tbuckley/cabot-search huggingface dataset:
AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability
Authors: Bum-Joon Park, Young Sun Oh, Seung Yong Park, So Jung Choi, Cornelia Rudolph, Brigitte Schlegelberger, Sunghoon Kim
Journal: Cancer Research (2006)

AIMP3 (previously known as p18) was shown to up-regulate p53 in response to DNA damage. Here, we show that AIMP3 couples oncogenic stresses to p53 activation to prevent cell transformation. Growth factor- or Ras-dependent induction of p53 was blocked by single allelic loss of AIMP3 as well as by suppression of AIMP3. AIMP3 heterozygous cells became susceptible to cell transformation induced by oncogenes such as Ras or Myc alone. The transformed AIMP3+/- cells showed severe abnormality in cell division and chromosomal structure. Thus, AIMP3 plays crucial roles in p53-mediated tumor-suppressive response against oncogenic stresses via differential activation of ATM and ATR, and in the maintenance of genomic stability.
Local Administration of Granulocyte/Macrophage Colony-stimulating Factor Increases the Number and Activation State of Dendritic Cells in the Sentinel Lymph Node of Early-Stage Melanoma
Authors: Ronald J. C. L. M. Vuylsteke, Barbara G. Molenkamp, Hester A. Gietema, Paul A. M. van Leeuwen, Pepijn G. J. T. B. Wijnands, Wim Vos, Paul J. van Diest, Rik J. Scheper, Sybren Meijer, Tanja D. de Gruijl
Journal: Cancer Research (2004)

Abstract The initial tumor-draining lymph node, the sentinel lymph node, not only constitutes the first expected site of micrometastasis but also the first point of contact between tumor-associated antigens and the adaptive immune system. A tumor-induced decrease in the frequency and activation state of sentinel lymph node dendritic cells will impair the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Here, we demonstrate that intradermal administration of granulocyte macrophage-colony stimulating factor around the excision site of stage I primary melanoma tumors increases the number and activation state of dendritic cells in the paracortical areas of the sentinel lymph node and enhances their binding to T cells. We conclude that local treatment of melanoma patients with granulocyte macrophage-colony stimulating factor, before surgery, conditions the sentinel lymph node microenvironment to enhance mature dendritic cell recruitment and hypothesize that this may be more conducive to the generation of T-cell–mediated antitumor immunity.
Cardiovascular phenotyping in mice
Authors: P. A. Doevendans, M. J. Daemen, E. D. De Muinck, J. F. Smits
Journal: Cardiovascular Research (1998)

Progress in molecular genetics has changed cardiovascular research. The mouse has turned out to be an invaluable model for mammalian genetic modifications to mimic and analyse cardiovascular pathology. Through the introduction of transgene and gene targeting technology, regulatory systems can be studied at the molecular level. Recent technical developments have down-sized the equipment for physiological measurements to the mouse level. Micro-surgery has developed to the level where most manipulations previously performed in larger animals can now be applied to mice. However, different investigators report considerable differences in values for physiological parameters. Whether these differences are related to the variation in mouse strains or experimental procedures remains to be established, but awareness of the variation can be relevant for prospective mouse investigators. In the present review, the physiological measurements performed in mice to date are discussed and complemented with results from genetically manipulated animals. In addition the various surgical procedures and their practical application are illustrated.
Early Protection Against Sudden Death by n-3 Polyunsaturated Fatty Acids After Myocardial Infarction
Authors: Roberto Marchioli, Federica Barzi, Elena Bomba, Carmine Chieffo, Domenico Di Gregorio, Rocco Di Mascio, Maria Grazia Franzosi, Enrico Geraci, Giacomo Levantesi, Aldo Pietro Maggioni, Loredana Mantini, Rosa Maria Marfisi, G. Mastrogiuseppe, Nicola Mininni, Gian Luigi Nicolosi, Massimo Santini, Carlo Schweiger, Luigi Tavazzi, Gianni Tognoni, Corrado Tucci, Franco Valagussa
Journal: Circulation (2002)

Background — Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (&lt;3 months) myocardial infarction. Methods and Results — In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P =0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P =0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. Conclusions — The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.
IRF4: Immunity. Malignancy! Therapy?
Authors: Arthur L. Shaffer, N.C. Tolga Emre, Paul B. Romesser, Louis M. Staudt
Journal: Clinical Cancer Research (2009)

IRF4, a member of the Interferon Regulatory Factor (IRF) family of transcription factors, is expressed in cells of the immune system, where it transduces signals from various receptors to activate or repress gene expression. IRF4 expression is a key regulator of several steps in lymphoid-, myeloid-, and dendritic-cell differentiation, including the differentiation of mature B cells into antibody-secreting plasma cells. IRF4 expression is also associated with many lymphoid malignancies, with recent evidence pointing to an essential role in multiple myeloma, a malignancy of plasma cells. Interference with IRF4 expression is lethal to multiple myeloma cells, irrespective of their genetic etiology, making IRF4 an "Achilles' heel" that may be exploited therapeutically.
Human Protein Z.
Authors: G J Broze, J P Miletich
Journal: Journal of Clinical Investigation (1984)

Protein Z was purified from human plasma by a four-step procedure which included barium citrate adsorption, ammonium sulfate fractionation, DEAE-Sepharose chromatography, and blue agarose chromatography with a yield of 20%. It is a 62,000 mol wt protein with an extinction coefficient of 12.0. The concentration of Protein Z in pooled, citrated plasma is 2.2 micrograms/ml and its half-life in patients starting warfarin anticoagulation therapy is estimated to be less than 2.5 d. The NH2-terminal sequence is Ala-Gly-Ser-Tyr-Leu-Leu-(Gla)-(Gla)-Leu-Phe-(Gla)-Gly-Asn-Leu. Neither Protein Z nor its cleavage products, which were obtained by treatment of Protein Z with thrombin or plasmin, incorporated [3H]diisopropyl fluorophosphate. The physiological function of Protein Z remains unknown.
Comparison of Quality of Care for Patients in the Veterans Health Administration and Patients in a National Sample
Authors: Steven M. Asch, Elizabeth A. McGlynn, Mary M. Hogan, Rodney A. Hayward, Paul Shekelle, Lisa Rubenstein, Joan Keesey, John Adams, Eve A. Kerr
Journal: Annals of Internal Medicine (2004)

Background: The Veterans Health Administration (VHA) has introduced an integrated electronic medical record, performance measurement, and other system changes directed at improving care. Recent comparisons with other delivery systems have been limited to a small set of indicators. Objective: To compare the quality of VHA care with that of care in a national sample by using a comprehensive quality-of-care measure. Design: Cross-sectional comparison. Setting: 12 VHA health care systems and 12 communities. Patients: 596 VHA patients and 992 patients identified through random-digit dialing. All were men older than 35 years of age. Measurements: Between 1997 and 2000, quality was measured by using a chart-based quality instrument consisting of 348 indicators targeting 26 conditions. Results were adjusted for clustering, age, number of visits, and medical conditions. Results: Patients from the VHA scored significantly higher for adjusted overall quality (67% vs. 51%; difference, 16 percentage points [95% CI, 14 to 18 percentage points]), chronic disease care (72% vs. 59%; difference, 13 percentage points [CI, 10 to 17 percentage points]), and preventive care (64% vs. 44%; difference, 20 percentage points [CI, 12 to 28 percentage points]), but not for acute care. The VHA advantage was most prominent in processes targeted by VHA performance measurement (66% vs. 43%; difference, 23 percentage points [CI, 21 to 26 percentage points]) and least prominent in areas unrelated to VHA performance measurement (55% vs. 50%; difference, 5 percentage points [CI, 0 to 10 percentage points]). Limitations: Unmeasured residual differences in patient characteristics, a lower response rate in the national sample, and differences in documentation practices could have contributed to some of the observed differences. Conclusions: Patients from the VHA received higher-quality care according to a broad measure. Differences were greatest in areas where the VHA has established performance measures and actively monitors performance.
The treatment of cutaneous malignancies with topically applied cycloheximide
Authors: ANTHONY VIVIER
Journal: British Journal of Dermatology (1979)

Results obtained from an animal test system for epidermal cytotoxic drugs prompted the topical use of 1% cycloheximide in the treatment of histologically confirmed superficial basal cell carcinomata of the skin. Excellent clinical clearing of lesions has been demonstrated and this has been confirmed by post treatment biopsies. Preliminary findings in solar keratoses and intraepidermal carcinomata of the skin are also reported.
Epidemiology of the Sexually Transmitted Diseases
Authors: Peter L. Perine, H. Hunter Handsfield, King K. Holmes, Joseph H. Blount
Journal: Annual Review of Public Health (1985)

In recent decades, there has been remarkable growth in scientific research examining the multiple ways in which racism can adversely affect health. This interest has been driven in part by the striking persistence of racial/ethnic inequities in health and ...Read More
Pelvic Granuloma Due to Enterobius Vermicularis
Authors: Thomas J. Brooks
Journal: JAMA (1962)

A 32-year-old woman with a complicated obstetrical history entered the hospital with complaints of menorrhagia, dysmenorrhea, extreme nervousness, and anorexia. The most significant finding at operation was the presence of multiple pearly nodules scattered about the pelvic peritoneum, especially about the fimbria of the uterine tubes. The nodules proved to be typical granulomata, presumably tuberculous, and antituberculous therapy was begun immediately after surgery. Further studies, however, revealed ova of Enterobius vermicularis in the patient's feces and also in the granulomatous lesions. A family history of infestation with pinworms was elicited. An 8-day course of piperazine citrate (1.0 gm. twice daily) cleared up the infestation, and 6 weeks after surgery the patient was free from symptoms.
Is the neutrophil the key effector cell in severe asthma?
Authors: A V Kamath
Journal: Thorax (2005)

The importance of the neutrophil as the dominant inflammatory cell in many of the non-atopic and more severe phenotypes of asthma is now clear

Eosinophilic inflammation has long been considered one of the most distinctive pathological hallmarks of asthma1 and features in many contemporary definitions of this disease. A plethora of studies published from the mid 1990s onwards have suggested, however, that airway eosinophilia is not a universal finding. This has fuelled debate that discrete pathological phenotypes of asthma may exist, with the neutrophil—rather than the eosinophil—dominating in certain circumstances.2–4 We present data that support the current renewed interest in the neutrophil as a primary driver of airways inflammation, particularly in the most severe forms of asthma. There are also some intriguing data to suggest that, when the eosinophil has been “red carded” and disappears from the inflamed airway, the neutrophil may be drawn in and act as the substitute granulocyte.

The hypothesis that the eosinophil is the key effector cell involved in the pathogenesis of asthma has run into trouble for several reasons: (1) eosinophilic inflammation is present in the airway lumen of only 50% of asthmatic subjects;4 (2) even intense eosinophilic inflammation, as occurs in eosinophilic bronchitis, fails to induce asthma;5 (3) many asthma exacerbations occur …
Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis
Authors: David D. Tieu, Anju T. Peters, Roderick T. Carter, Lydia Suh, David B. Conley, Rakesh Chandra, James Norton, Leslie C. Grammer, Kathleen E. Harris, Atsushi Kato, Robert C. Kern, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2010)
Diagnosis of pulmonary hypertension from radiographic estimates of pulmonary arterial size.
Authors: A Bush, H Gray, D M Denison
Journal: Thorax (1988)

The reported accuracy of radiographic measurements in predicting pulmonary hypertension is very variable. Measurements of right and left descending pulmonary artery diameter have been reported to provide a correct diagnosis in as many as 98% of patients. A study was carried out to determine the predictive value of measurements made from the chest radiographs of 50 normal subjects and of 27 patients undergoing right heart catheterisation for cardiac or pulmonary vascular disease, taking account of radiographic magnification. After such corrections a right descending pulmonary artery diameter over 16.7 mm or a left descending pulmonary artery diameter of over 16.9 mm distinguished 12 of 23 pulmonary hypertensive subjects, with no false positive results. The diameter was then arbitrarily squared (any differences between patients and control subjects being exaggerated) and the product was divided by either predicted or actual lung volume in an attempt to correct for body size. The new index distinguished 19 of 23 patients with pulmonary hypertension, with one false positive, when the divisor was actual lung volume; when predicted lung volume was used 18 of 23 patients were distinguished, again with one false positive result.
New and TALENted Genome Engineering Toolbox
Authors: Jarryd M. Campbell, Katherine A. Hartjes, Timothy J. Nelson, Xiaolei Xu, Stephen C. Ekker
Journal: Circulation Research (2013)

Recent advances in the burgeoning field of genome engineering are accelerating the realization of personalized therapeutics for cardiovascular disease. In the postgenomic era, sequence-specific gene-editing tools enable the functional analysis of genetic alterations implicated in disease. In partnership with high-throughput model systems, efficient gene manipulation provides an increasingly powerful toolkit to study phenotypes associated with patient-specific genetic defects. Herein, this review emphasizes the latest developments in genome engineering and how applications within the field are transforming our understanding of personalized medicine with an emphasis on cardiovascular diseases.
Inhibition of Prostasin Secretion by Serine Protease Inhibitors in the Kidney
Authors: Kozo Iwashita, Kenichiro Kitamura, Takefumi Narikiyo, Masataka Adachi, Naoki Shiraishi, Taku Miyoshi, Junko Nagano, Do Gia Tuyen, Hiroshi Nonoguchi, Kimio Tomita
Journal: Journal of the American Society of Nephrology (2003)

A serine protease, prostasin, has been shown to stimulate the activity of amiloride-sensitive sodium channels (ENaC). Prostasin is a glycosylphosphatidylinositol-anchored protein that is found free in physiologic fluids and tissue culture medium, but the mechanism by which prostasin is secreted from the cells has not been elucidated. The current studies found that serine protease inhibitor aprotinin blocked the secretion of prostasin in a mouse cortical collecting duct (CCD) cell line (M-1 cells). A synthetic serine protease inhibitor, nafamostat mesilate (NM), which is commonly used for the treatment of pancreatitis and disseminated intravascular coagulation in Japan, also inhibited the secretion of prostasin in M-1 cells. Continuous infusion of NM into rats resulted in a substantial decrease in urinary prostasin and urinary sodium excretion. p-guanidinobenzoic acid and 6-amidino-2-naphtol, catalytically inactive metabolites of NM, had no effect on prostasin secretion both in M-1 cells and in rats. These findings suggest that a serine protease-sensitive mechanism is involved in the secretion of prostasin in vitro as well as in vivo. Potassium secretion in the CCD is tightly linked to sodium reabsorption through EnaC; therefore, NM-induced decrease in prostasin secretion and subsequent inhibition of ENaC activity could account for the side effects of hyponatremia and/or hyperkalemia that are found sometimes in patients treated with NM. The results indicate an important role for prostasin in sodium reabsorption in the kidney under pathophysiologic conditions.
Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth.
Authors: T Skorski, P Kanakaraj, D H Ku, M Nieborowska-Skorska, E Canaani, G Zon, B Perussia, B Calabretta
Journal: The Journal of Experimental Medicine (1994)

The p210bcr/abl tyrosine kinase appears to be responsible for initiating and maintaining the leukemic phenotype in chronic myelogenous leukemia (CML) patients. p21ras-p120GAP interactions play a central role in transducing mitogenic signals. Therefore, we investigated whether p21ras and p120GAP are regulated by p210bcr/abl, and whether this activation is functionally significant for CML cell proliferation. We report that transient expression of p210bcr/abl in fibroblast-like cells induces simultaneous activation of p21ras and inhibition of GTPase-promoting activity of p120GAP, and confirm these data showing that downregulation of p210bcr/abl expression in CML cells with bcr/abl antisense oligodeoxynucleotides induces both inhibition of p21ras activation and stimulation of GTPase-promoting activity of p120GAP. Tyrosine phosphorylation of two p120GAP-associated proteins, p190 and p62, which may affect p120GAP activity, also depends on p210bcr/abl tyrosine kinase expression. Direct dependence of these effects on the kinase activity is proven in experiments in which expression of c-MYB protein in fibroblast-like cells or downregulation of c-MYB expression resulting in analogous inhibition of CML cell proliferation does not result in the same changes. Use of specific antisense oligodeoxynucleotides to downregulate p21ras expression revealed a requirement for functional p21ras in the proliferation of Philadelphia chromosome-positive CML primary cells. Thus, the p210bcr/abl-dependent regulation of p120GAP activity is responsible, in part, for the maintenance of p21ras in the active GTP-bound form, a crucial requirement for CML cell proliferation.
Cost-Effectiveness of Alternative Blood-Screening Strategies for West Nile Virus in the United States
Authors: Caroline T Korves, Sue J Goldie, Megan B Murray
Journal: PLoS Medicine (2005)

Background West Nile virus (WNV) is endemic in the US, varying seasonally and by geographic region. WNV can be transmitted by blood transfusion, and mandatory screening of blood for WNV was recently introduced throughout the US. Guidelines for selecting cost-effective strategies for screening blood for WNV do not exist. Methods and Findings We conducted a cost-effectiveness analysis for screening blood for WNV using a computer-based mathematical model, and using data from prospective studies, retrospective studies, and published literature. For three geographic areas with varying WNV-transmission intensity and length of transmission season, the model was used to estimate lifetime costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios associated with alternative screening strategies in a target population of blood-transfusion recipients. We compared the status quo (baseline screening using a donor questionnaire) to several strategies which differed by nucleic acid testing of either pooled or individual samples, universal versus targeted screening of donations designated for immunocompromised patients, and seasonal versus year-long screening. In low-transmission areas with short WNV seasons, screening by questionnaire alone was the most cost-effective strategy. In areas with high levels of WNV transmission, seasonal screening of individual samples and restricting screening to blood donations designated for immunocompromised recipients was the most cost-effective strategy. Seasonal screening of the entire recipient pool added minimal clinical benefit, with incremental cost-effectiveness ratios exceeding US$1.7 million per quality-adjusted life-year gained. Year-round screening offered no additional benefit compared to seasonal screening in any of the transmission settings. Conclusions In areas with high levels of WNV transmission, seasonal screening of individual samples and restricting screening to blood donations designated for immunocompromised recipients is cost saving. In areas with low levels of infection, a status-quo strategy using a standard questionnaire is cost-effective.
PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcRγ to induce slow leukocyte rolling
Authors: Alexander Zarbock, Clare L. Abram, Matthias Hundt, Amnon Altman, Clifford A. Lowell, Klaus Ley
Journal: The Journal of Experimental Medicine (2008)

E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the β2 integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of Gαi-protein–coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)–containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin–mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr−/− or hck−/− lyn−/− fgr−/− mice. Neutrophils from Tyrobp−/− Fcrg−/− mice lacking both DAP12 and FcRγ were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp−/− Fcrg−/− mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRγ is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.