tbuckley/cabot-search huggingface dataset:
Deficiency of SPARC suppresses intestinal tumorigenesis in APCMin/+ mice
Authors: O. J Sansom, F. C Mansergh, M. J Evans, J. A Wilkins, A. R Clarke
Journal: Gut (2007)

<b>Background and aims:</b> SPARC (secreted protein acidic, rich in cysteine) is a matricellular protein that has been found to be activated in a number of human cancers. More recently, it has been shown to be upregulated in human gastric and colorectal cancer. We therefore wished to address the functional importance of SPARC upregulation to intestinal tumorigenesis <i>in vivo</i>. <b>Methods:</b> SPARC upregulation was determined in intestinal adenomas of tumour-prone Apc<sup>Min/+</sup> mice at both the RNA and the protein level. To determine the functional importance of SPARC for intestinal tumorigenesis we then intercrossed <i>Sparc</i> knockout mice with <i>Apc<sup>Min/+</sup></i> mice (n = 20). Intestinal enterocyte migration was examined using bromodeoxyuridine labelling studies. <b>Results:</b> Levels of murine Sparc and several related proteins were upregulated in adenomas arising in <i>Apc<sup>Min/+</sup></i> mice. A deficiency of Sparc strongly suppressed adenoma formation in <i>Apc<sup>Min/+</sup></i> mice (p⩾0.0001). Importantly, a deficiency of Sparc also accelerated enterocyte migration (p = 0.01), as perturbed slow epithelial migration may underpin adenoma formation in the intestine. <b>Conclusions:</b> These data implicate Sparc in both cell migration and tumour formation, and identify Sparc as a potential therapeutic target for colorectal cancer.
Targeted Anti–Vascular Endothelial Growth Factor Receptor-2 Therapy Leads to Short-term and Long-term Impairment of Vascular Function and Increase in Tumor Hypoxia
Authors: Marcela Franco, Shan Man, Limor Chen, Urban Emmenegger, Yuval Shaked, Alison M. Cheung, Allison S. Brown, Daniel J. Hicklin, F. Stuart Foster, Robert S. Kerbel
Journal: Cancer Research (2006)

Abstract Because antiangiogenic therapies inhibit the growth of new tumor-associated blood vessels, as well as prune newly formed vasculature, they would be expected to reduce the supply of oxygen and thus increase tumor hypoxia. However, it is not clear if antiangiogenic treatments lead only to consistent and sustained increases in hypoxia, or transient decreases in tumor hypoxia along with periods of increased hypoxia. We undertook a detailed analysis of an orthotopically transplanted human breast carcinoma (MDA-MB-231) over a 3-week treatment period using DC101, an anti–vascular endothelial growth factor receptor 2 antibody. We observed consistent reductions in microvascular density, blood flow (measured by high-frequency micro-ultrasound), and perfusion. These effects resulted in an increase in the hypoxic tumor fraction, measured with an exogenous marker, pimonidazole, concurrent with an elevation in hypoxia-inducible factor-1α expression, an endogenous marker. The increase in tumor hypoxia was evident within 5 days and remained so throughout the entire course of treatment. Vascular perfusion and flow were impaired at days 2, 5, 7, 8, 14, and 21 after the first injection, but not at 4 hours. A modest increase in the vessel maturation index was detected after the 3-week treatment period, but this was not accompanied by an improvement in vascular function. These results suggest that sustained hypoxia and impairment of vascular function can be two consistent consequences of antiangiogenic drug treatment. The implications of the results are discussed, particularly with respect to how they relate to different theories for the counterintuitive chemosensitizing effects of antiangiogenic drugs, even when hypoxia is increased. (Cancer Res 2006; 66(7): 3639-48)
Ethnic difference and diagnostic value of exhaled nitric oxide levels for predicting asthma in children
Authors: Gary Wong, Ting Fan Leung, Edmung Yung
Journal: European Respiratory Journal (2012)

Exhaled nitric oxide (eNO) has been use as non-invasive marker of airway inflammation but normal reference data in children are limited. Levels of eNO in a random sample of 1099 Chinese children aged 11-18 years recruited from Hong Kong were measured online by a chemiluminescence analyzer according to ERS/ATS standard. Each student also completed an ISAAC questionnaire. Children who had never been diagnosed to have asthma and did not have any symptoms of wheeze, rhinitis or eczema were considered as normal controls. Ninety-four steroid naive asthmatics were recruited from the Asthma Clinic for eNO measurement for comparison. Among the control children, there were 369 boys and 373 girls. In control children, the eNO levels (median, interquantile range) were significantly higher ( P <0.001) in males (11.4 ppb; 7.7-21.6) than in females (9.0 ppb; 5.9-13.4). For asthmatic males, the median eNO (interquartile range) was 45.5 ppb (28.3-74.1); for asthmatic females, 47.2 (28.8-69.5). Using a cutoff of 15 ppb for girls, the sensitivity and specificity for differentiating asthma from controls are 86% and 78% (AUC of ROC curve =0.89); for boys, the sensitivity and specificity are 80.4% and 79.4% using a cutoff of 25 ppb (AUC of ROC curve = 0.84). This is one of the largest studies of eNO in children and demonstrates a gender difference of eNO levels in Chinese schoolchildren and their levels are higher than the reported values for Caucasians. Different cutoff vales for boys and girls are needed when eNO is used for supporting the diagnosis of asthma in children.Supported by HKRGC CUHK4512/06M and CUHK 477110.
The Requirements for Transferrin-Dependent Adherence of Human Granulocytes to Pollen Grains
Authors: J. A. Mackay, S. Sass‐Kuhn, R. Moqbel, G. M. Walsh, A. B. Kay
Journal: Allergy (1986)

Human granulocyte/pollen binding protein (GPBP), previously identified as serum transferrin, promoted prolonged firm adherence of neutrophils to Timothy grass pollen. Some characteristics of this adherence reaction are reported. GPBP‐induced binding was time‐, temperature‐ and concentration‐dependent. Maximal adherence was observed by 2 h and was only slightly decreased at 18 h. The optimal temperature for adherence was 37° C. Concentrations of GPBP as low as 1.25 μ g/ml gave significantly greater binding than the albumin or lactoferrin control. Eosinophils, monocytes and lymphocytes did not appear to participate in GPBP‐induced pollen binding reactions at concentrations up to 300 μg/ml. In the presence of GPBP, neutrophils adhered to a range of grass, weed and tree pollens. These included timothy, meadow, false oat, rye, giant and short ragweed, plantain, silver birch and ash. GPBP did not facilitate the adherence of granulocytes to inert particles of similar size such as Sephadex beads and agarose. The adherence was Mg ++ ‐ but not Ca ++ ‐ dependent and was not inhibited by a monoclonal antibody to the transferrin receptor (OKT9). Transferrin/GPBP did not bind to either neutrophils or pollen grains. A purified commercial transferrin reacted in all respects like GPBP in these pollen binding studies. These observations indicate that GPBP/transferrin‐induced adherence of granulocytes to pollen grains is a hitherto unrecognized property of transferrin which appears unrelated to iron transport or the conventional transferrin receptor.
Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation
Authors: Jean-Marc Hyvelin, Katherine Howell, Alistair Nichol, Christine M. Costello, Robert J. Preston, Paul McLoughlin
Journal: Circulation Research (2005)

Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase–dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.
Detection of Hypoglycemia With the GlucoWatch Biographer
Authors: Kenneth R. Pitzer, Shashi Desai, Tim Dunn, Steve Edelman, Yalia Jayalakshmi, John Kennedy, Janet A. Tamada, Russell O. Potts
Journal: Diabetes Care (2001)

OBJECTIVE—Hypoglycemia is a common acute complication of diabetes therapy. The GlucoWatch biographer provides frequent and automatic glucose measurements with an adjustable low-glucose alarm. We have analyzed the performance of the biographer low-glucose alarm relative to hypoglycemia as defined by blood glucose ≤3.9 mmol/l. RESEARCH DESIGN AND METHODS—The analysis was based on 1,091 biographer uses from four clinical trials, which generated 14,487 paired (biographer and blood glucose) readings. RESULTS—The results show that as the low-glucose alert level of the biographer is increased, the number of true positive alerts (alarm sounds and blood glucose ≤3.9 mmol/l) and false positive alerts (alarm sounds but blood glucose &amp;gt;3.9 mmol/l) increased. When analyzed as a function of varying low-glucose alert levels, the results show receiver operator characteristic curves consistent with a highly useful diagnostic tool. Setting the alert level from 1.1 to 1.7 mmol/l above the level of concern is likely to optimize the trade-off between true positives and false positives for each user. When the same blood glucose data are analyzed for typical monitoring practices (two or four measurements per day), the results show that fewer hypoglycemic events are detected than those detected with the biographer. CONCLUSIONS—The frequent and automatic nature of the biographer readings allows more effective detection of hypoglycemia than that achieved with current medical practice.
Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent <i>RAF</i> Fusions and Frequent Inactivation of DNA Repair Genes
Authors: Juliann Chmielecki, Katherine E. Hutchinson, Garrett M. Frampton, Zachary R. Chalmers, Adrienne Johnson, Chanjuan Shi, Julia Elvin, Siraj M. Ali, Jeffrey S. Ross, Olca Basturk, Sohail Balasubramanian, Doron Lipson, Roman Yelensky, William Pao, Vincent A. Miller, David S. Klimstra, Philip J. Stephens
Journal: Cancer Discovery (2014)

Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (∼500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in approximately 23% of tumors. The most prevalent fusion, SND1-BRAF, resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1-BRAF-transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease.PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors.
Normalizing Effects of Modafinil on Sleep in Chronic Cocaine Users
Authors: Peter T. Morgan, Edward Pace-Schott, Brian Pittman, Robert Stickgold, Robert T. Malison
Journal: American Journal of Psychiatry (2010)

Objective The purpose of the present study was to determine the effect of morning-dosed modafinil on sleep and daytime sleepiness in chronic cocaine users. Method Twenty cocaine-dependent participants were randomly assigned to receive modafinil, 400 mg (N=10), or placebo (N=10) every morning at 7:30 a.m. for 16 days in an inpatient, double-blind randomized trial. Participants underwent polysomnographic sleep recordings on days 1 to 3, 7 to 9, and 14 to 16 (first, second, and third weeks of abstinence). The Multiple Sleep Latency Test was performed at 11:30 a.m., 2:00 p.m., and 4:30 p.m. on days 2, 8, and 15. For comparison of sleep architecture variables, 12 healthy comparison participants underwent a single night of experimental polysomnography that followed 1 night of accommodation polysomnography. Results Progressive abstinence from cocaine was associated with worsening of all measured polysomnographic sleep outcomes. Compared with placebo, modafinil decreased nighttime sleep latency and increased slow-wave sleep time in cocaine-dependent participants. The effect of modafinil interacted with the abstinence week and was associated with longer total sleep time and shorter REM sleep latency in the third week of abstinence. Comparison of slow-wave sleep time, total sleep time, and sleep latency in cocaine-dependent and healthy participants revealed a normalizing effect of modafinil in cocaine-dependent participants. Modafinil was associated with increased daytime sleep latency, as measured by the Multiple Sleep Latency Test, and a nearly significant decrease in subjective daytime sleepiness. Conclusions Morning-dosed modafinil promotes nocturnal sleep, normalizes sleep architecture, and decreases daytime sleepiness in abstinent cocaine users. These effects may be relevant in the treatment of cocaine dependence.
Auxiliary liver transplantation: Regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure-a multicenter European study
Authors: M Chenard-Neu, K Boudjema, J Bernuau, C Degott, J Belghiti, D Cherqui, V Costes, J Domergue, F Durand, J Erhard, B De Hemptinne, G Gubernatis, A Hadengue, J Kemnitz, M McCarthy, H Maschek, G Mentha, K Oldhafer, B Portmann, M Praet, J Ringers, X Rogiers, L Rubbia, S Schalm, F T Kate, O Terpstra, B Van Hoek, R Williams, E Zafrani, J Cinqualbre, P Wolf, D Jaeck, J Bellocq
Journal: Hepatology (1996)

Auxiliary liver transplantation (LT) is a special procedure of LT which could be proposed to patients with fulminant hepatic failure (FHF) and has for aim that complete regeneration of the native liver (NL) left in place will allow the graft recipient to resume normal liver function after allograft withdrawal. We report 30 cases of auxiliary LT performed for FHF in 12 European centers. Twenty-five of 30 patients were younger than 50 years. The cause of FHF was hepatitis A virus (HAV) in 4 patients, hepatitis B virus (HBV) in 7, paracetamol overdose in 5, ecstasy in 2, hepatotoxic drugs in 4, autoimmune hepatitis in 2, liver lesions of preeclampsia in 1 and unknown in 5. A postoperative, both clinical and histological follow-up of more than 3 weeks was obtained in 22 patients, enabling us to look for indicators predictive of NL regeneration and outcome. Histological changes observed in the NL included complete regeneration in 68%, incomplete regeneration with obvious fibrous sequelae in 14% and severe liver fibrosis or cirrhosis in 18%, of the 22 patients studied. The percentage and distribution of necrosis observed in tissue samples of the NL at the time of transplantation was not related to the final outcome. Complete NL regeneration was observed in 15 patients, out of whom 14 were younger than 40 years. Patients with complete regeneration were mainly affected by FHF due to HAV, HBV, or paracetamol overdose. After a follow-up of 18/11 (mean/median) months (range, 3 to 67 months), 19 of the 30 patients (63%) survived and 13 of them (68%), i.e., 43% of the 30 patients, had resumed normal NL function, with interrupted immunosuppression, the ultimate goal of emergency auxiliary LT. We conclude that, in patients with FHF, auxiliary LT is a procedure feasible in a number of centers and is associated with a complete regeneration capability of the NL in a majority of survivors, especially in those younger than 40 years. Confirmation of these encouraging preliminary results by large-scale prospective studies is required.
Immune regulation by peripheral Tregs induced upon homotypic T cell/T cell interactions
Authors: K Thummler, J Leipe, A Ramming, I Prots, H Schulze-Koops, A Skapenko
Journal: Annals of the Rheumatic Diseases (2010)

Autoimmune diseases such as rheumatoid arthritis are characterised by persistently activated CD4 T cells which circulate from the synovial tissues into the lymph nodes where they encounter multiple contacts with bystander cells including resting CD4 T cells.The authors have recently shown that activated T cells induce the proliferation and production of cytokines with immunoregulatory potential from resting CD4 T cells by homotypic T cell interaction.Since the compromised function of regulatory T cells (Tregs) results in the development of autoimmune diseases, the authors investigated the function of these T cells resulting from the interaction of activated T cells and resting CD4 T cells and the mechanism mediating this novel cellular interaction.Resting CD4 T cells on July 15,
FoxO4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1
Authors: Min Zhu, Sean C. Goetsch, Zhaoning Wang, Robert Luo, Joseph A. Hill, Jay Schneider, Sidney M. Morris, Zhi-Ping Liu
Journal: Circulation Research (2015)

Rationale: Inflammation in post–myocardial infarction (MI) is necessary for myocyte repair and wound healing. Unfortunately, it is also a key component of subsequent heart failure pathology. Transcription factor forkhead box O4 (FoxO4) regulates a variety of biological processes, including inflammation. However, its role in MI remains unknown. Objective: To test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1). Methods and Results: We induced MI in wild-type and FoxO4 −/− mice. FoxO4 −/− mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size. FoxO4 −/− hearts had significantly fewer neutrophils, reduced expression of cytokines, and competitive nitric oxide synthase inhibitor Arg1. We generated conditional FoxO4 knockout mice with FoxO4 deleted in cardiac mycoytes or endothelial cells. FoxO4 endothelial cell–specific knockout mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression, whereas FoxO4 cardiac mycoyte–specific knockout mice had no significant difference in cardiac function and post-MI inflammation from those of control littermates. FoxO4 binds the Foxo-binding site in the Arg1 promoter and activates Arg1 transcription. FoxO4 knockdown in human aortic endothelial cells upregulated nitric oxide on ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in wild-type mice had similar cardioprotection and reduced inflammation after MI as FoxO4 inactivation and administration of nitric oxide synthase inhibitor to FoxO4 KO mice reversed the beneficial effects of FoxO4 deletion on post-MI cardiac function. Conclusions: FoxO4 activates Arg1 transcription in endothelial cells in response to MI, leading to downregulation of nitric oxide and upregulation of neutrophil infiltration to the infarct area.
Learning and Memory in Rape Victims With Posttraumatic Stress Disorder
Authors: Melissa A. Jenkins, Philip J. Langlais, Dean Delis, Ronald Cohen
Journal: American Journal of Psychiatry (1998)

Studies have shown memory deficits among combat veterans with posttraumatic stress disorder (PTSD); however, high rates of comorbid conditions, including alcoholism, make it difficult to definitively associate these findings with the PTSD diagnosis. In this study the authors examined memory functioning among rape survivors without alcoholism or substance abuse but with PTSD.Rape victims with (N = 15) and without (N = 16) PTSD were compared to age- and education-matched nontraumatized comparison subjects (N = 16) on measures of learning and memory.The subjects with PTSD performed significantly worse than the other groups on delayed free recall. The deficits were ameliorated by cueing and recognition testing.Recall deficits in noncombat PTSD patients strengthen the theory that memory deficits are associated with the PTSD diagnosis. The deficits were mild and were not attributable to comorbid depression, anxiety, or substance abuse.
American Society of Clinical Oncology Policy Statement Update: Tobacco Control—Reducing Cancer Incidence and Saving Lives
Journal: Journal of Clinical Oncology (2003)

As an international medical society dedicated to cancer prevention, the American Society of Clinical Oncology (ASCO) advocates a fundamental reform of United States and international policy toward addictive tobacco products. ASCO's goal is the immediate reduction of tobacco use and ultimate achievement of a tobacco-free world. The centerpiece of ASCO's policy is the recommendation for an independent commission to study the tobacco problem in all of its dimensions: social, medical, legal, and economic (both domestically and globally). The commission membership should include broad-based representation and expertise on tobacco issues. In ASCO's view, tobacco control efforts to date have been less than successful because they are too fragmented and incremental, leaving many important issues unaddressed. A more comprehensive solution could flow from this study, including input from a variety of government agencies involved with public health, agriculture, First Amendment and other legal considerations, and international trade. The study, within defined time limits, should culminate in a report that outlines a strategy for achieving immediate reduction of tobacco use and ultimate achievement of a tobacco-free world, including explicit plans and a timetable for implementation. Although this comprehensive approach to tobacco control will take many years to implement even under the best of circumstances, there are certain measures that could be undertaken immediately with meaningful impact on tobacco usage. These include: Increasing efforts to discourage tobacco use, particularly among the young Raising federal excise taxes by at least $2 per pack and encouraging states to consider tobacco taxes as a first resort in revenue enhancement Ensuring that tobacco settlement funds be devoted only to health-related projects, including medical treatment, biomedical research, and tobacco prevention efforts Requiring disclosure of all ingredients in tobacco products Comprehensively reforming third-party payment for tobacco cessation efforts Additional restriction of secondhand smoke in any places where the public may congregate Supporting necessary research into tobacco addiction, toxicities, and prevention strategies Enhancing global tobacco control, including a halt of United States government promotion of tobacco products