tbuckley/cabot-search huggingface dataset:
NFAT1 Supports Tumor-induced Anergy of CD4+ T Cells
Authors: Brian T. Abe, Daniel S. Shin, Enric Mocholi, Fernando Macian
Journal: Cancer Research (2012)

Abstract Cancer cells express antigens that elicit T cell-mediated responses, but these responses are limited during malignant progression by the development of immunosuppressive mechanisms in the tumor microenvironment that drive immune escape. T-cell hyporesponsiveness can be caused by clonal anergy or adaptive tolerance, but the pathophysiological roles of these processes in specific tumor contexts has yet to be understood. In CD4+ T cells, clonal anergy occurs when the T-cell receptor is activated in the absence of a costimulatory signal. Here we report that the key T-cell transcription factor NFAT mediates expression of anergy-associated genes in the context of cancer. Specifically, in a murine model of melanoma, we found that cancer cells induced anergy in antigen-specific CD4+ T-cell populations, resulting in defective production of several key effector cytokines. NFAT1 deficiency blunted the induction of anergy in tumor antigen-specific CD4+ T cells, enhancing antitumor responses. These investigations identified tumor-induced T-cell hyporesponsiveness as a form of clonal anergy, and they supported an important role for CD4+ T-cell anergy in driving immune escape. By illustrating the dependence of tumor-induced CD4+ T-cell anergy on NFAT1, our findings open the possibility of targeting this transcription factor to improve the efficacy of cancer immunotherapy or immunochemotherapy. Cancer Res; 72(18); 4642–51. ©2012 AACR.
Self recognition in allogeneic radiation bone marrow chimeras. A radiation- resistant host element dictates the self specificity and immune response gene phenotype of T-helper cells
Authors: A Singer, KS Hathcock, RJ Hodes
Journal: The Journal of Experimental Medicine (1981)

The specificity of the self-recognition repertoire in fully allogeneic (A {arrow} B), semiallogeneic (A {arrow} A x B and A x B {arrow} A), and double donor (A + B {arrow} A) radiation bone marrow chimeras was assessed by the ability of their spleen cells to generate in vitro primary plaque-forming cell (PFC) responses to trinitrophenyl- keyhole limpet hemocyanin. In contrast to spleen cells from semiallogeneic and double donor chimeras, intact spleen cells from fully allogeneic BI0 {arrow} B10.A and B10.A {arrow} B10 chimeras were not capable of generating responses to trinitrophenyl (TNP)-keyhole limpet hemocyanin. However, cultures containing a mixture of both B10 {arrow} B10.A and B10.A {arrow} B10 spleen cells did respond, demonstrating that all the cell populations required for the in vitro generation of T-dependent PFC responses were able to differentiate into functional competence in a fully allogeneic major histocompatibility complex (MHC) environment. The self recognition repertoire of T-helper cells from fully allogeneic A {arrow} B chimeras was determined to be specific for the recognition of host, not donor, MHC determinants in that they were able to collaborate with cells expressing only host MHC determinants but not with cells expressing only donor MHC determinants, even though the functional lymphocytes in these chimeras were shown to be of donor origin. Experiments utilizing double donor A + B {arrow} A chimeras further demonstrated that the ability of chimeric T cells to recognize allogeneic MHC determinants as self structures was a function of a radiation-resistant host element and not simply a consequence of the tolerization of T cell precursors to allogeneic MHC determinants, because strain A lymphocytes isolated from A + B {arrow} A chimeras were tolerant to both A and B MHC determinants but were restricted to the self recognition of syngeneic host type A MHC determinants. Finally, the Ir gene phenotype expressed by B10 {arrow} B10.A and B10.A {arrow} B10 chimeric lymphocytes was determined by their ability to function in the Ir gene controlled response to TNP-poly-L-(Tyr,Glu)-poly-D,L-Ala-poly- L-Lys [(T,G)-A--L]. The ability of lymphocytes to function in TNP-(T,G)-A--L responses was not determined by their genotype but rather paralleled the specificity of their self recognition repertoire for high responder (H-2 (b)) determinants. The possible degeneracy of the MHC-specific self recognition repertoire is discussed, and a model is proposed for Ir gene regulation in which expression of Ir gene function by lymphocytes is an antigen-nonspecific consequence of the specificity and cross-reactivity of their self recognition repertoire.
Analysis of Gene Expression Profiles of Microdissected Cell Populations Indicates that Testicular Carcinoma <i>In situ</i> Is an Arrested Gonocyte
Authors: Si Brask Sonne, Kristian Almstrup, Marlene Dalgaard, Agnieszka Sierakowska Juncker, Daniel Edsgard, Ludmila Ruban, Neil J. Harrison, Christian Schwager, Amir Abdollahi, Peter E. Huber, Søren Brunak, Lise Mette Gjerdrum, Harry D. Moore, Peter W. Andrews, Niels E. Skakkebaek, Ewa Rajpert-De Meyts, Henrik Leffers
Journal: Cancer Research (2009)

Testicular germ cell cancers in young adult men derive from a precursor lesion called carcinoma in situ (CIS) of the testis. CIS cells were suggested to arise from primordial germ cells or gonocytes. However, direct studies on purified samples of CIS cells are lacking. To overcome this problem, we performed laser microdissection of CIS cells. Highly enriched cell populations were obtained and subjected to gene expression analysis. The expression profile of CIS cells was compared with microdissected gonocytes, oogonia, and cultured embryonic stem cells with and without genomic aberrations. Three samples of each tissue type were used for the analyses. Unique expression patterns for these developmentally very related cell types revealed that CIS cells were very similar to gonocytes because only five genes distinguished these two cell types. We did not find indications that CIS was derived from a meiotic cell, and the similarity to embryonic stem cells was modest compared with gonocytes. Thus, we provide new evidence that the molecular phenotype of CIS cells is similar to that of gonocytes. Our data are in line with the idea that CIS cells may be gonocytes that survived in the postnatal testis. We speculate that disturbed development of somatic cells in the fetal testis may play a role in allowing undifferentiated cells to survive in the postnatal testes. The further development of CIS into invasive germ cell tumors may depend on signals from their postpubertal niche of somatic cells, including hormones and growth factors from Leydig and Sertoli cells.
Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors
Authors: Jerry Guintivano, Tori Brown, Alison Newcomer, Marcus Jones, Olivia Cox, Brion S. Maher, William W. Eaton, Jennifer L. Payne, Holly C. Wilcox, Zachary A. Kaminsky
Journal: American Journal of Psychiatry (2014)

Considerable research suggests that suicide involves effects of genes, the environment, and their interaction. Analysis of three independent data sets of post-mortem brains revealed signs of increased methylation in one particular gene, SKA2, a finding that was extended to peripheral blood samples from other cohorts of prospectively followed individuals.
Hepatitis C infection and the patient with end-stage renal disease
Authors: Fabrizio Fabrizi, F. Fred Poordad, Paul Martin
Journal: Hepatology (2002)

Hepatitis C virus (HCV) remains common in patients with end-stage renal disease (ESRD) and is an important cause of liver disease in this population. Acquisition of HCV infection continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis patients remains controversial because the course of HCV typically extends over decades, whereas dialysis patients have higher morbidity and mortality rates than those of the general population limiting long-term follow-up. However, recent reports suggest that HCV infection affects the survival of chronic dialysis patients as well as renal transplant (RT) recipients. The severity of preexisting liver disease on pretransplantation liver biopsy may provide useful prognostic information about clinical outcome after RT; liver biopsy should be incorporated in the evaluation and management of RT candidates with HCV. Recent surveys with long-term follow-up have documented adverse effects of HCV on patient and graft survival. Use of renal grafts from HCV-infected donors in recipients with HCV does not appear to result in a greater burden of liver disease albeit with short-term follow-up. There is only limited data about interferon (IFN) therapy in chronic dialysis patients, although sustained responses are reported. Preliminary data on IFN plus ribavirin therapy in dialysis patients with hepatitis C have given encouraging results, but randomized trials are needed. Interferon remains contraindicated post-RT because of concern about precipitating graft dysfunction.
INTRACELLULAR CHANGES DUE TO NEUTRAL RED AS REVEALED IN THE PANCREAS AND KIDNEY OF THE MOUSE BY THE ELECTRON MICROSCOPE
Authors: Jules M. Weiss
Journal: The Journal of Experimental Medicine (1955)

The effects of sublethal amounts of the cationic dye, neutral red, upon the structure of pancreatic exocrine cells, and upon the mitochondria of renal distal tubule cells, have been studied with the electron microscope. It was found that neutral red is a cytoplasmic toxin which causes reproducible and characteristic changes in the ergastoplasm, the zymogen granules, the mitochondria, and possibly in the Golgi complex. Ergastoplasmic membranes and granules and zymogen granules lose definition and become continuous with the cytoplasmic matrix. Mitochondria lose their internal folds, develop vacuoles which contain a solution of neutral red in high concentration, and form the nidus for the development of sudanophilic, argyrophilic, osmiophilic inclusions which appear in the cytoplasm after neutral red administration. Golgi granules, one of the three elements of the Golgi complex, appear to increase in number and to be scattered more widely through the cytoplasm than is normal. No consistent changes were found in the cell membrane or nucleus. The ability of the mitochondria to concentrate the cation, neutral red, taken with its well known ability to concentrate the cationic Janus dyes and methylene blue, and its probable role in concentrating those cationic dyes which have been used to demonstrate the "vacuome," is interpreted to signify that one of the functions of mitochondria may be to concentrate intracellar cations.
Intake of Selected Micronutrients and the Risk of Surgically Treated Benign Prostatic Hyperplasia: A Case-Control Study from Italy
Authors: Alessandra Tavani, Elisa Longoni, Cristina Bosetti, Luigino Dal Maso, Jerry Polesel, Maurizio Montella, Valerio Ramazzotti, Eva Negri, Silvia Franceschi, Carlo La Vecchia
Journal: European Urology (2005)
Pathophysiology of rhinitis. Lactoferrin and lysozyme in nasal secretions.
Authors: G D Raphael, E V Jeney, J N Baraniuk, I Kim, S D Meredith, M A Kaliner
Journal: Journal of Clinical Investigation (1989)

The antimicrobial proteins lactoferrin (Lf) and lysozyme (Ly) are invariably found in nasal secretions. To investigate the cellular sources and the secretory control of these nasal proteins in vivo, 34 adult subjects underwent nasal provocation tests with methacholine (MC), histamine (H), and gustatory stimuli. Nasal lavages were collected and analyzed for total protein (TP), albumin (Alb), Lf, and Ly. MC (25 mg), H (1 mg), and gustatory stimuli (spicy foods) all increased the concentrations of TP, Alb, Lf, and Ly. However, when each protein was assessed as a percentage of TP (i.e., Alb% = Alb/TP; Lf% = Lf/TP; Ly% = Ly/TP), MC and gustatory stimuli, which both induce glandular secretion, selectively augmented Lf% and Ly% without changing Alb%, while H, which primarily increases vascular permeability, increased Alb% without significantly affecting Lf% or Ly%. Gel electrophoresis and immunoblotting analysis of nasal secretions demonstrated both Lf and Ly in cholinergically induced secretions. Furthermore, histochemical analyses of nasal turbinate tissue revealed Lf and Ly colocalization within the serous cells of submucosal glands, providing evidence that both proteins are strictly glandular products within the nasal mucosa. Therefore, both Lf and Ly are produced and secreted from the glands, and their secretion may be pharmacologically regulated in attempts to improve host defenses.
Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741
Authors: Charles S. Fuchs, Richard M. Goldberg, Daniel J. Sargent, Jeffrey A. Meyerhardt, Brian M. Wolpin, Erin M. Green, Henry C. Pitot, Michael Pollak
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer. Experimental Design: The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer. Results: Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome. Conclusion: Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies.
Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells
Authors: Vishwa Deep Dixit, Eric M. Schaffer, Robert S. Pyle, Gary D. Collins, Senthil K. Sakthivel, Ravichandran Palaniappan, James W. Lillard, Dennis D. Taub
Journal: Journal of Clinical Investigation (2004)

Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.
Role of microRNA in chronic lymphocytic leukemia onset and progression
Authors: Veronica Balatti, Yuri Pekarky, Carlo M Croce
Journal: Journal of Hematology & Oncology (2015)

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia occurring as indolent or aggressive form. CLL clinical features and genetic abnormalities are well documented, but molecular details are still under investigation. MicroRNAs are small non-coding RNAs involved in several cellular processes and expressed in a tissue-specific manner. MicroRNAs regulate gene expression, and their deregulation can alter expression levels of genes involved in development/progression of tumors. In CLL, microRNAs can function as oncogenes or tumor suppressors and can also serve as markers for CLL onset/progression. Here, we discuss the most recent findings about the role of microRNAs in CLL and how this knowledge can be used to identify new biomarkers and treatment approaches.
Adenosine production in the ischemic kidney.
Authors: W L Miller, R A Thomas, R M Berne, R Rubio
Journal: Circulation Research (1978)

We conducted experiments to determine (1) tissue, blood, and urine levels of adenosine produced by the ischemic kidney under conditions of renal artery occlusion, and (2) the site(s) of production and release of adenosine by the kidney. Concentrations of adenosine, inosine, and hypoxanthine in the dog urine were found to increase after 2 minutes of renal artery occlusion as were concentrations of these metabolites in renal tissue after 10 minutes of renal artery occlusion. Renal venous plasma levels of inosine and hypoxanthine also were elevated after 3 minutes of arterial occlusion. In modified stop-flow experiments, adenosine appeared in the urine in a peak that corresponded most closely with proximal tubule fluid. 5'-Nucleotidase, the enzyme which catalyzes the dephosphorylation of 5'-AMP or 5'-IMP to adenosine or inosine, respectively, was found to be located primarily on the external membranes and mitochondria of proximal tubule cells, but not in distal tubule or collecting duct cells. Since adenosine has been demonstrated to elicit renal vasoconstriction and is produced by the ischemic kidney, it is suggested that adenosine may be involved in the mediation of postocclusion renal ischemia.
lncRNA-MIAT Regulates Microvascular Dysfunction by Functioning as a Competing Endogenous RNA
Authors: Biao Yan, Jin Yao, Jing-Yu Liu, Xiu-Miao Li, Xiao-Qun Wang, Yu-Jie Li, Zhi-Fu Tao, Yu-Chen Song, Qi Chen, Qin Jiang
Journal: Circulation Research (2015)

Rationale: Pathological angiogenesis is a critical component of diseases, such as ocular disorders, cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes, such as cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of these biological processes. However, the role of lncRNA in diabetes mellitus–induced microvascular dysfunction is largely unknown. Objective: To elucidate whether lncRNA-myocardial infarction–associated transcript (MIAT) is involved in diabetes mellitus–induced microvascular dysfunction. Methods and Results: Using quantitative polymerase chain reaction, we demonstrated increased expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion, vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously ameliorated diabetes mellitus–induced retinal microvascular dysfunction in vivo, and inhibited endothelial cell proliferation, migration, and tube formation in vitro. Bioinformatics analysis, luciferase assay, RNA immunoprecipitation, and in vitro studies revealed that MIAT functioned as a competing endogenous RNA, and formed a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function. Conclusions: This study highlights the involvement of lncRNA-MIAT in pathological angiogenesis and facilitates the development of lncRNA-directed diagnostics and therapeutics against neovascular diseases.
Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation
Authors: Martha Wadleigh, Paul G. Richardson, David Zahrieh, Stephanie J. Lee, Corey Cutler, Vincent Ho, Edwin P. Alyea, Joseph H. Antin, Richard M. Stone, Robert J. Soiffer, Daniel J. DeAngelo
Journal: Blood (2003)
Primary pulmonary tumours of neurogenic origin.
Authors: G Roviaro, M Montorsi, F Varoli, R Binda, A Cecchetto
Journal: Thorax (1983)

Primary intrapulmonary neurogenic tumours are extremely rare. In a series of 1664 patients with pulmonary neoplasms observed during 1967-80 only four such tumours were identified (0.2%). All four patients underwent surgical excision. The histological diagnosis was benign neurilemmoma in three cases and malignant schwannoma in the fourth. The patients with neurilemmoma are alive and well four to 12 years after surgery, but the patient with malignant schwannoma died from metastatic spread of the tumour four months after surgery. No association with von Recklinghausen's disease was observed. Macroscopic and microscopic features generally lead to a correct diagnosis in benign types, but the histological diagnosis of malignant schwannoma may present some difficulties and requires the establishment of a definite origin in a nervous structure, identification of benign neurofibroma in different areas of the same tumour, and a high density of cells with appreciable pleomorphism, with mitosis and atypia. Benign tumours carry a good prognosis with little tendency to recur, but malignant schwannoma has a high invasive tendency and is associated with a low survival rate.
Interleukin-10 Expression Mediated by an Adeno-Associated Virus Vector Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats
Authors: Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Tatsuya Nomoto, Mutsuko Nonaka-Sarukawa, Ryosuke Uchibori, Yoshikazu Maeda, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Kazuyuki Shimada, Keiya Ozawa
Journal: Circulation Research (2007)

Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P<0.01). IL-10 also significantly reduced mean PA pressure (22.8+/-1.5 versus 29.7+/-2.8 mm Hg, P<0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35+/-0.04 versus 0.42+/-0.05, P<0.05), and percent medial thickness of the PA (12.9+/-0.3% versus 21.4+/-0.4%, P<0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-beta1 and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-beta1 or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.