasch, Peter M. Schmidt, Pavel I. Nedvetsky, Tatiana Y. Nedvetskaya, Arun Kumar H.S., Sabine Meurer, Martin Deile, Ashraf Taye, Andreas Knorr, Harald Lapp, Helmut Müller, Yagmur Turgay, Christiane Rothkegel, Adrian Tersteegen, Barbara Kemp-Harper, Werner Müller-Esterl, Harald H.H.W. Schmidt
Journal: Journal of Clinical Investigation (2006)

ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite. Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc–protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.
Serum levels of soluble interferon alfa/beta receptor as an inhibitory factor of interferon in the patients with chronic hepatitis C
Authors: Eishiro Mizukoshi, Shuichi Kaneko, Kyosuke Kaji, Shuichi Terasaki, Eiki Matsushita, Masahiro Muraguchi, Yasukazu Ohmoto, Kenichi Kobayashi
Journal: Hepatology (1999)

Human serum contains a soluble form of interferon alfa/beta (sIFN alpha/beta) receptors, the functional and clinical significance of which has not been investigated in patients with chronic hepatitis C. In the present study, serum levels of sIFN alpha/beta receptor were assessed in 81 patients with chronic hepatitis C and correlated with the effectiveness of IFN therapy in these patients. Serum levels of sIFN alpha/beta receptor were significantly higher in patients with chronic hepatitis C than in healthy control patients (P <.0001). In these patients, serum levels of sIFN alpha/beta receptor were correlated with those of alanine transaminase (ALT) (P <.05), (2'-5')serum oligo(A) synthetase (2-5AS) (P <.0001), and pathological stages of liver fibrosis (P <.01). In 55 patients with chronic hepatitis C who underwent IFN therapy, there was an inverse correlation between the pretherapeutic serum levels of sIFN alpha/beta receptor and the rate of increase in serum levels of 2-5AS after the start of IFN (P <.01). Pretherapeutic serum levels of sIFN alpha/beta receptor were significantly lower in patients who showed sustained response to IFN therapy compared with those who did not respond to the therapy (P <.05). Multivariate analysis showed that low levels of serum sIFN alpha/beta receptor (</=4.0 ng/mL) (P <.05) and serological hepatitis C virus genotype II (P <.05) were independent variables contributing to sustained response to IFN therapy. Thus, pretherapeutic serum levels of sIFN alpha/beta receptor were correlated with the effectiveness of IFN therapy, suggesting that sIFN alpha/beta receptor suppresses the effectiveness of IFN therapy in patients with chronic hepatitis C.
Absence of SOCS3 Regulation on gp130 Signaling in the Cardiac Myocyte Results in Increased Voltage-gated Sodium Channel (SCN5A) Current, Arrhythmogenicity and Cardiomyopathy
Authors: Toshitaka Yajima
Journal: Circulation (2009)

Abstract #3059 Toshitaka Yajima, Hanbing Zhou, Stanley Park, Jonathan Housman, Zhao-Hua Zhong, Byung-Kwan Lim, Platoshyn Oleksandr, Yusu Gu, Nancy Dalton, Tomoko Yajima, Jason X.-j. Yuan, Kirk U. Knowlton, Univ of California San Diego, La Jolla, CA Toshitaka Yajima, 2009 Finalist and Presenting Author
Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling
Authors: Yangbing Zhao, Maria R. Parkhurst, Zhili Zheng, Cyrille J. Cohen, John P. Riley, Luca Gattinoni, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan
Journal: Cancer Research (2007)

Adoptive cell transfer (ACT) of tumor-reactive lymphocytes has been shown to be an effective treatment for cancer patients. Studies in murine models of ACT indicated that antitumor efficacy of adoptively transferred T cells is dependent on the differentiation status of the cells, with lymphocyte differentiation inversely correlated with in vivo antitumor effectiveness. T-cell in vitro development technologies provide a new opportunity to generate naive T cells for the purpose of ACT. In this study, we genetically modified human umbilical cord blood-derived hematopoietic stem cells (HSCs) to express tumor antigen-specific T-cell receptor (TCR) genes and generated T lymphocytes by coculture with a murine cell line expressing Notch-1 ligand, Delta-like-1 (OP9-DL1). Input HSCs were differentiated into T cells as evidenced by the expression of T-cell markers, such as CD7, CD1a, CD4, CD8, and CD3, and by detection of TCR excision circles. We found that such in vitro differentiated T cells expressed the TCR and showed HLA-A2-restricted, specific recognition and killing of tumor antigen peptide-pulsed antigen-presenting cells but manifested additional natural killer cell-like killing of tumor cell lines. The genetic manipulation of HSCs has broad implications for ACT of cancer.
Timed regulation of P-element-induced wimpy testis–interacting RNA expression during rat liver regeneration
Authors: Francesca Rizzo, Adnan Hashim, Giovanna Marchese, Maria Ravo, Roberta Tarallo, Giovanni Nassa, Giorgio Giurato, Antonio Rinaldi, Angela Cordella, Marcello Persico, Pia Sulas, Andrea Perra, Giovanna M. Ledda-Columbano, Amedeo Columbano, Alessandro Weisz
Journal: Hepatology (2014)

Small noncoding RNAs comprise a growing family of molecules that regulate key cellular processes, including messenger RNA (mRNA) degradation, translational repression, and transcriptional gene silencing. P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) represent a class of small RNAs initially identified in the germline of a variety of species, where they contribute to maintenance of genome stability, and recently found expressed also in stem and somatic cells, where their role and responsiveness to physiopathological signals remain elusive. Here, we investigated piRNA expression in rat liver and its response to the stimuli exerted by regenerative proliferation of this organ. Quantitative polymerase chain reaction analysis identify in the liver the RNAs encoding PIWIL2/HILI, PIWIL4/HIWI2, and other components of the piRNA biogenesis pathways, suggesting that this is indeed functional. RNA sequencing before, during, and after the wave of cell proliferation that follows partial hepatectomy (PH) identified ˜1,400 mammalian germline piRNAs expressed in rat liver, including 72 showing timed changes in expression 24-48 hours post-PH, a timing that corresponds to cell transition through the S phase, returning to basal levels by 168 hours, when organ regeneration is completed and hepatocytes reach quiescence. Conclusion : The piRNA pathway is active in somatic cells of the liver and is subject to regulation during the pathophysiological process of organ regeneration, when these molecules are available to exert their regulatory functions on the cell genome and transcriptome, as demonstrated by the identification of several liver mRNAs representing candidate targets of these regulatory RNAs. (Hepatology 2014;60:798–806)
Cardiorespiratory consequences of sleep apnoea syndrome in patients with massive obesity
Authors: J-P. Laaban, D. Cassuto, E. Orvoën-Frija, M-C. Iliou, O. Mundler, D. Léger, J-M. Oppert
Journal: European Respiratory Journal (1998)

Assessment of cardiorespiratory consequences of sleep apnoea syndrome (SAS) is difficult owing to confounding factors, especially obesity, that are strongly associated with SAS. This study was designed to assess the cardiorespiratory consequences of SAS by comparing the results of a comprehensive cardiorespiratory evaluation in apnoeic and nonapnoeic patients with massive obesity. In a retrospective chart-review study, we studied 60 patients with massive obesity defined by a body mass index (BMI) >40 kg.m(-2), presenting no chronic respiratory disease, who underwent an extensive assessment of cardiorespiratory consequences of obesity, including overnight polysomnography, lung function tests, arterial blood gas analysis, evaluation of vascular risk factors, myocardial scintigraphy with dipyridamole stress-test, isotopic ventriculography, Doppler echocardiography and Holter electrocardiogram recording. SAS defined by an apnoea + hypopnoea index (AHI) > or = 10 was diagnosed in 42% of patients (25 out of 60). Mean+/-SD AHI of SAS-positive (SAS+) patients was 38+/-24. Age, BMI, ventilatory function parameters, prevalence of smoking history and diabetes mellitus did not differ significantly in SAS+ versus SAS-negative (SAS-) groups. The following complications were observed more frequently in SAS+ than in SAS- patients: daytime hypoxaemia (35 vs 9%, p<0.02), pulmonary arterial hypertension (36 vs 7%, p<0.05) and increased interventricular septal thickness (50 vs 15%, p<0.03). No association was found between SAS on the one hand and systemic arterial hypertension, coronary artery disease, left ventricular dysfunction and nocturnal cardiac arrhythmias on the other. Nocturnal apnoeas in massive obesity may thus be associated with moderate daytime hypoxaemia, mild pulmonary arterial hypertension and moderate left ventricular hypertrophy, but not with severe cardiorespiratory complications.
Regulated expression of telomerase activity in human T lymphocyte development and activation.
Authors: N P Weng, B L Levine, C H June, R J Hodes
Journal: The Journal of Experimental Medicine (1996)

Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells, and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. In the present study, telomerase activity was analyzed in normal human T lymphocytes. It was found that telomerase is expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T lymphocytes, and at a low to undetectable level in peripheral blood T lymphocytes. Moreover, telomerase activity is highly inducible in peripheral T lymphocytes by activation through CD3 with or without CD28 costimulation, or by stimulation with phorbol myristate acetate (PMA)/ionomycin. The induction of telomerase by anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation required RNA and protein synthesis, and was blocked by herbimycin A, an inhibitor of S pi protein tyrosine kinases. The immunosuppressive drug cyclosporin A selectively inhibited telomerase induction by PMA/ionomycin and by anti-CD3, but not by anti-CD3/CD28. Although telomerase activity in peripheral T lymphocytes was activation dependent and correlated with cell proliferation, it was not cell cycle phase restricted. These results indicate that the expression of telomerase in normal human T lymphocytes is both developmentally regulated and activation induced. Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for cell division and clonal expansion.
Concanavalin A-inducible, interleukin-2-producing T cell hybridoma.
Authors: L Harwell, B Skidmore, P Marrack, J Kappler
Journal: The Journal of Experimental Medicine (1980)

The fusion of an AKR T cell tumor line to normal B6D2F1, T cells resulted in the production of a cloned T cell hybridoma (FS6-14.13) inducible with the mitogen concanavalin A (Con A). The supernate from Con A-stimulated hybridoma cells was active both in the stimulation of an anti-sheep red blood cell response by partially T cell-depleted B cells and in the stimulation of the growth of antigen-specific T cell blasts. The active principle in both assays had a molecular weight of approximately 30-40,000. These results indicated the presence of interleukin 2 (IL2) in the hybridoma supernate. The activity of the hybridoma supernate in B cell responses was dependent on the presence of adherent cells and a few contaminating T cells. On the other hand, Con A-stimulated supernates from normal spleen cells were active after either adherent cell removal or severe T cell depletion. These results suggested that IL2 was the only active helper factor in the hybridoma supernate, but that additional helper factors were present in supernates from Con A-stimulated normal spleen cells.
Epithelial tubulogenesis through branching morphogenesis
Authors: R O Stuart, E J Barros, E Ribeiro, S K Nigam
Journal: Journal of the American Society of Nephrology (1995)

Branching tubulogenesis of the ureteric bud, which gives rise to the urinary collecting system, is of considerable clinical interest because this process plays a major role in determining nephron number in the kidney. Data from in vitro model systems, including organ culture of the embryonic kidney and renal epithelial cells cultured in three-dimensional collagen matrices, indicate that growth factors, extracellular matrix composition, matrix-remodeling proteinases, and integrin expression are important factors in tubulogenesis and branching in the renal epithelium. One possibility is that gradients of soluble factors in the interstitial milieu of the embryonic kidney regulate the directionality of tubulogenesis and the degree of branching. Growth factors that enhance branching also appear to up-regulate matrix-remodeling extracellular proteinases. Redundancy in the ability of growth factors to induce tubulogenesis and branching may explain the apparent lack of a renal phenotype observed in targeted growth factor gene deletion experiments in mice. At the same time, differential effects in the efficiency of growth factors in inducing branching and/or changes in local matrix composition may be important in regulating the degree of arborization of the developing collecting system.
Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex
Authors: Hua-Feng Zhang, Akihiro Tomida, Ritsuko Koshimizu, Yasunari Ogiso, Shuhong Lei, Takashi Tsuruo
Journal: Cancer Research (2004)

Abstract DNA topoisomerase I (TOP1)-DNA covalent complexes are the initial lesions produced by antitumor camptothecins (CPTs). The TOP1-directed drugs stimulate degradation of TOP1 via the ubiquitin-proteasome pathway. We found that proteasome inhibition prevents degradation of DNA-bound TOP1 and sustains high levels of covalent complexes, thus enhancing CPT-induced cell death. Consistent with this, increased degradation of TOP1-DNA covalent complexes was seen in acquired CPT-resistant cells. We found that the resistant cells showed elevated expressions of Cul3, a member of the cullin family of E3 ubiquitin ligases. The reduction in Cul3 expression by small interfering RNA decreased degradation of TOP1-DNA covalent complexes. Conversely, Cul3 overexpression by stable transfection promoted covalent complex degradation and reduced CPT-induced cell death without affecting basal TOP1 expression levels. These results indicate that Cul3, by promoting proteasomal degradation of TOP1-DNA covalent complexes, becomes an important regulator for cellular CPT sensitivity.
Lyt-23+ cyclophosphamide-sensitive T cells regulate the activity of an interleukin 2 inhibitor in vivo.
Authors: C Hardt, M Röllinghoff, K Pfizenmaier, H Mosmann, H Wagner
Journal: The Journal of Experimental Medicine (1981)

Sera of thymus-bearing normal mice contain high levels of Interleukin 2 (II-2) inhibitor, whereas sera of athymic nu/nu mice do not. Evidence is presented that cyclophosphamide-sensitive Lyt-23+ T cells induce high II-2 inhibitor activity in the recipient nu/nu mice in the course of a graft-vs.-host reaction. The II-2 inhibitor has an approximately 50,000 mol wt. Its function is neither antigen specific nor H-2 restricted. During ontogeny, its activity parallels the development of T cell reactivity, i.e., it is absent both in the amniotic fluid and in sera of unborn mice, but increases to high levels during the early postnatal phase. The II-2 inhibitor described is viewed as an example of a T cell-dependent, in vivo regulatory mechanism able to effectively counteract the nonspecific activity of the Lyt-1+ helper T cell-derived II-2. Because the II-2 inhibitor activity is rather high in vivo, II-2 activity will exist only in close proximity to its producer cell, thereby maintaining specificity during the in vivo induction of cytotoxic T lymphocytes
ST-segment elevation myocardial infarction in China from 2001 to 2011 (the China PEACE-Retrospective Acute Myocardial Infarction Study): a retrospective analysis of hospital data
Authors: Jing Li, Xi Li, Qing Wang, Shuang Hu, Yongfei Wang, Frederick A Masoudi, John A Spertus, Harlan M Krumholz, Lixin Jiang
Journal: The Lancet (2014)