tbuckley/cabot-search huggingface dataset:
Lipoxygenases in the Cardiovascular System
Authors: Hartmut Kuhn
Journal: Circulation Research (2004)

ipoxygenases (LOXs) are nonheme iron-containing enzymes that catalyze dioxygenation of free or esterified polyenoic fatty acids to the corresponding hydroperoxides. 1 Although LOXs in plants have been known for almost a century, the first mammalian LOXs were not discovered until the mid 1970s. 2 In 1984 a 15-LOX activity was described in human atherosclerotic lesions, 3 and since then the number of reports connecting LOXs to the cardiovascular system has steadily increased. 4 -12 Cardiovascular research requires suitable animal models, with rats, mice, and rabbits as the preferred species.Unfortunately, concerning LOXs, there are profound differences between these animal species and humans.In humans there are 6 functional LOX genes that encode for separate LOX isoforms, 13 but only 3 of them (5-LOX, platelet-type 12-LOX, reticulocyte-type 15-LOX) appear to be important for vascular disorders.Except for the 5-LOX gene (mapped to chromosome 10), all human LOX genes are located on the short arm of chromosome 17.In mice, however, there are 7 functional LOX genes, and they were mapped to synthetic regions of the murine genome. 13In contrast to humans, there is no reticulocyte-type 15-LOX in mice, but the leukocyte-type 12-LOX appears to be its functional equivalent.This difference needs to be considered if the enzymes exhibit their biological activities via the formation of bioactive arachidonic acid oxygenation products (12S-HETE in mice versus 15S-HETE in humans).In rabbits, the situation is even more complex.Here, 2 separate genes have been discovered encoding for a reticulocyte-type 15-LOX and a leukocyte-type 12-LOX. 14Expression of the 2 genes is under the control of distinct regulatory sequences, and their tissue-specific expression patterns are also quite different. 8Similar species-specific differences between orthologous LOX isoforms have also been described for the human 15-LOX2, which is an arachidonate 8-LOX in mice, and for the murine epidermis-type 12S-LOX (no functional human gene).These differences indicate that care should be taken if experimental data on LOX metabolism in the cardiovascular system are being transferred from one species to another.
Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma
Authors: Thomas E. Hutson, Ian D. Davis, Jean-Pascal H. Machiels, Paul L. De Souza, Sylvie Rottey, Bao-fa Hong, Richard J. Epstein, Katherine L. Baker, Lauren McCann, Theresa Crofts, Lini Pandite, Robert A. Figlin
Journal: Journal of Clinical Oncology (2009)

Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC.This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily.The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naïve, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT.Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.
Optimising management of delirium
Authors: C. J. Ryan
Journal: BMJ (2001)

Editor—In reviewing the management of delirium, Meagher asserts that antipsychotic drugs are effective in patients with delirium.1 There is, however, little evidence to support this assertion. There are no placebo controlled trials of antipsychotic drugs in patients with delirium. One trial compared antipsychotic drugs with benzodiazepines and found that antipsychotic drugs were superior, but, given that it is widely acknowledged that benzodiazepines may worsen delirium, this result hardly constitutes evidence of efficacy.2 Most clinicians have gained the impression that antipsychotic drugs speed recovery in delirium, but their anecdotal observations must be doubted. Most episodes of delirium last only several days and will improve when the patient's underlying medical condition resolves. In practice, medical management is always instituted simultaneously with prescription of antipsychotic drugs. As a consequence, it would be very difficult for clinicians to isolate the relative effect of an antipsychotic drug on the resolution of delirium. Uncontrolled trials suggesting efficacy will present the same problems.

Delirium often manifests with hallucinations, delusions, or thought disorder. In other psychiatric disorders, such as schizophrenia, these symptoms are improved by antipsychotic drugs, so it is reasonable to postulate that these drugs may also help in cases of delirium. But this hypothesis may be invalid. Treatments for asthma will not necessarily help pneumonia, although both illnesses cause shortness of breath. With so little evidence to support the use of antipsychotic drugs in patients with delirium, management strategies invoking them must be extremely cautious. Meagher proposes a strategy for the management of severe behavioural disturbance in patients with delirium that could quickly lead to doses of haloperidol of up to 100 mg per day. Doses this high may be associated with anticholinergic toxicity and akathisia—a sense of inner restlessness—that may worsen agitation rather than quell it. Such doses also entail an increased risk of torsades de pointes and the neuroleptic malignant syndrome.3,4

Moreover, if the analogy with schizophrenia is valid, it is unlikely that patients would benefit from more than 12 mg of haloperidol per day.5 Antipsychotic drugs should be avoided until all non-pharmacological management options are exhausted. If they are to be used, haloperidol is the drug of choice, but doses should not exceed 12 mg per day. If pharmacological management of behavioural disturbance is required after this, then benzodiazepines should be used, with the understanding that gaining control of the behavioural disturbance may involve an unavoidable perpetuation of the delirium that is driving disturbance. Obviously, there is an urgent need for placebo controlled trials.
Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non–Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial
Authors: Karen Kelly, Nasser K. Altorki, Wilfried E.E. Eberhardt, Mary E.R. O'Brien, David R. Spigel, Lucio Crinò, Chun-Ming Tsai, Joo-Hang Kim, Eun Kyung Cho, Philip C. Hoffman, Sergey V. Orlov, Piotr Serwatowski, Jiuzhou Wang, Margaret A. Foley, Julie D. Horan, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

Purpose Epidermal growth factor receptor (EGFR) –tyrosine kinase inhibitors have proven efficacy in advanced non–small-cell lung cancer (NSCLC). We hypothesized that erlotinib would be efficacious in the adjuvant setting. Patients and Methods An international randomized, double-blind, placebo-controlled study was conducted in patients with completely resected IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization. Patients were assigned 2:1 to erlotinib 150 mg once per day or placebo for 2 years. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country. The primary end point was disease-free survival (DFS); key secondary end points were overall survival (OS) and DFS and OS in patients whose tumors had EGFR-activating mutations (EGFRm-positive). Results A total of 973 patients were randomly assigned (November 26, 2007, to July 7, 2010). There was no statistically significant difference in DFS (median, 50.5 months for erlotinib and 48.2 months for placebo; hazard ratio, 0.90; 95% CI, 0.74 to 1.10; P = .324). Among the 161 patients (16.5%) in the EGFRm-positive subgroup, DFS favored erlotinib (median, 46.4 v 28.5 months; hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .039), but this was not statistically significant because of the hierarchical testing procedure. OS data are immature. Rash and diarrhea were common adverse events occurring in 528 (86.4%) and 319 (52.2%) patients treated with erlotinib, respectively, versus 110 (32.1%) and 54 (15.7%) patients receiving placebo. The most common grade 3 adverse events in patients treated with erlotinib were rash (22.3%) and diarrhea (6.2%). Conclusion Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup. Further evaluation of erlotinib is warranted in the EGFRm-positive subgroup.
Multicentre risk-adapted management for stage I non-seminomatous germ cell tumours
Authors: P. Maroto, X. García del Muro, J. Aparicio, L. Paz-Ares, J.A. Arranz, J. Guma, J. Terrassa, J. Barnadas, J. Dorta, J.R. Germà-Lluch
Journal: Annals of Oncology (2005)
Defective Transcription/Repair Factor IIH Recruitment to Specific UV Lesions in Trichothiodystrophy Syndrome
Authors: Vanessa Chiganças, Keronninn Lima-Bessa, Anne Stary, Carlos F.M. Menck, Alain Sarasin
Journal: Cancer Research (2008)

Abstract Most trichothiodystrophy (TTD) patients present mutations in the xeroderma pigmentosum D (XPD) gene, coding for a subunit of the transcription/repair factor IIH (TFIIH) complex involved in nucleotide excision repair (NER) and transcription. After UV irradiation, most TTD/XPD patients are more severely affected in the NER of cyclobutane pyrimidine dimers (CPD) than of 6-4-photoproducts (6-4PP). The reasons for this differential DNA repair defect are unknown. Here we report the first study of NER in response to CPDs or 6-4PPs separately analyzed in primary fibroblasts. This was done by using heterologous photorepair; recombinant adenovirus vectors carrying photolyases enzymes that repair CPD or 6-4PP specifically by using the energy of light were introduced in different cell lines. The data presented here reveal that some TTD/XPD mutations affect the recruitment of TFIIH specifically to CPDs, but not to 6-4PPs. This deficiency is further confirmed by the inability of TTD/XPD cells to recruit, specifically for CPDs, NER factors that arrive in a TFIIH-dependent manner later in the NER pathway. For 6-4PPs, we show that TFIIH complexes carrying an NH2-terminal XPD mutated protein are also deficient in recruitment of NER proteins downstream of TFIIH. Treatment with the histone deacetylase inhibitor trichostatin A allows the recovery of TFIIH recruitment to CPDs in the studied TTD cells and, for COOH-terminal XPD mutations, increases the repair synthesis and survival after UV, suggesting that this defect can be partially related with accessibility of DNA damage in closed chromatin regions. [Cancer Res 2008;68(15):6074–83]
Airway Smooth Muscle in Asthma
Authors: Marc B. Hershenson, Melanie Brown, Blanca Camoretti-Mercado, Julian Solway
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Airway smooth muscle plays a multifaceted role in the pathogenesis of asthma. We review the current understanding of the contribution of airway myocytes to airway inflammation, airway wall remodeling, and airflow obstruction in this prevalent disease syndrome. Together, these roles make airway smooth muscle an attractive target for asthma therapy.
Transcriptional Profiles Predict Disease Outcome in Patients with Cutaneous T-Cell Lymphoma
Authors: Ivan V. Litvinov, David A. Jones, Denis Sasseville, Thomas S. Kupper
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Average survival of cutaneous T-cell lymphoma (CTCL) is associated with clinical stage at diagnosis, where stage I has a favorable survival prognosis, whereas patients with more advanced stages succumb to their disease within 5 years. Although the majority of patients present with an early-stage CTCL, 15% to 20% of them will inevitably progress. Current state-of-the-art clinical criteria cannot identify individuals with stage I disease who are at risk of progression. The purpose of the current work is to gain novel molecular insight into the pathophysiology of CTCL to be able to identify patients with poor versus favorable prognosis. Our previous work used microarray analysis of skin biopsies from 62 CTCL patients to perform an unsupervised analysis of gene expression, which revealed three distinct transcription profile clusters. Experimental Design: In the present study, we used reverse transcription-PCR to confirm gene expression levels for a subset of representative genes in each cluster. We also performed a Kaplan-Meier analysis of survival and disease progression based on the 6 years of clinical follow-up. Results: Our reverse transcription-PCR results confirmed the upregulation of representative genes for each cluster, whereas clinical analysis documents that all stage I cases that progressed to stage II and beyond were in poor and intermediate prognosis clusters 1 and 3 and none were in favorable prognosis cluster 2. This analysis also identified certain genes that were preferentially expressed in favorable (e.g., WIF-1) versus poor (e.g., IL-17F) prognosis clusters. Conclusion: This work suggests that it may be possible to stratify CTCL patients into low-risk, intermediate-risk, and high-risk groups based on gene expression. Clin Cancer Res; 16(7); 2106–14. ©2010 AACR.
Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry
Authors: Ling Zhang, Xin-Mei Peng, Guri L. V. Damu, Rong-Xia Geng, Cheng-He Zhou
Journal: Medicinal Research Reviews (2013)

Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
H-2M3a violates the paradigm for major histocompatibility complex class I peptide binding.
Authors: J M Vyas, J R Rodgers, R R Rich
Journal: The Journal of Experimental Medicine (1995)

The major histocompatibility (MHC) class I-b molecule H-2M3a binds and presents N-formylated peptides to cytotoxic T lymphocytes. This requirement potentially places severe constraints on the number of peptides that M3a can present to the immune system. Consistent with this idea, the M3a-Ld MHC class I chimera is expressed at very low levels on the cell surface, but can be induced significantly by the addition of specific peptides at 27 degrees C. Using this assay, we show that M3a binds many very short N-formyl peptides, including N-formyl chemotactic peptides and canonical octapeptides. This observation is in sharp contrast to the paradigmatic size range of peptides of 8-10 amino acids binding to most class I-a molecules and the class I-b molecule Qa-2. Stabilization by fMLF-benzyl amide could be detected at peptide concentrations as low as 100 nM. While N-formyl peptides as short as two amino acids in length stabilized expression of M3a-Ld, increasing the length of these peptides added to the stability of peptide-MHC complexes as determined by 27-37 degrees C temperature shift experiments. We propose that relaxation of the length rule may represent a compensatory adaptation to maximize the number of peptides that can be presented by H-2M3a.
Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus
Authors: Masayuki Amagai, Kazuyuki Tsunoda, Harumi Suzuki, Koji Nishifuji, Shigeo Koyasu, Takeji Nishikawa
Journal: Journal of Clinical Investigation (2000)

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3–/– mice, but not Dsg3+/– littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3–/– mice were then adoptively transferred into Rag-2–/– immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3–/– mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.
TCT-115 Hybrid endovascular repair for aortic arch pathology: intermediate outcomes and complications
Authors: Woong Chol Kang, Pyung Chun Oh, Jong Goo Seo, Soon Yong Suh, Kyounghoon Lee, Seung Hwan Han, Taehoon Ahn, Eak Kyun Shin, Young Guk Ko, Donghoon Choi, Won Heum Shim
Journal: Journal of the American College of Cardiology (2012)
Oxygen radical scavengers selectively inhibit interleukin 8 production in human whole blood.
Authors: L E DeForge, J C Fantone, J S Kenney, D G Remick
Journal: Journal of Clinical Investigation (1992)

The hydroxyl radical (OH.) scavenger dimethyl sulfoxide (DMSO) was found to dose-dependently inhibit interleukin 8 (IL-8) production in LPS-stimulated human whole blood. At a concentration of 1% (vol/vol), DMSO blocked IL-8 release by approximately 90% in the presence of 1 microgram/ml LPS at a 24-h time point, but did not affect cell viability or reduce the production of tumor necrosis factor (TNF), interleukin 6, or interleukin-1 beta (IL-1 beta). DMSO was found to directly inhibit IL-8 expression at the level of transcription. Furthermore, this effect was not LPS-specific, in that IL-8 production was reduced by DMSO to a similar extent upon stimulation of blood with phytohemagglutinin, aggregated immune complexes, TNF, or IL-1 beta. Other oxygen radical scavengers that have been shown to inhibit OH.-dependent reactions (dimethyl thiourea, thiourea, mannitol, and ethanol) also inhibited IL-8 production. Conversely, addition of H2O2 caused a dose-dependent stimulation of IL-8 release. These results provide evidence that reactive oxygen metabolites play an important role in the regulation of IL-8 production and suggest that reduction of IL-8 release may contribute to the beneficial effects of antioxidants in experimental models of inflammation and ischemia/reperfusion injury.
Somatic<i>SDHB</i>Mutation in an Extraadrenal Pheochromocytoma
Authors: Francien H. van Nederveen, Esther Korpershoek, Jacques W.M. Lenders, Ronald R. de Krijger, Winand N.M. Dinjens
Journal: New England Journal of Medicine (2007)

To the Editor: As many as 25% of pheochromocytomas — catecholamine-producing tumors located along the sympathetic nervous system, including the adrenals — occur in hereditary tumor syndromes that i...
Obstructive sleep apnoea treatment and fasting lipids: a comparative effectiveness study
Authors: Brendan T. Keenan, Greg Maislin, Bernie Y. Sunwoo, Erna Sif Arnardottir, Nicholas Jackson, Isleifur Olafsson, Sigurdur Juliusson, Richard J. Schwab, Thorarinn Gislason, Bryndis Benediktsdottir, Allan I. Pack
Journal: European Respiratory Journal (2014)

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes. Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified. At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed. Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA.