tbuckley/cabot-search huggingface dataset:
Abstract 4914: A novel integrative network study identifies key genes and pathways in the progression of Hepatitis C virus induced hepatocellular carcinoma
Authors: Zhongming Zhao, Siyuan Zheng
Journal: Cancer Research (2011)

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality in the world. Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, the molecular mechanisms underlying its progression remain elusive. To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. This integrative approach to searching for deregulated networks during each pathological stage is different from typical search of common pathway resources like Gene Ontology or KEGG biochemical pathways. It has at least two advantages: 1) a high throughput protein interaction network covers more genes; and 2) the resulting network gives gene interaction information, which provides a simpler framework to explore the functional associations between genes and generate new biological hypotheses. By comparing sets of consecutive pathological stages, we identified four networks in five groups of samples corresponding to normal, cirrhosis, dysplasia, early HCC and advanced HCC. The functional annotation of each network demonstrates a high degree of consistency with current knowledge of HCC. By assembling these functions into a modular map, we were able to depict the stepwise pathways that are dysregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signaling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2-mediated cell cycle signaling in early and advanced HCC. CDC2 (alternative symbol CDK1), a regulatory gene in cell cycle control, is particularly interesting due to its topological position in temporally deregulated networks. Our study uncovers a temporal spectrum of functional deregulation, and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4914. doi:10.1158/1538-7445.AM2011-4914
Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes.
Authors: G Rayman, S A Williams, P D Spencer, L H Smaje, P H Wise, J E Tooke
Journal: BMJ (1986)

The microvascular response of foot skin to minor thermal injury and the skin of the anterior abdominal wall to injury from a needle was assessed by laser Doppler flowmetry in 23 patients with type I diabetes and 21 healthy control subjects. After minor thermal injury mean (SD) maximum skin blood flow was significantly lower in the diabetic group than the control group (0.53 (0.11) v 0.72 (0.10) V, in arbitrary units of flow, respectively, p less than 0.001) and was negatively correlated with the duration of diabetes (r = -0.60; p less than 0.01). After needle injury a similar pattern of impairment was seen, the peak flow value recorded being significantly lower in the diabetic group than the control group (0.28 (0.10) v 0.41 (0.09) V, respectively; p less than 0.001) and also negatively correlated with the duration of diabetes (r = -0.61; p less than 0.01). There was a significant relation between the response obtained at the two sites of injury in the diabetic group (r = +0.72, p less than 0.001) but not in the control group. The impairment in response was not related to diabetic control and was not explicable in terms of a reduction in superficial skin capillary density. The inability of the diabetic skin microvasculature to respond normally to injury may be an important factor in the development of foot ulceration that often follows minor trauma.
Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction
Authors: Ismael Samudio, Romain Harmancey, Michael Fiegl, Hagop Kantarjian, Marina Konopleva, Borys Korchin, Kumar Kaluarachchi, William Bornmann, Seshagiri Duvvuri, Heinrich Taegtmeyer, Michael Andreeff
Journal: Journal of Clinical Investigation (2009)

The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling--the continuing reduction of oxygen without ATP synthesis--has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells--cultured alone or on bone marrow stromal cells--to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.
Pulmonary Artery Agenesis
Authors: MORTON C. GLUCK, KENNETH M. MOSER
Journal: Circulation (1970)

Pulmonary artery agenesis is one of several diagnostic possibilities which may present with similar chest roentgenographic features, including unilateral pulmonary hypoperfusion and nonvisualization of a pulmonary artery. We have applied ventilation and perfusion scintiphotography as an aid in differentiating agenesis from the other conditions with which it may be confused. Four patients presenting with the chest roentgenographic features suggestive of pulmonary artery agenesis were evaluated, when possible, with complete pulmonary function studies, bronchography, cardiac catheterization, and pulmonary and aortic angiography. In all patients, the distribution of ventilation and perfusion were evaluated with the Anger scintillation camera, 133 xenon being used for the ventilation study and 131 I-MAA for the perfusion study. In each patient, perfusion scintiphotography showed no blood flow to the affected lung, while ventilation scintiphotography disclosed preservation of homogeneous ventilation to that lung. Absence of pulmonary artery flow to one lung with maintenance of relatively normal ventilation limits the broad range of diagnostic possibilities to three entities: pulmonary artery agenesis, thrombotic occlusion, and branch stenosis. The history and physical findings should give clues to the latter two diagnoses.
Photodynamic Therapy of Early Squamous Cell Carcinomas of the Esophagus: A Review of 31 Cases
Authors: J.-F. Savary, P. Grosjean, P. Monnier, C. Fontolliet, G. Wagnieres, D. Braichotte, H. van den Bergh
Journal: Endoscopy (1998)

Background and Study Aims: Patients with cancers of the head and neck have a strong tendency to develop early synchronous and metachronous carcinomas of the esophagus. In many of these patients, whose general condition is poor as a result of alcohol and tobacco abuse, the second primary cancers require minimally invasive treatment. The aims of this study were to evaluate the efficacy of photodynamic therapy for the treatment of early esophageal carcinomas and to compare the results obtained with three different photosensitizers (hematoporphyrin derivative), porfimer sodium (Photofrin II), and meta-(tetrahydroxyphenyl)chlorin (m-THPC).
US advisory panellists on drug's safety had ties to manufacturers
Authors: J. Lenzer, K. Epstein
Journal: BMJ (2012)

At least four members of a key committee advising the US Food and Drug Administration on the safety of a top selling drug have had financial ties to its manufacturers, raising questions about the rigor with which the agency minimises potential conflicts of interest.

Court documents reviewed by the BMJ and Washington Monthly show that at least four advisers conducted research for Bayer AG or other manufacturers or licensees of drospirenone, the synthetic progestogen contained in several oral contraceptive pills whose safety was under review. Another adviser agreed to conduct research for the company but never did. The advisers served as paid key opinion leaders, researchers, consultants, or speakers for Bayer and other manufacturers of drospirenone. 

Each of the advisers with ties to manufacturers told the BMJ that they fully disclosed their ties to the FDA, although the FDA declined to release advisers’ financial conflict of interest forms, saying that they are “confidential” and cannot be shared. 

There is no reason to that think the advisers did not make the requisite disclosures. However, when asked whether the agency was aware of any financial ties between its advisers and manufacturers or distributors of drospirenone, the FDA spokeswoman Morgan Liscinsky said, “No waivers were issued.” Waivers can be issued to …
Category of exposure to HIV and age in the progression to AIDS: longitudinal study of 1199 people with known dates of seroconversion
Authors: P. Pezzotti, A. N Phillips, M. Dorrucci, A. C. Lepri, N. Galai, D. Vlahov, G. Rezza
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objectives</b>: To determine whether rate of development of AIDS is affected by category of exposure to HIV and whether the more rapid development found in older subjects persists for each exposure category. <b>Design</b>: Longitudinal study of people with known date of seroconversion to HIV. <b>Setting</b>: 16 HIV treatment centres throughout Italy. <b>Subjects</b>: 1199 people infected with HIV through use of injected drugs, homosexual sex, or heterosexual sex. <b>Main outcome measures</b>: AIDS as defined by 1987 definition of Centers for Disease Control (including and excluding neoplasms) and by 1993 European definition. <b>Results</b>: 225 subjects (18.8%) progressed to AIDS (Centers for Disease Control 1987 definition) during median follow up of 5.8 years. Univariate analyses showed more rapid progression to AIDS for older subjects compared with younger subjects and for homosexual men compared with other exposure categories. The age effect was of similar size in each exposure category and in men and women. In a bivariate model with age and exposure categories simultaneously included as covariates, differences by exposure category disappeared for use of injected drugs and heterosexual sex compared with homosexual sex (relative hazards 1.02 (95% confidence interval 0.71 to 1.45) and 1.07 (0.70 to 1.64) respectively), while the age effect remained (relative hazard 1.55 (1.32 to 1.83) for 10 year increase in age). Analyses using the other definitions for AIDS did not appreciably change these results. <b>Conclusions</b>: There was no evidence of differences in rate of development of AIDS by exposure category, while there was a strong tendency for more rapid development in older subjects for all three groups. This supports the view that external cofactors do not play major role in AIDS pathogenesis but that age is of fundamental importance. <h3>Key messages</h3> Many studies have found an age effect on progression to AIDS, but it is not clear if this is due to specific AIDS defining diseases such as neoplasms and if it differs by exposure groups or by sex Our study of 1199 subjects with known date of seroconversion to HIV showed that older subjects progressed to AIDS more rapidly in all exposure groups considered, for both men and women, and for different definitions of AIDS After adjustment for age at seroconversion, there was no evidence of different rates of progression among subjects belonging to different exposure categories Behavioural cofactors do not seem to play a major role in AIDS pathogenesis but age is of fundamental importance in disease progression
Her-2/<i>neu</i> Overexpression and Amplification in Uterine Papillary Serous Carcinoma
Authors: Brian M. Slomovitz, Russell R. Broaddus, Thomas W. Burke, Nour Sneige, Pamela T. Soliman, Weiguo Wu, Charlotte C. Sun, Mark F. Munsell, David M. Gershenson, Karen H. Lu
Journal: Journal of Clinical Oncology (2004)

Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value.Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records.Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P < or = .05).Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.
The protective effect of farm milk consumption on childhood asthma and atopy: The GABRIELA study
Authors: Georg Loss, Silvia Apprich, Marco Waser, Wolfgang Kneifel, Jon Genuneit, Gisela Büchele, Juliane Weber, Barbara Sozanska, Hanna Danielewicz, Elisabeth Horak, R.J. Joost van Neerven, Dick Heederik, Peter C. Lorenzen, Erika von Mutius, Charlotte Braun-Fahrländer
Journal: Journal of Allergy and Clinical Immunology (2011)
Identification of a T3/T cell receptor complex in chickens.
Authors: C L Chen, L L Ager, G L Gartland, M D Cooper
Journal: The Journal of Experimental Medicine (1986)

A mouse mAb, CT-3, recognizes on chicken T cells a complex of three polypeptides, Mr 20,000, 19,000, and 17,000, two of which are N-glycosylated. The CT-3 antibody is mitogenic for chicken T cells, and it coprecipitates two additional polypeptides of Mr 49,000 and 38,000 in lysates of T cell membranes. Ontogeny studies revealed that 5-6 d after thymic influx of hemopoietic stem cells, their thymocyte progeny begin to express the T3/TCR complex. After hatching 1 wk later, the CT-3+ cells begin splenic migration in large numbers.
Ocular Pigment Deposits: Drug-Induced False-Positives
Authors: M. L. Clark
Journal: JAMA (1970)

To the Editor.—  In a recent study involving antipsychotic drugs of various chemical structures, the apparent development of drug-induced pigment deposits on the anterior  was noted in several subjects under all treatment conditions including placebo. Contrary to what is known concerning such pigment deposition under long-term, high-dose chlorpromazine hydrochloride therapy,1this occurred relatively rapidly (three months) on modest doses of various medications including a thioxanthine and a butyrophenone. Although we were alerted to the possibility of false-positives by the occurrence of these findings in the placebo group it was, nevertheless, some time before a proper explanation came to light. This occurred when DeLong's reference2to axial punctuate  came to the attention of the ophthalmologist carrying out the slit-lamp examinations in the study.  DeLong called attention to a benign condition in which small, punctate opacities occurred on the anterior lens capsules, often scattered sparsely into the anterior
CLINICAL AND VIROLOGICAL EFFECTS OF HIGH-DOSE RECOMBINANT INTERFERON-α IN DISSEMINATED AIDS-RELATED KAPOSI'S SARCOMA
Authors: Ronald De Wit, CharlesA.B. Boucher, KeesH.N. Veenhof, JanK.M.E. Schattenkerk, PietJ.M. Bakker, SvenA. Danner
Journal: The Lancet (1988)
Lead Poisoning in Missile-Silo Workers
Authors: John A. Lambie
Journal: JAMA (1967)

"MINUTEMAN DISEASE," lead poisoning in missile-silo workers, has been reported once before.<sup>1</sup>This is but another addition to the long list of industries and occupations in which lead poisoning is encountered.<sup>2</sup>Despite the fact that lead toxicity is well known and industries employ many means to prevent lead poisoning in workers, instances of lead poisoning continue to occur.<sup>3</sup>Recently two cases of lead poisoning involving Minuteman missile-silo workers were seen during construction of these silos in this area. Their case reports follow, together with a discussion of errors in determination of patients' blood and urine lead values. <h3>Report of Cases</h3><h3>Case 1.—</h3> A 22-year-old man, first seen in the Grand Forks Clinic on March 9, 1966, complained of lower abdominal cramping pain and low back pain of two weeks' duration. He had been constipated for several months. Since July 1965 he had been employed to grind red
Oxidative Stress Markers in the Brain of Patients With Cirrhosis and Hepatic Encephalopathy
Authors: Boris Görg, Natalia Qvartskhava, Hans-Jürgen Bidmon, Nicola Palomero-Gallagher, Gerald Kircheis, Karl Zilles, Dieter Häussinger
Journal: Hepatology (2010)

Cell culture studies and animal models point to an important role of oxidative/nitrosative stress in the pathogenesis of cerebral ammonia toxicity. However, it is unknown whether oxidative/nitrosative stress in the brain is also characteristic of hepatic encephalopathy (HE) in humans. We therefore analyzed post mortem cortical brain tissue samples from patients with cirrhosis dying with or without HE in comparison with brains from patients without liver disease. Significantly elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation were found in the cerebral cortex of HE patients, but not of patients with cirrhosis but without HE. Glutamine synthetase (GS) activity was significantly decreased, whereas GS protein expression was not significantly affected. Protein expression of the glutamate/aspartate cotransporter was up-regulated in HE, whereas protein expression of neuronal and inducible nitric oxide synthases, manganese-dependent and copper/zinc-dependent superoxide dismutase, and glial glutamate transporter-1 were not significantly increased. Conclusion: These data indicate that HE in patients with cirrhosis is associated with oxidative/nitrosative stress, protein tyrosine nitration, and RNA oxidation, suggesting a role of oxidative stress in the pathogenesis of HE in patients with cirrhosis. Hepatology 2010
Asymptomatic peptic ulcer disease.
Authors: M J Dew
Journal: BMJ (1987)

Peptic ulcer disease is usually diagnosed on the basis of well recognised symptoms confirmed by endoscopy or barium study. Within the community an unknown number of people, however, may have peptic ulcer disease without symptoms, some of whom present only because of haemorr? hage or perforation.1 Roughly a third of the cases of perforated peptic ulcer, for example, occur in people without any previous symptoms, as do a fifth of gastrointestinal haemorrhage.23 There are no series reporting asymptomatic people who have been studied with endoscopy, and though necropsy studies indicate that almost a fifth of the population may have some evidence of peptic ulcer disease?active ulcer, scars, or previous surgery?the proportion of those without symptoms has not been recorded; nor is it clear whether the ulcer was a feature of the terminal illness.4 Trials of treatment
Halothane Protects Cardiomyocytes Against Reoxygenation-Induced Hypercontracture
Authors: Berthold Siegmund, Wolfgang Schlack, Yury V. Ladilov, Claudia Balser, H. Michael Piper
Journal: Circulation (1997)

Resupply of oxygen to the myocardium after extended periods of ischemia or hypoxia can rapidly aggravate the already existing injury by provoking hypercontracture of cardiomyocytes (acute reperfusion injury). Previous studies indicated that halothane can protect ischemic-reperfused myocardium. The aim of the present study was to analyze on the cellular level the mechanism by which halothane may protect against reoxygenation-induced hypercontracture.To simulate ischemia-reperfusion, isolated adult rat cardiomyocytes were incubated at pH 6.4 under anoxia and reoxygenated at pH 7.4 in the presence or absence of 0.4 mmol/L halothane. Reoxygenation was started when intracellular Ca2+ (measured with fura 2) had increased to > or = 10(-5) mol/L and pHi (BCECF) had decreased to 6.5. Development of hypercontracture was determined microscopically. In the control group, reoxygenation provoked oscillations of cytosolic Ca2+ (72+/-9 per minute at fourth minute of reoxygenation) accompanied by development of hypercontracture (to 65+/-3% of end-ischemic cell length). When halothane was added on reoxygenation, Ca2+ oscillations were markedly reduced (4+/-2 per minute, P<.001) and hypercontracture was virtually abolished (90+/-4% of end-ischemic cell length, P<.001). Halothane did not influence the recovery of pHi during reoxygenation. Similar effects on Ca2+ oscillations and hypercontracture were observed when ryanodine (3 micromol/L), an inhibitor of the sarcoplasmic reticulum Ca2+ release, or cyclopiazonic acid (10 micromol/L), an inhibitor of the sarcoplasmic reticulum Ca2+ pump, were applied instead of halothane.Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture by preventing oscillations of intracellular Ca2+ during the early phase of reoxygenation.