tbuckley/cabot-search huggingface dataset:
CD4+CD25+ Regulatory Lymphocytes Induce Regression of Intestinal Tumors in <i>ApcMin/+</i> Mice
Authors: Susan E. Erdman, Jane J. Sohn, Varada P. Rao, Prashant R. Nambiar, Zhongming Ge, James G. Fox, David B. Schauer
Journal: Cancer Research (2005)

Abstract Colorectal cancer in humans results from sequential genetic changes in intestinal epithelia commencing with inactivation of the APC tumor suppressor gene. Roles for host immunity in epithelial tumorigenesis are poorly understood. It has been previously shown that CD4+CD25+ lymphocytes inhibit colitis-associated epithelial tumors in Rag-deficient mice. Here we show that addition of CD4+CD25+ lymphocytes in ApcMin/+ mice reduces multiplicity of epithelial adenomas. Interleukin-10 was required in regulatory cells for therapeutic effect. Recipients of regulatory cells showed increased apoptosis and down-regulation of cyclooxygenase-2 within tumors coincident with tumor regression. These data suggest a role for regulatory lymphocytes in epithelial homeostasis in the ApcMin/+ mouse model of intestinal polyposis. Similarities with cancer of the breast, prostate, lung, and other sites raise the possibility of broader roles for regulatory lymphocytes in prevention and treatment of epithelial cancers in humans.
Anoxia/Reoxygenation-Induced Tolerance With Respect to Polymorphonuclear Leukocyte Adhesion to Cultured Endothelial Cells
Authors: Gediminas Cepinskas, Cameron W. Lush, Peter R. Kvietys
Journal: Circulation Research (1999)

Abstract —Exposing human umbilical vein endothelial cells (HUVECs) to anoxia/reoxygenation (A/R) results in an increase in polymorphonuclear leukocyte (PMN) adhesion to HUVECs. This A/R-induced hyperadhesion is completely prevented by a previous (24 hours earlier) exposure of HUVECs to A/R. This phenomenon has been termed “A/R tolerance.” Exposing HUVECs to A/R induces an increase in nuclear factor κB (NF-κB) in HUVEC nuclei within 4 hours. Interfering with either NF-κB activation (proteasome inhibitor) or translocation (double-stranded oligonucleotides containing NF-κB binding sequence) prevents the development of A/R tolerance (ie, the increase in A/R-induced PMN adhesion to HUVECs is the same after the first and second A/R challenges). NO production by HUVECs is increased after the second A/R challenge, but not after the first A/R challenge. Inhibition of NO synthase (NOS) during the second A/R challenge prevents the development of A/R tolerance with respect to PMN adhesion. However, while HUVECs contained endothelial NOS protein, no inducible NOS was detected in either tolerant or nontolerant cells. Further studies indicated that inhibition of GTP-cyclohydrolase I (an enzyme involved in de novo synthesis of an important cofactor for NOS activity, tetrahydrobiopterin) prevented the generation of NO in A/R-tolerant cells. Extracellular generation of NO (NO donor) did not effect the hyperadhesion response induced by the initial A/R challenge. A/R also induced an oxidant stress in naive HUVECs, but not in A/R-tolerant HUVECs. Inhibition of NOS during the second A/R insult results in the generation of an oxidant stress similar to that observed after the first A/R challenge. Taken together, the findings of the present study are consistent with a role for NF-κB in the development of A/R tolerance (with respect to PMN adhesion), perhaps by transcriptional regulation of GTP-cyclohydrolase. The increased NO production during the second A/R insult reduces PMN adhesion most likely by reducing the intracellular oxidant stress induced by A/R.
Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis
Authors: J G Walker
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis. <b>Objective:</b> To document Jak-STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue. <b>Methods:</b> Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3-STAT4 were assessed. <b>Results:</b> STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6. <b>Conclusion:</b> CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro-apoptotic and anti-inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti-inflammatory effects.
Fibroblasts in Kidney Fibrosis Emerge via Endothelial-to-Mesenchymal Transition
Authors: Elisabeth M. Zeisberg, Scott E. Potenta, Hikaru Sugimoto, Michael Zeisberg, Raghu Kalluri
Journal: Journal of the American Society of Nephrology (2008)

In June 2017, a media frenzy ensued after Michelle Carter was convicted of involuntary manslaughter in the state of Massachusetts for facilitating the suicide of Conrad Roy. The verdict stirred controversy and cast a spotlight on facilitation of suicide, i.e., a person9s act(s) done with the purpose of helping another to die by suicide. One form of facilitation, physician-assisted suicide, has been extensively debated in the existing literature. In this article, we set out to explore the legal and forensic ramifications of non–physician-assisted suicide, which we refer to as facilitated suicide. We first conducted a review of all fifty states9 legislation regarding facilitated suicide: forty-four states prohibit it by statute, and three states prohibit it through common law. Thirteen states specifically outlaw verbal facilitation of suicide. We then surveyed the case law to identify legal precedent to the Commonwealth v. <i>Carter</i> verdict. <i>Final Exit Network, Inc. v. State</i> and <i>State v. Melchert-Dinkel</i> provide contrasting yet complementary perspectives on the interplay between speech and assisted suicide. Finally, we detailed the role of forensic psychiatry in investigating facilitated suicide, specifically among adolescents and youths.
Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction.
Authors: K Peter, T E O'Toole
Journal: The Journal of Experimental Medicine (1995)

The integrin alpha L beta 2 (leukocyte function-associated molecule 1, CD11a/CD18) mediates activation-dependent adhesion of leukocytes. The cytoplasmic domains of alpha L beta 2 have been demonstrated to modulate adhesiveness of alpha L beta 2. Affinity changes of alpha L beta 2 for its ligand or postreceptor events can be responsible for this modulation of adhesiveness. To investigate the possible role of the alpha L beta 2 cytoplasmic domains in postreceptor events we constructed cDNA encoding chimeric proteins with intracellular alpha L beta 2 domains, which are responsible for alpha L beta 2 specific intracellular interactions, and extracellular alpha IIIb beta 3 (GP IIb/IIIa) domains, which allow the assessment of the receptor affinity state. The cDNA was stably transfected in Chinese hamster ovary cells and chimeric heterodimer formation proven by immunoprecipitations and flow cytometry. The chimeric receptors mediate adhesion to immobilized fibrinogen, and this adhesion is increased by phorbol myristate acetate and abolished by cytochalasin D. However, neither treatment affects the affinity state of the chimeric receptor, suggesting involvement of the cytoskeleton in the regulation of alpha L beta 2 mediated cell adhesion. To exclude the possibility of postoccupancy affinity changes of the chimeric receptors, we locked the receptors into a high affinity state by creating a deletion variant. The region deleted (VGFFK) is highly conserved in integrin alpha subunit cytoplasmic domains. Cotransfection of this deletion variant with a beta subunit truncation (beta 3 delta 724) and a triple mutation at 758-760 (TTT to AAA) of beta 2 abolishes adhesion without changing the affinity state. A single mutation (TTT to TAT) reduces adhesion by half without affinity change. Scanning electron microscopy reveals impaired spreading of these truncated/mutated chimeras. Immunofluorescence microscopy demonstrates a correlation between impaired adhesion and a decrease in the ability to form focal adhesions and to organize the cytoskeleton into stress fibers. These results describe the integrin/cytoskeleton interaction, the organization of the cytoskeleton, and cell spreading as postreceptor events modulating alpha L beta 2 cytoplasmic domain mediated cell adhesion. Furthermore, we demonstrate that the cytoplasmic domain of the beta 2 subunit, and within it the TTT region, are required for these postreceptor events. Additionally, we present a new approach, using deletion variants to lock integrins in a high affinity state without interfering with the investigated integrin/cytoskeleton interaction. This approach may be generally useful to investigate the role of postreceptor events in integrin-mediated cell adhesion and migration.
Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia
Authors: David A. Lewis, Raymond Y. Cho, Cameron S. Carter, Kevin Eklund, Sarah Forster, Mary Ann Kelly, Debra Montrose
Journal: American Journal of Psychiatry (2008)

Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA A ) receptors containing α 2 subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA A receptors containing α 2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA A receptors containing α 2 or α 3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results: Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at α 2 subunit containing GABA A receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.
Epidermal transit times
Authors: CHRISTOPHER S. POTTEN
Journal: British Journal of Dermatology (1975)

Radio-isotope disappearance curves and autoradiography (labelled DNA precursors and labelled amino acids) have been used to estimate the minimum transit times for four regions of epidermis in mice. The post-mitotic maturation time in the basal layer has been estimated and the results interpreted in relation to proliferation rates and epidermal organisation.
The Many Faces of Airway Inflammation
Authors: P. M. O'BYRNE, D. S. POSTMA
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are among the world's most prevalent diseases. The prevalence of asthma has been incasing over the past 20 yr in most countries where this has been studied, and it affects up to 10% of the populations of most developed countries. COPD is the sixth cause of death in the world and affects 4-6% of people more than 45 yr of age. In 1985, more than 5.4 million Americans were estimated to have COPD and COPD is the most rapidly rising cause of death among individuals over the age of 65 yr in the United States (1). These diseases constitute a major financial burden to society, wit both direct and indirect costs. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities, with airway obstruction being the sine qua non of both diseases. The airway obstruction in asthma must be reversible to establish a diagnosis, whereas COPD is defined as a syndrome characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months of observation (2). Both diseases are now known to be caused by lung inflammation induced by different initiating factors, most likely environmental allergens, occupational sensitizing agents, or viral respiratory infections in asthma and cigarette smoking in COPD. However, some patients wit asthma who do not smoke also develop irreversible airway obstruction similar to COPD. Also, the treatments used to manage both diseases resemble each other. This review compares and contrasts asthma and COPD wit regard to the following aspects: the risks for development, th functional and structural abnormalities,the inflammatory activity and the site of the inflammation, animal models of both diseases and current and potential new treatments for the diseases. The review was developed as a result of a workshop held in Whistler, Canada, involving clinical and basic scientists actively working in these two areas. It is hoped that by comparing the two diseases, new insights can be attained about each.
Calcium/Calmodulin-Dependent Kinase I and Calcium/Calmodulin-Dependent Kinase Kinase Participate in the Control of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells
Authors: Oswaldo G. Rodriguez-Mora, Michelle M. LaHair, James A. McCubrey, Richard A. Franklin
Journal: Cancer Research (2005)

Abstract Calcium is universally required for cell growth and proliferation. Calmodulin is the main intracellular receptor for calcium. Although calcium and calmodulin are well known to be required for cell cycle regulation, the target pathways for their action remain poorly defined. Potential targets include the calcium/calmodulin-dependent kinases (CaM-K). The aim of this study was to determine the role of the CaM-Ks on cell proliferation and progress through the cell cycle in breast cancer cells. CaM-KI inhibition with either KN-93 or specific interfering RNA (siRNA) caused an arrest in the cell cycle in the human breast cancer cell line, MCF-7. This arrest occurred in the G1 phase of the cell cycle. Supporting this finding, CaM-K inhibition using KN-93 also resulted in a reduction of cyclin D1 protein and pRb phosphorylation when cells were compared with control cultures. Furthermore, inhibition of the upstream activator of CaM-KI, CaM-KK, using siRNA also resulted in cell cycle arrest. In summary, CaM-KK and CaM-KI participate in the control of the G0-G1 restriction check point of the cell cycle in human breast cancer cells. This arrest seems due to an inhibition in cyclin D1 synthesis and a reduction in pRb phosphorylation. To the best of our knowledge, this is the first time that CaM-KK has been reported to be involved in mammalian cell cycle regulation and that CaM-Ks are regulating breast cancer cell cycle.
Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer
Authors: Christina M. Annunziata, Joyce O'Shaughnessy
Journal: Clinical Cancer Research (2010)

Abstract Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly (ADP-ribose) polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian, and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability, rendering susceptibility to agents that induce additional and lethal DNA damage. Clin Cancer Res; 16(18); 4517–26. ©2010 AACR.
Nausea and vomiting due to insulin glargine in patient with type 1 diabetes mellitus
Authors: Anthony N Dixon, Stephen C Bain
Journal: BMJ (2005)

Insulin glargine is a new insulin analogue with delayed absorption and a prolonged duration of action.1 A 34 year old woman who had had type 1 diabetes for six years had previously been treated with premixed biphasic isophane insulin (Humulin M3), twice a day. This regimen had been changed to a basal bolus regimen of Actrapid and Insulatard during pregnancy, but she subsequently resumed twice daily injections (but …
Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?
Authors: M. Quaak, C. P. van Schayck, A. M. Knaapen, F. J. van Schooten
Journal: European Respiratory Journal (2009)

Tobacco smoking continues to be the largest preventable cause of premature morbidity and mortality throughout the world, including chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although most smokers are highly motivated to quit and many smoking cessation therapies are available, cessation rates remain very low. Recent research strongly suggests that variation in genetic background is an important determinant of smoking behaviour and addiction. Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, it is likely that assessment of genetic background could be a promising tool to guide selection of the most effective cessation treatment for an individual smoker. Recently, it has been shown that genetic variants in the dopaminergic system, opioid receptors, the bupropion-metabolising enzyme CYP2B6 and the nicotine-metabolising enzyme CYP2A6 may play an important role in predicting smoking cessation responses to nicotine replacement therapy and bupropion treatment. Despite the progress that has been made, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.
Emission of carcinogenic components with automobile exhausts.
Authors: U Stenberg, T Alsberg, R Westerholm
Journal: Environmental Health Perspectives (1983)

Different sampling methods for mutagenic polynuclear aromatic hydrocarbons (PAH) are described. These methods involve either direct sampling of raw exhausts which prior to filtering are cooled in a condenser, or filter sampling of exhausts diluted in a tunnel. The relevance of gas-phase PAHs of samples from diluted exhausts is discussed; methods used are either adsorbents (XAD-2) or cryogenic condensation. The emission of benzo(a)pyrene and certain other PAHs is reported from vehicles using different fuels (gasoline, diesel, LPG, alcohols) or different emission control systems. The emission of some volatiles, such as benzene, ethylene and alkylnitrites, is also presented from different types of fuels used.
Oxidized Low-Density Lipoprotein Downregulates Endothelial Basic Fibroblast Growth Factor Through a Pertussis Toxin-Sensitive G-Protein Pathway
Authors: Po-Yuan Chang, Sherry Luo, Tao Jiang, Yuan-Teh Lee, Shao-Chun Lu, Philip D. Henry, Chu-Huang Chen
Journal: Circulation (2001)

Background Oxidized LDL (oxLDL) inhibits angiogenesis in part by downregulating endothelial basic fibroblast growth factor (bFGF). To determine the mechanism of the downregulation, we investigated the signal transduction pathway involving potential phospholipid mediators. Methods and Results Cultured bovine aortic endothelial cells were incubated with PBS (lipoprotein-free control), LDL, or copper oxLDL under serum-free conditions. At 24 hours, oxLDL (50 μg/mL) decreased bFGF mRNA (Northern blot), bFGF protein (Western blot and ELISA), and concomitant DNA synthesis, all by 40% to 50% compared with PBS. LDL had no effect. Pretreating the cells with 100 ng/mL pertussis toxin (PTX) for 18 hours before oxLDL exposure almost completely blocked the inhibitory effects of oxLDL. In contrast, inhibiting other major cellular signal transduction pathways with PD-98059 (mitogen-activated protein kinase kinase inhibitor), HA-1004 (inhibitor of cGMP- and cAMP-dependent protein kinase), or Ro-31-8220 (protein kinase C inhibitor) or chelating intracellular Ca 2+ with BAPTA-AM failed to attenuate any of the oxLDL effects assayed. Addition to the cultures of WEB 2086, a specific antagonist of the PTX-sensitive G protein–coupled platelet-activating factor (PAF) receptor, blocked the action of oxLDL. Whereas PAF dispersed in the culture medium failed to produce oxLDL-like effects, degradation of PAF and PAF-like phospholipids accumulated in oxLDL with a recombinant human PAF acetylhydrolase eliminated the inhibitory effects of oxLDL on bFGF expression and DNA synthesis. Conclusions OxLDL suppresses endothelial bFGF expression and DNA synthesis through a PTX-sensitive heterotrimeric G-protein pathway involving mediator phospholipids similar, but not identical, to PAF.