tbuckley/cabot-search huggingface dataset:
NADPH oxidase–derived free radicals are key oxidants in alcohol-induced liver disease
Authors: Hiroshi Kono, Ivan Rusyn, Ming Yin, Erwin Gäbele, Shunhei Yamashina, Anna Dikalova, Maria B. Kadiiska, Henry D. Connor, Ronald P. Mason, Brahm H. Segal, Blair U. Bradford, Steven M. Holland, Ronald G. Thurman
Journal: Journal of Clinical Investigation (2000)

In North America, liver disease due to alcohol consumption is an important cause of death in adults, although its pathogenesis remains obscure. Despite the fact that resident hepatic macrophages are known to contribute to early alcohol-induced liver injury via oxidative stress, the exact source of free radicals has remained a mystery. To test the hypothesis that NADPH oxidase is the major source of oxidants due to ethanol, we used p47phox knockout mice, which lack a critical subunit of this major source of reactive oxygen species in activated phagocytes. Mice were treated with ethanol chronically, using a Tsukamoto-French protocol, for 4 weeks. In wild-type mice, ethanol caused severe liver injury via a mechanism involving gut-derived endotoxin, CD14 receptor, production of electron spin resonance–detectable free radicals, activation of the transcription factor NF-κB, and release of cytotoxic TNF-α from activated Kupffer cells. In NADPH oxidase–deficient mice, neither an increase in free radical production, activation of NF-κB, an increase in TNF-α mRNA, nor liver pathology was observed. These data strongly support the hypothesis that free radicals from NADPH oxidase in hepatic Kupffer cells play a predominant role in the pathogenesis of early alcohol-induced hepatitis by activating NF-κB, which activates production of cytotoxic TNF-α.
Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells
Authors: Ute E. Burkhardt, Ursula Hainz, Kristen Stevenson, Natalie R. Goldstein, Mildred Pasek, Masayasu Naito, Di Wu, Vincent T. Ho, Anselmo Alonso, Naa Norkor Hammond, Jessica Wong, Quinlan L. Sievers, Ana Brusic, Sean M. McDonough, Wanyong Zeng, Ann Perrin, Jennifer R. Brown, Christine M. Canning, John Koreth, Corey Cutler, Philippe Armand, Donna Neuberg, Jeng-Shin Lee, Joseph H. Antin, Richard C. Mulligan, Tetsuro Sasada, Jerome Ritz, Robert J. Soiffer, Glenn Dranoff, Edwin P. Alyea, Catherine J. Wu
Journal: Journal of Clinical Investigation (2013)

Background. Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity.
Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program
Authors: Linda M. Delahanty, Qing Pan, Kathleen A. Jablonski, Karol E. Watson, Jeanne M. McCaffery, Alan Shuldiner, Steven E. Kahn, William C. Knowler, Jose C. Florez, Paul W. Franks
Journal: Diabetes Care (2011)

We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss-inducing interventions (lifestyle and metformin) versus placebo.Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end).Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (-0.63 and -0.93 kg/allele, P ≤ 0.005, respectively). Gene-treatment interactions were observed for short-term (LYPLAL1 rs2605100, P(lifestyle*SNP) = 0.032; GNPDA2 rs10938397, P(lifestyle*SNP) = 0.016; MTCH2 rs10838738, P(lifestyle*SNP) = 0.022) and long-term (NEGR1 rs2815752, P(metformin*SNP) = 0.028; FTO rs9939609, P(lifestyle*SNP) = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (P(lifestyle*SNP) < 0.05).Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing.
Authors: T S Khurana, R A Prendergast, H S Alameddine, F M Tomé, M Fardeau, K Arahata, H Sugita, L M Kunkel
Journal: The Journal of Experimental Medicine (1995)

Duchenne muscular dystrophy (DMD) is characterized by clinical weakness and progressive necrosis of striated muscle as a consequence of dystrophin deficiency. While all skeletal muscle groups are thought to be affected, enigmatically, the extraocular muscles (EOM) appear clinically unaffected. Here we show that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium ([Ca2+]i) in EOM. At variance with a previous report, we find no evidence for dystrophin-related protein/utrophin up-regulation in EOM. In vitro experiments demonstrate that extraocular muscles are inherently more resistant to necrosis caused by pharmacologically elevated [Ca2+]i levels when compared with pectoral musculature. We believe that EOM are spared in DMD because of their intrinsic ability to maintain calcium homeostasis better than other striated muscle groups. Our results indicate that modulating levels of [Ca2+]i in muscle may be of potential therapeutic use in DMD.
Dose-Response Effects of Insulin Glargine in Type 2 Diabetes
Authors: Zhihui Wang, Maka S. Hedrington, Nino Gogitidze Joy, Vanessa J. Briscoe, M. Antoinette Richardson, Lisa Younk, Wendell Nicholson, Donna B. Tate, Stephen N. Davis
Journal: Diabetes Care (2010)

OBJECTIVE To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or &amp;gt;24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P &amp;lt; 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal. CONCLUSION A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.
Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis
Authors: M D Rutter
Journal: Gut (2004)

<b>Background and aims:</b> Colonoscopic surveillance for cancer in longstanding extensive ulcerative colitis relies heavily on non-targeted mucosal biopsies. Chromoendoscopy can aid detection of subtle mucosal abnormalities. We hypothesised that routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies. <b>Patients and methods:</b> One hundred patients with longstanding extensive ulcerative colitis attending for colonoscopic surveillance underwent "back to back" colonoscopies. During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm. Pancolonic indigo carmine (0.1%) was used during the second colonoscopic examination, and any additional visible abnormalities were biopsied. <b>Results:</b> Median extubation times for the first and second colonoscopies were 11 and 10 minutes, respectively. The non-targeted biopsy protocol detected no dysplasia in 2904 biopsies. Forty three mucosal abnormalities (20 patients) were detected during the pre-dye spray colonoscopy of which two (two patients) were dysplastic: both were considered to be dysplasia associated lesions/masses. A total of 114 additional abnormalities (55 patients) were detected following dye spraying, of which seven (five patients) were dysplastic: all were considered to be adenomas. There was a strong trend towards statistically increased dysplasia detection following dye spraying (p = 0.06, paired exact test). The targeted biopsy protocol detected dysplasia in significantly more patients than the non-targeted protocol (p = 0.02, paired exact test). <b>Conclusions:</b> No dysplasia was detected in 2904 non-targeted biopsies. In comparison, a targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were only visible after indigo carmine application. Careful mucosal examination aided by pancolonic chromoendoscopy and targeted biopsies of suspicious lesions may be a more effective surveillance methodology than taking multiple non-targeted biopsies.
S68 Bioavailability of VEGF in Idiopathic Pulmonary Fibrosis
Authors: SL Barratt, C Jarrett, T Blythe, GI Welsh, T Maher, DO Bates, AB Millar
Journal: Thorax (2012)

<h3>Introduction</h3> Vascular endothelial growth factor (VEGF) is both a growth and permeability factor implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). VEGF exerts its biological effects through receptors: VEGFR-1, VEGFR-2, Neuropilin-1(NRP-1) and Neuropilin-2 (NRP-2). The presence of hypoxia and its treatment by high flow oxygen have been proposed to contribute to lung injury. VEGF gene transcription is tightly regulated by a hypoxia response element (HRE). We hypothesised that: VEGF and its receptors would be differentially expressed between normal (NF) and fibrotic fibroblasts (FF). Hypoxia and hyperoxia may alter fibroblast VEGF expression. <h3>Methods</h3> NF(n=5) and FF(n=5) (from patients with proven usual interstitial pneumonia) were extracted from lung biopsies using the explant method. VEGF receptors levels were analysed at the mRNA and protein level (qPCR and western blotting (WB)). Pan VEGF isoforms were detected at the protein level using WB and ELISA. Fibroblasts were grown in culture for 24 hours in normoxic, hyperoxic (90% O2) and hypoxic conditions (21% O2 with CoCl2). <h3>Results</h3> Both NF and FF expressed VEGFR1, VEGFR2, NRP-1 and NRP-2. No significant difference was detected in receptor expression at mRNA or protein level, but a trend towards reduced protein expression of VEGFR1 and NRP-2 in FF vs NF was observed. FF expressed significantly more total VEGF than NF by ELISA (Figure 1): (NF 180.5 pg/ml vs FF 332.0 pg/ml, p=0.01) and by WB (normalised densitometry value: NF 116 vs 162, p=0.046). Moreover, a significant increase in VEGF expression was observed in both normal and fibrotic fibroblasts in response to hypoxic growth conditions (NF 205.7 pg/ml vs 1382.0 pg/ml, p=0.05, FF 394.6 pg/ml vs 1113 pg/ml.0, p=0.01). A trend towards increased VEGF expression was also seen in FFvsNF exposed to hyperoxic conditions. <h3>Conclusions</h3> Differential expression of VEGF between NF and FF suggests a potential role in the development of IPF. The observation that hypoxia and possibly hyperoxia may alter VEGF bioavailability has implications in the use of oxygen therapy in the management of this disease.
Immunologic response and safety in birch pollen sublingual versus oral vestibule immunotherapy: A pilot study
Authors: Jean-Pierre Allam, Eike Wuestenberg, Hendrik Wolf, Ludger Klimek, Elke Decot, Andreas Horn, Jörg Schnitker, Thomas Bieber, Natalija Novak
Journal: Journal of Allergy and Clinical Immunology (2014)
Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence
Authors: Joseph Cheung, Xavier Estivill, Razi Khaja, Jeffrey R MacDonald, Ken Lau, Lap-Chee Tsui, Stephen W Scherer
Journal: Genome biology (2003)

Abstract Background Previous studies have suggested that recent segmental duplications, which are often involved in chromosome rearrangements underlying genomic disease, account for some 5% of the human genome. We have developed rapid computational heuristics based on BLAST analysis to detect segmental duplications, as well as regions containing potential sequence misassignments in the human genome assemblies. Results Our analysis of the June 2002 public human genome assembly revealed that 107.4 of 3,043.1 megabases (Mb) (3.53%) of sequence contained segmental duplications, each with size equal or more than 5 kb and 90% identity. We have also detected that 38.9 Mb (1.28%) of sequence within this assembly is likely to be involved in sequence misassignment errors. Furthermore, we have identified a significant subset (199,965 of 2,327,473 or 8.6%) of single-nucleotide polymorphisms (SNPs) in the public databases that are not true SNPs but are potential paralogous sequence variants. Conclusion Using two distinct computational approaches, we have identified most of the sequences in the human genome that have undergone recent segmental duplications. Near-identical segmental duplications present a major challenge to the completion of the human genome sequence. Potential sequence misassignments detected in this study would require additional efforts to resolve.
Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function
Authors: Julia F. Charles, Lih-Yun Hsu, Erene C. Niemi, Arthur Weiss, Antonios O. Aliprantis, Mary C. Nakamura
Journal: Journal of Clinical Investigation (2012)

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b–/loLy6Chi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell–suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.
Oxygen Sensitivity of Cloned Voltage-Gated K <sup>+</sup> Channels Expressed in the Pulmonary Vasculature
Authors: Joanne T. Hulme, Elizabeth A. Coppock, Antonio Felipe, Jeffery R. Martens, Michael M. Tamkun
Journal: Circulation Research (1999)

Abstract —Hypoxic pulmonary vasoconstriction is initiated by inhibiting one or more voltage-gated potassium (Kv) channel in the vascular smooth muscle cells (VSMCs) of the small pulmonary resistance vessels. Although progress has been made in identifying which Kv channel proteins are expressed in pulmonary arterial (PA) VSMCs, there are conflicting reports regarding which channels contribute to the native O 2 -sensitive K + current. In this study, we examined the effects of hypoxia on the Kv1.2, Kv1.5, Kv2.1, and Kv9.3 α subunits expressed in mouse L cells using the whole-cell patch-clamp technique. Hypoxia (P o 2 =≈30 mm Hg) reversibly inhibited Kv1.2 and Kv2.1 currents only at potentials more positive than 30 mV. In contrast, hypoxia did not alter Kv1.5 current. Currents generated by coexpression of Kv2.1 with Kv9.3 α subunits were reversibly inhibited by hypoxia in the voltage range of the resting membrane potential (E M ) of PA VSMCs (≈28% at −40 mV). Coexpression of Kv1.2 and Kv1.5 α subunits produced currents that displayed kinetic and pharmacological properties distinct from Kv1.2 and Kv1.5 channels expressed alone. Moreover, hypoxia reversibly inhibited Kv1.2/Kv1.5 current activated at physiologically relevant membrane potentials (≈65% at −40 mV). These results indicate that (1) hypoxia reversibly inhibits Kv1.2 and Kv2.1 but not Kv1.5 homomeric channels, (2) Kv1.2 and 1.5 α subunits can assemble to form an O 2 -sensitive heteromeric channel, and (3) only Kv1.2/Kv1.5 and Kv2.1/Kv9.3 heteromeric channels are inhibited by hypoxia in the voltage range of the PA VSMC E M . Thus, these heteromeric channels are strong candidates for the K + channel isoforms initiating hypoxic pulmonary vasoconstriction.
Transcriptional and posttranscriptional regulation of macrophage-specific colony stimulating factor gene expression by tumor necrosis factor. Involvement of arachidonic acid metabolites.
Authors: M L Sherman, B L Weber, R Datta, D W Kufe
Journal: Journal of Clinical Investigation (1990)

The effects of tumor necrosis factor (TNF) on the regulation of macrophage-specific colony stimulating factor (CSF-1) gene expression have been studied in HL-60 cells during monocytic differentiation. CSF-1 transcripts were undetectable in uninduced HL-60 cells, reached maximal levels by 3 h of exposure to TNF, and returned to that of control cells by 24 h. Transcriptional run-on analysis demonstrated that exposure to TNF stimulated the rate of CSF-1 gene transcription by 6.4-fold. The combination of a protein synthesis inhibitor, cycloheximide, and TNF increased levels of CSF-1 mRNA compared with treatment by TNF alone. We also studied the signal transduction mechanisms responsible for regulating TNF-induced CSF-1 mRNA levels. Both 4-bromophenacyl bromide and quinacrine, inhibitors of phospholipase A2 activity, blocked TNF-induced increases in CSF-1 transcripts in a concentration-dependent manner, while caffeic acid and nordihydroguaiaretic acid, inhibitors of the 5-lipoxygenase pathway, had no detectable effect on induction of CSF-1 RNA. PGE2 or dibutyryl cAMP treatment of HL-60 cells in the presence of TNF blocked the expression of CSF-1 mRNA in a dose-dependent manner. These findings suggest that the increase in CSF-1 RNA observed during TNF treatment is regulated, at least in part, by both transcriptional and posttranscriptional mechanisms, and that PGE2 and cAMP regulate transcriptional activation of the CSF-1 gene by TNF.
Does IQ explain socioeconomic inequalities in health? Evidence from a population based cohort study in the west of Scotland
Authors: G David Batty, Geoff Der, Sally Macintyre, Ian J Deary
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To test the hypothesis that IQ is a fundamental cause of socioeconomic inequalities in health. <b>Design</b> Cross sectional and prospective cohort study, in which indicators of IQ were assessed by written test and socioeconomic position by self report. <b>Setting</b> West of Scotland. <b>Participants</b> 1347 people (739 women) aged 56 in 1987. <b>Main outcome measures</b> Total mortality and coronary heart disease mortality (ascertained between 1987 and 2004); respiratory function, self reported minor psychiatric morbidity, long term illness, and self perceived health (all assessed in 1988). <b>Results</b> In sex adjusted analyses, indices of socioeconomic position (childhood and current social class, education, income, and area deprivation) were significantly associated with each health outcome. Thus the greatest risk of ill health and mortality was evident in the most socioeconomically disadvantaged groups, as expected. After adjustment for IQ, a marked attenuation in risk occurred for poor mental health (range of attenuation in risk ratio across the five socioeconomic indicators: 15-58%), long term illness (25-53%), poor self perceived health (41-56%), respiratory function (44-66%), coronary heart disease mortality (31-111%), and total mortality (45-131%). Despite the clear reduction in the magnitude of these effects after controlling for IQ, in half of the associations examined the risk of ill health in socioeconomically disadvantaged people was still at least twice that of advantaged people. Statistical significance was lost for only 5/25 separate socioeconomic health gradients that showed significant relations in sex adjusted analyses. <b>Conclusions</b> Scores from the IQ test used here did not completely explain the socioeconomic gradients in health. However, controlling for IQ did lead to a marked reduction in the magnitude of these gradients. Further exploration of the currently scant information about IQ, socioeconomic position, and health is needed.
Sex Steroids Used in Hormonal Treatment Increase Vascular Procoagulant Activity by Inducing Thrombin Receptor (PAR-1) Expression
Authors: Olaf Herkert, Herbert Kuhl, Jurgen Sandow, Rudi Busse, Valérie B. Schini-Kerth
Journal: Circulation (2001)

The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear.This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestrel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17alpha-ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-keto-desogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin.These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity.