tbuckley/cabot-search huggingface dataset:
Development of a DNA Microarray for Toxicology Based on Hepatotoxin-Regulated Sequences
Authors: JF Waring
Journal: Environmental Health Perspectives (2003)

Toxicogenomics is an emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of compounds. One of the main tools used in toxicogenomics is DNA microarrays. We have used a novel strategy to create a library highly enriched for genes expressed in the liver under hepatotoxic conditions. Using this library, we have created a new oligonucleotide microarray dedicated to the study of rat liver function. Oligonucleotide probes for these genes were designed and used in experimental hybridization studies to deduce the correct sequence orientation and to determine those sequences exhibiting differential regulation under a variety of toxicity-related treatments and conditions. The final array was benchmarked on treatments with 3-methylcholanthrene, Aroclor 1254, and cyclopropane carboxylic acid. Our results showed that the subtractive hybridization greatly enriched for genes regulated during a hepatotoxic response. Overall, our strategy for design of a new rat toxicology microarray can be applied to other systems as well and should aid greatly in the development of microarrays targeted for specific scientific areas.
Regulation of MCP-1 chemokine transcription by p53
Authors: Katrin Hacke, Bladimiro Rincon-Orozco, Gilles Buchwalter, Simone Y. Siehler, Bohdan Wasylyk, Lisa Wiesmüller, Frank Rösl
Journal: Molecular Cancer (2010)

Abstract Background Our previous studies showed that the expression of the monocyte-chemoattractant protein (MCP)-1, a chemokine, which triggers the infiltration and activation of cells of the monocyte-macrophage lineage, is abrogated in human papillomavirus (HPV)-positive premalignant and malignant cells. In silico analysis of the MCP-1 upstream region proposed a putative p53 binding side about 2.5 kb upstream of the transcriptional start. The aim of this study is to monitor a physiological role of p53 in this process. Results The proposed p53 binding side could be confirmed in vitro by electrophoretic-mobility-shift assays and in vivo by chromatin immunoprecipitation. Moreover, the availability of p53 is apparently important for chemokine regulation, since TNF-α can induce MCP-1 only in human keratinocytes expressing the viral oncoprotein E7, but not in HPV16 E6 positive cells, where p53 becomes degraded. A general physiological role of p53 in MCP-1 regulation was further substantiated in HPV-negative cells harboring a temperature-sensitive mutant of p53 and in Li-Fraumeni cells, carrying a germ-line mutation of p53. In both cases, non-functional p53 leads to diminished MCP-1 transcription upon TNF-α treatment. In addition, siRNA directed against p53 decreased MCP-1 transcription after TNF-α addition, directly confirming a crosstalk between p53 and MCP-1. Conclusion These data support the concept that p53 inactivation during carcinogenesis also affects immune surveillance by interfering with chemokine expression and in turn communication with cells of the immunological compartment.
Making sense of the COP9 signalosome: a regulatory protein complex conserved from Arabidopsis to human
Authors: Ning Wei, Xing-Wang Deng
Journal: Trends in Genetics (1999)

The COP9 signalosome, once defined as a repressor complex of light-activated development in Arabidopsis, has recently been found in humans and is probably present in most multicellular organisms. The COP9 signalosome is closely related to the lid sub-complex of the 26S proteasome in structural composition and probably shares a common evolutionary ancestor. A multifaceted role of the COP9 signalosome in cell-signaling processes is hinted at by its associated novel kinase activity, as well as the involvement of its subunits in regulating multiple cell-signaling pathways and cell-cycle progression. The molecular genetic studies in Arabidopsis suggest that the complex functions as part of a highly conserved regulatory network, whose physiological role in animals remains to be determined.
Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma: Yesterday, Today, and Tomorrow
Authors: Frederick R. Appelbaum
Journal: Journal of Clinical Oncology (2008)

Twenty-five years ago (it seems like yesterday), we published a brief review of the use of hematopoietic cell transplantation (HCT) for the treatment of non-Hodgkin's lymphoma (NHL) summarizing early results using autologous, syngeneic, and allogeneic sources of marrow. 1 The first series of patients treated for recurrent NHL using high-dose chemotherapy with cryopreserved autologous marrow support was published in 1978 in a study showing that cryopreserved marrow did, indeed, hasten hematopoietic recovery and that this approach could cure otherwise incurable patients, at least in the setting of recurrent Burkitt's lymphoma. 2Several years later, we reported the result of syngeneic HCT for NHL, demonstrating cure of patients with recurrent NHL of more common histologic subtypes using high-dose chemoradiotherapy with syngeneic marrow support. 3Our initial study of allogeneic HCT for recurrent NHL likewise reported longterm survival in a minority of patients, suggesting that allogeneic transplantation is an option for patients with known marrow involvement and further raising the question of a graft-versus-lymphoma effect, analogous to that reported for leukemia.
Increased levels of interleukin-16 in the airways of tobacco smokers: relationship with peripheral blood T lymphocytes
Authors: M. Laan, I. Qvarfordt, G. C Riise, B. A Andersson, S. Larsson, A. Linden
Journal: Thorax (1999)

<h3>BACKGROUND</h3> The mechanisms behind the development of systemic immunomodulation among tobacco smokers are not fully understood, but several studies have indicated a role for CD8+ and/or CD4+ T cells. Interleukin (IL)-16, a cytokine released from inflammatory cells as well as bronchial epithelial cells, can recruit and activate CD4+ T cells. A study was undertaken to establish whether the IL-16 level is increased in the airways of tobacco smokers and to determine whether airway levels of IL-16 are related to the number and function of systemic T lymphocytes. <h3>METHODS</h3> Bronchoalveolar lavage (BAL) fluid was collected from eight never smokers and 18 tobacco smokers without clinical airway symptoms, and from 16 tobacco smokers with clinical airway symptoms. Interleukin-16 protein levels in BAL fluid were determined using enzyme-linked immunosorbent assay (ELISA). Peripheral blood was collected for determination of CD4+ T cell content using flow cytometry. The responsiveness of systemic lymphocytes in smokers was assessed by measuring the proliferative response of peripheral blood lymphocytes to the superantigen staphylococcus enterotoxin A (SEA). <h3>RESULTS</h3> The IL-16 protein level in the BAL fluid was significantly higher in tobacco smokers than in non-smokers. However, among tobacco smokers the IL-16 level was similar in asymptomatic smokers and in those with airway symptoms. The level of IL-16 in the BAL fluid of smokers correlated negatively with the percentage of CD4+ T cells and positively with superantigen stimulated lymphocyte proliferation in peripheral blood. <h3>CONCLUSIONS</h3> In tobacco smokers the airway IL-16 level is increased and it is possible that this increase in IL-16 influences systemic immunomodulation by altering the number and responsiveness of systemic T lymphocytes.
Long-Term Outcomes of Pre-emptive Valganciclovir Compared with Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation
Authors: Tomas Reischig, Petra Hribova, Pavel Jindra, Ondrej Hes, Mirko Bouda, Vladislav Treska, Ondrej Viklicky
Journal: Journal of the American Society of Nephrology (2012)

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.
Reversibility of Antipsychotic Treatment–Related Diabetes in Patients With Schizophrenia
Authors: Marc De Hert, Linda Hanssens, Ruud van Winkel, Martien Wampers, Dominique Van Eyck, Andre Scheen, Joseph Peuskens
Journal: Diabetes Care (2006)

At present, antipsychotic drugs are not specifically referred to in the list of substances that can induce diabetes in the most recent American Diabetes Association guidelines (1), but there is a growing body of evidence that antipsychotic drugs might have diabetogenic properties (2,3). At present, there are no clear guidelines on what the best therapeutic strategies are when diabetes is detected during treatment with antipsychotics. Data from pharmacovigilance studies suggest that a significant proportion of recent-onset cases of diabetes can be reversed. Recent Belgian guidelines for screening and monitoring patients treated with antipsychotics propose a switch to an antipsychotic with a safer metabolic profile, but this …
Targeted Measles Virus Vector Displaying Echistatin Infects Endothelial Cells via αvβ3 and Leads to Tumor Regression
Authors: Louay K. Hallak, Jaime R. Merchan, Chris M. Storgard, Joseph C. Loftus, Stephen J. Russell
Journal: Cancer Research (2005)

Abstract Targeting tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin αvβ3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin αvβ3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 106 plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin αvβ3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors.
NEUROPSYCHIATRIC DISORDERS OCCURRING IN CUSHING'S SYNDROME
Authors: N. S. SCHLEZINGER, W. A. HORWITZ
Journal: American Journal of Psychiatry (1940)

1. The clinical and post-mortem findings in an unusual case of Cushing's syndrome are described. There existed in this patient a depressive psychosis and an extrapyramidal neurologic disorder, the overt development of both being associated temporally with that of the specific endocrine disorder. It is suggested that the etiology of the complex clinical picture observed in this case may be a neuroendocrine disorder on an encephalitic basis. 2. A review of the literature reveals that mental symptoms not infrequently occur in Cushing's syndrome and that mental depression of varying degree has been a prominent feature in these psychiatric disorders. The mental symptoms may be a direct manifestation of the underlying specific endocrinopathy although the mechanism of their production remains obscure. The possibility that the form of psychiatric disorder, namely depression, in these cases bears a close relationship to manic depressive and involutional psychoses is pointed out. 3. Patients hospitalized with depressive psychoses should be carefully examined for evidence of Cushing's syndrome.
An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension
Authors: Florian Alonso, Nathalie Krattinger, Lucia Mazzolai, Alexander Simon, Gérard Waeber, Paolo Meda, Jacques-Antoine Haefliger
Journal: Cardiovascular Research (2010)

Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40−/−), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40−/− mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin–angiotensin system of Cx40−/− mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-κB) to the Cx43 gene promoter, increasing Cx43 expression. In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-κB pathways.
Impairment of T and B Cell Development by Treatment with a Type I Interferon
Authors: Qun Lin, Chen Dong, Max D. Cooper
Journal: The Journal of Experimental Medicine (1998)

Type I interferons α and β, naturally produced regulators of cell growth and differentiation, have been shown to inhibit IL-7–induced growth and survival of B cell precursors in vitro. After confirming an inhibitory effect on B lymphopoiesis in an ex vivo assay, we treated newborn mice with an active IFN-α2/α1 hybrid molecule to assess its potential for regulating B and T cell development in vivo. Bone marrow and splenic cellularity was greatly reduced in the IFN-α2/α1–treated mice, and B lineage cells were reduced by &amp;gt;80%. The bone marrow progenitor population of CD43+B220+HSA− cells was unaffected, but development of the CD19+ pro–B cells and their B lineage progeny was severely impaired. Correspondingly, IL-7–responsive cells in the bone marrow were virtually eliminated by the interferon treatment. Thymus cellularity was also reduced by &amp;gt;80% in the treated mice. Phenotypic analysis of the residual thymocytes indicated that the inhibitory effect was exerted during the pro–T cell stage in differentiation. In IFN-α/β receptor−/− mice, T and B cell development were unaffected by the IFN-α2/α1 treatment. The data suggest that type I interferons can reversibly inhibit early T and B cell development by opposing the essential IL-7 response.
The Effect of Upper Airway Obstruction and Arousal on Peripheral Arterial Tonometry in Obstructive Sleep Apnea
Authors: Christopher P. O'Donnell, Lawrence Allan, Paul Atkinson, Alan R. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

We evaluated the effects of airflow limitation and arousal on digital vascular tone in 10 patients with obstructive sleep apnea (OSA) using the recently developed, noninvasive technique of peripheral arterial tonometry (PAT). Subjects were maintained at a therapeutic level of continuous positive airway pressure, and nasal pressure was acutely dropped for three to five breaths during nonrapid eye movement sleep over a range of pressures from 9.3 ± 1.3 to 1.9 ± 1.3 cm H2O, leading to increasing airway obstruction and decreasing levels of inspiratory airflow. In the absence of a detectable electroencephalographic (EEG) arousal, severe reductions of inspiratory airflow to below 200 ml/second caused significant decreases in PAT amplitude (1.000 ± 0.007 to 0.869 ± 0.007 arbitrary units; p < 0.001), whereas mild airflow limitation (> 200 ml/second) had no effect (1.000 ± 0.009 to 1.011 ± 0.007 arbitrary units). The presence of an EEG arousal accentuated the response to airflow obstruction, such that the PAT amplitude decreased more (p < 0.001) in the presence of arousal (1.000 ± 0.007 to 0.767 ± 0.010 arbitrary units) than in the absence of arousal (1.000 ± 0.007 to 0.923 ± 0.007 arbitrary units). We conclude that airflow obstruction in patients with OSA causes an acute digital vasoconstriction that is accentuated in the presence of an EEG arousal.
Frequencies of mitogen-reactive B cells in the mouse. I. Distribution in different lymphoid organs from different inbred strains of mice at different ages
Authors: J Andersson, A Coutinho, F Melchers
Journal: The Journal of Experimental Medicine (1977)

Frequencies of mitogen-reactive B cells have been determined in vitro under culture conditions which allow every growth-inducible B cell to grow and mature into a clone of Ig-secreting PFC. The frequencies of LPS-reactive B cells in the spleen of 6- to 8-wk old mice were between 1 in 3 and 1 in 10 splenic B cells from the following inbred strains of mice: C3H/Tif; BALB/c; BALB/c nu/nu; C57BL/6J; DBA/2J; C57BL/6J x DBA/(2J)F(1); and CBA and A/J. Very similar frequencies are found for lipoprotein-reactive B cells in BALB/c, BALB/c nu/nu, C3H/Tif, and C3H/HeJ mice. No LPS-reactive cells but normal frequencies of lipoprotein-reactive cells were found in C3H/HeJ mice, genetically nonreactive to LPS. SJL mice had significantly lower frequencies of LPS- and of lipoprotein-reactive B cells (1 in approximately 30 B cells). The number of LPS- and of lipoprotein-reactive B cells in spleen was dependent upon the age of the mouse. Newborn spleen contained approximately 10 percent of the number of reactive cells found at 6- to 8-wk of age. From there the frequencies declined again to drop below 5 percent of the maximal number at ages beyond 11 mo. LPS-reactive B cells yielding IgM- and IgG-PFC responses could be found in mesenteric lymph nodes, bone marrow, thymus, thoracic duct, and peripheral blood of 6- to 8-wk old mice. Their frequencies were one in three to five lymph node cells, 1 in 50 to 100 bone marrow cells, one in 10(5) thymus cells, and 1 in 20 to 40 thoracic duct or peripheral blood cells.
A Newly Established Murine Model of Nasal Polyps Demonstrates B Cell Activation, Similar to Human Nasal Polyps
Authors: Dong-Young Kim, Sun Hye Lee, Dae Woo Kim, Chae-Seo Rhee, Roderick G. Carter, Robert P. Schleimer, Seong Ho Cho
Journal: Journal of Allergy and Clinical Immunology (2015)
Mast Cells Are Key Promoters of Contact Allergy that Mediate the Adjuvant Effects of Haptens
Authors: Anne Dudeck, Jan Dudeck, Julia Scholten, Anke Petzold, Sangeetha Surianarayanan, Anja Köhler, Katrin Peschke, David Vöhringer, Claudia Waskow, Thomas Krieg, Werner Müller, Ari Waisman, Karin Hartmann, Matthias Gunzer, Axel Roers
Journal: Immunity (2011)
Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma
Authors: Cigall Kadoch, Jing Li, Valerie S. Wong, Lingjing Chen, Soonmee Cha, Pamela Munster, Clifford A. Lowell, Marc A. Shuman, James L. Rubenstein
Journal: Clinical Cancer Research (2013)

To elucidate the mechanistic basis for efficacy of intrathecal rituximab. We evaluated complement activation as well as the pharmacokinetics of intraventricular rituximab in patients who participated in two phase 1 multicenter studies.We evaluated complement activation as a candidate mediator of rituximab within the central nervous system (CNS). Complement C3 and C5b-9 were quantified by ELISA in serial cerebrospinal fluid (CSF) specimens after intraventricular rituximab administration. We determined rituximab concentration profiles in CSF and serum. A population three- compartment pharmacokinetic model was built to describe the disposition of rituximab following intraventricular administration. The model was derived from results of the first trial and validated with results of the second trial.Complement C3 and C5b-9 were reproducibly activated in CSF after intraventricular rituximab. Ectopic expression of C3 mRNA and protein within CNS lymphoma lesions was localized to myeloid cells. Constitutive high C3 activation at baseline was associated with adverse prognosis. A pharmacokinetic model was built, which contains three distinct compartments, to describe the distribution of rituximab within the neuroaxis after intraventricular administration.We provide the first evidence of C3 activation within the neuroaxis with intraventricular immunotherapy and suggest that complement may contribute to immunotherapeutic responses of rituximab in CNS lymphoma. Penetration of rituximab into neural tissue is supported by this pharmacokinetic model and may contribute to efficacy. These findings have general implications for intraventricular immunotherapy. Our data highlight potential innovations to improve efficacy of intraventricular immunotherapy both via modulation of the innate immune response as well as innovations in drug delivery.
GLIAL CELLS IN NEUROTOXICITY DEVELOPMENT
Authors: M. Aschner, J. W. Allen, H. K. Kimelberg, R. M. LoPachin, W. J. Streit
Journal: The Annual Review of Pharmacology and Toxicology (1999)

Neuroglial cells of the central nervous system include the astrocytes, oligodendrocytes, and microglia. Their counterparts in the peripheral nervous system are the Schwann cells. The term neuroglia comes from an erroneous concept originally coined by Virchow (1850), in which he envisioned the neurons to be embedded in a layer of connective tissue. The term, or its shortened form--glia, has persisted as the preferred generic term for these cells. A reciprocal relationship exists between neurons and glia, and this association is vital for mutual differentiation, development, and functioning of these cell types. Therefore, perturbations in glial cell function, as well as glial metabolism of chemicals to active intermediates, can lead to neuronal dysfunction. The purpose of this review is to explore neuroglial sites of neurotoxicant actions, discuss potential mechanisms of glial-induced or glial-mediated central nervous system and peripheral nervous system damage, and review the role of glial cells in neurotoxicity development.