tbuckley/cabot-search huggingface dataset:
Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression
Authors: Maddalena Frau, Maria L. Tomasi, Maria M. Simile, Maria I. Demartis, Fabiana Salis, Gavinella Latte, Diego F. Calvisi, Maria A. Seddaiu, Lucia Daino, Claudio F. Feo, Stefania Brozzetti, Giuliana Solinas, Satoshi Yamashita, Toshikazu Ushijima, Francesco Feo, Rosa M. Pascale
Journal: Hepatology (2012)

Down-regulation of the liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and up-regulation of widely expressed MAT2A , encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Here we found Mat1A:Mat2A switch and low SAM levels, associated with CpG hypermethylation and histone H4 deacetylation of Mat1A promoter, and prevalent CpG hypomethylation and histone H4 acetylation in Mat2A promoter of fast-growing HCC of F344 rats, genetically susceptible to hepatocarcinogenesis. In HCC of genetically resistant BN rats, very low changes in the Mat1A:Mat2A ratio, CpG methylation, and histone H4 acetylation occurred. The highest MAT1A promoter hypermethylation and MAT2A promoter hypomethylation occurred in human HCC with poorer prognosis. Furthermore, levels of AUF1 protein, which destabilizes MAT1A messenger RNA (mRNA), Mat1A-AUF1 ribonucleoprotein, HuR protein, which stabilizes MAT2A mRNA, and Mat2A-HuR ribonucleoprotein sharply increased in F344 and human HCC, and underwent low/no increase in BN HCC. In human HCC, Mat1A:MAT2A expression and MATI/III:MATII activity ratios correlated negatively with cell proliferation and genomic instability, and positively with apoptosis and DNA methylation. Noticeably, the MATI/III:MATII ratio strongly predicted patient survival length. Forced MAT1A overexpression in HepG2 and HuH7 cells led to a rise in the SAM level, decreased cell proliferation, increased apoptosis, down-regulation of Cyclin D1, E2F1, IKK, NF-κB , and antiapoptotic BCL2 and XIAP genes, and up-regulation of BAX and BAK proapoptotic genes. In conclusion, we found for the first time a post-transcriptional regulation of MAT1A and MAT2A by AUF1 and HuR in HCC. Low MATI/III:MATII ratio is a prognostic marker that contributes to determine a phenotype susceptible to HCC and patients' survival. Conclusion : Interference with cell cycle progression and I-kappa B kinase (IKK)/nuclear factor kappa B (NF-κB) signaling contributes to the antiproliferative and proapoptotic effect of high SAM levels in HCC. (HEPATOLOGY 2012;56:165–175)
Relationship between Group-Specific Component Protein and the Development of Asthma
Authors: Shin-Hwa Lee, Kyung-Hun Kim, Jin-Moo Kim, Sang-Hyuk Yoon, Tae Hoon Kim, Sung-Woo Park, Jong-Sook Park, Soo-Taek Uh, Ho Sung Lee, Yong Hoon Kim, Jin Hyun Kang, Il Yup Chung, Young Ki Paik, Taiyoun Rhim, Choon-Sik Park
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Airway inflammation and remodeling during asthma are attributed to the altered expression of biologically relevant proteins.To search for asthma-specific proteins in bronchoalveolar lavage fluid (BAL) from individuals with asthma and to validate the identified proteins in an experimental model of asthma.Liquid chromatography-tandem mass spectrometry was performed to identify proteins in BAL fluid found by two dimensional electrophoresis (2DE) to be differentially expressed in subjects with asthma versus control subjects. Group-specific component (Gc) and mRNA levels were measured using an ELISA, Western blots, and PCR. A neutralization study using an antibody against Gc protein was performed in an experimental asthma model.Based on 2DE, 15 proteins were significantly up-regulated or down-regulated in eight subjects with asthma compared with eight control subjects. The protein levels of Gc, hemopexin, and haptoglobin-b were increased, whereas the a1- antitrypsin and glutathione S-transferase levels were decreased in subjects with asthma. The Gc concentration in BAL fluid was significantly elevated in 67 subjects with asthma compared with that in 22 control subjects (P < 0.009). The Gc was significantly correlated with the neutrophil percentage in BAL fluid of subjects with asthma (P = 0.001). Gc mRNA and protein levels were higher in ovalbumin-sensitized/ challenged asthma mice than in sham-treated mice. Gc protein were expressed on alveolar macrophages and on epithelial cells. Treatment with an anti-Gc antibody dose-dependently reduced the ovalbumin sensitization/challenge-induced enhancement of airway hyperreactivity, airway inflammation, goblet cell hyperplasia,and levels of eotaxin, interleukin-4, -5, and -13, and interferon-g.Gc may be involved in the development of asthma, and the neutralization of Gc protein could be a therapeutic strategy for asthma.
Options to Control the Rising Health Care Costs of Older Americans
Authors: Edward L. Schneider
Journal: JAMA (1989)

The author rejects suggestions that age limits be set for the allocation of government-supported health benefits in order to reduce the projected growth of health care costs for older Americans. He proposes increased investment in research targeted toward preventing and treating those diseases that produce the greatest need for long-term care in our aging population. Increased attention to preventing disorders such as Alzheimer's disease and Parkinson's disease would not produce new and more costly burdens on the health care system and could lead to the compression of the needs for long-term care into a few short months or years, thereby decreasing the substantial cost of services for victims of the diseases which afflict older persons.
SOCS3 inhibits TPO-stimulated, but not spontaneous, megakaryocytic growth in primary myelofibrosis
Authors: R Chaligné, C Tonetti, R Besancenot, C Marty, J-J Kiladjian, G Socié, D Bordessoule, W Vainchenker, S Giraudier
Journal: Leukemia (2009)
Effects of Endocrine Disruptors on Dehydroepiandrosterone Sulfotransferase and Enzymes Involved in PAPS Synthesis: Genomic and Nongenomic Pathways
Authors: Robert Harris, Nahid Turan, Christopher Kirk, David Ramsden, Rosemary Waring
Journal: Environmental Health Perspectives (2007)

BackgroundSulfation plays an important role both in detoxification and in the control of steroid activity. Studies in rodents have shown that the conversion of dehydroepiandrosterone (DHEA) to DHEA-sulfate is involved in learning and the memory process.MethodsThe effects of a range of plasticizers and related compounds commonly encountered in the environment were evaluated kinetically against human DHEA sulfotransferase (SULT 2A1) and by reverse transcriptase-polymerase chain reaction (RT-PCR) against several enzymes involved in the synthesis of the sulfotransferase cofactor adenosine 3′-phosphate 5′-phosphosulfate (PAPS).ResultsWe found that several of the chemicals acted as competitive inhibitors of SULT 2A1 (Ki for 4-tert-octylphenol is 2.8 μM). Additionally, after treatment of TE 671 cells with 0.005–0.5 μM 4-n-octylphenol, bis(2-ethylhexyl)phthalate, and diisodecyl phthalate, real-time RT-PCR showed dose-dependent decreases in the steady-state mRNA levels of cysteine dioxygenase type I, sulfite oxidase, and 3′-phosphate 5′-phosphosulfate synthase I.ConclusionsThese data suggest that environmental contaminants may exert effects on neuronal function both by direct inhibition of sulfotransferase enzymes and by interrupting the supply of PAPS, which has wider implications for endocrine disruption and xenobiotic metabolism.
Reference Electrode Sites for Potential Difference Measurements in the Gastrointestinal Tract
Authors: B.J. Collins, R.A.J. Spence, R.J. McFarland, T.G. Parks, A.H.G. Love
Journal: Endoscopy (1983)

Simpler alternatives to the use of an intravenous reference electrode for potential difference measurement in the gastrointestinal tract were considered. Lancet puncture of the forearm skin, and intradermal injection of 0.1 ml 154 mmol/l NaCl into the forearm were shown to effectively abolish the skin-blood potential difference, thereby rendering such sites suitable for reference electrode placement. Another acceptable method was to use an intravenous "butterfly" cannula filled with heparinized saline. The tip of the electrolyte bridge was inserted into the distal end of the cannula, thereby making indirect contact with the bloodstream. It is suggested that the use of any one of these three methods of reference electrode placement would facilitate the measurement of esophageal or gastrointestinal potential difference during a routine endoscopy without significantly altering the accuracy of the measurements.
CHLORIN AS A THERAPEUTIC AGENT IN CERTAIN RESPIRATORY DISEASES
Authors: EDWARD B. VEDDER
Journal: JAMA (1924)

Chlorin has been used on several occasions to prevent certain infections. Kuster 1 states that in 1915 inhalations of chlorin were used successfully to clear up meningococcus and diphtheria carriers. Hale 2 used chlorin in unknown concentration at the University of Arkansas during the influenza epidemic, and believed that students who took this treatment suffered less from influenza than others. Employees in plants producing or using chlorin have always believed themselves to be relatively free from respiratory diseases. This was brought to our attention because, during the war, when the chlorin plant at Edgewood Arsenal was producing to full capacity, the great influenza epidemic struck the post, and the hospital was filled to overflowing. It is stated that no cases were recorded among the operatives of the chlorin plant, although every other organization on the arsenal had its full quota of cases. We therefore determined to investigate the value of
Transfusion‐dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis—prognostic relevance is independent of IPSS or karyotype
Authors: Ayalew Tefferi, Sergio Siragusa, Kebede Hussein, Susan M. Schwager, Curtis A. Hanson, Animesh Pardanani, Francisco Cervantes, Francesco Passamonti
Journal: American Journal of Hematology (2009)

The International Prognostic Scoring System (IPSS) and karyotype are useful tools for risk stratification in primary myelofibrosis (PMF). We examined the additional prognostic impact of red blood cell transfusion need among 254 consecutive patients (median age, 59 years). Sixty-two patients ( approximately 24%) required transfusions at diagnosis whereas 22 ( approximately 9%) became transfusion-dependent and 170 remained transfusion-independent during the first year postdiagnosis; after a median follow-up of 55 months, the respective median survivals were 35, 25, and 117 months (P < 0.01). Multivariable analysis confirmed the IPSS- and karyotype-independent prognostic weight of transfusion status. Among IPSS intermediate-1 risk patients, overall median survival of 82 months was modified to 60 or 118 months, based on presence or absence of transfusion need, respectively (P < 0.01). The corresponding figures for intermediate-2/high risk patients were 30 and 64 months (P < 0.01). Documented causes of death did not include iron overload. We conclude that transfusion status in PMF downgrades or upgrades prognosis within specific IPSS categories; transfusion need is a marker of aggressive disease biology in PMF, as it is in myelodysplastic syndromes.
Prospective study of the disadvantage of people from ethnic minority groups applying to medical schools in the United Kingdom.
Authors: I. C. McManus, P. Richards, S. L. Maitlis
Journal: BMJ (1989)

To assess whether the ethnic origin of applicants affects their likelihood of being accepted into medical school in the United Kingdom the outcome for the 2399 applicants who applied to read medicine at university in 1986 and included St Mary9s Hospital Medical School as one of their five choices was studied prospectively. Altogether 2040 of the 2399 applicants were British (United Kingdom) nationals, constituting 24.7% (n = 8249) of all home applicants for medicine in 1986, and 1971 of them with postal addresses in the United Kingdom were sent questionnaires asking about their ethnic origin, whether English was their first language, and about their attitudes to ethnic monitoring. A total of 1817 (92.2%) applicants returned the questionnaire, 401 (22.6%) saying that they were from an ethnic minority group and 393 (21.6%) having non-European surnames. Multiple logistic regression identified 11 significant predictors of successful application, of which grades at O and A level, application after A levels, and date of application were the most important. After taking these four variables into account the predicted acceptance rates for home students on the basis of their application forms alone were 47.8% for white applicants and 35.6% for applicants from ethnic minority groups compared with actual acceptance rates of 49.6% and 27.3%, respectively. The difference in success of white and non-white applicants could partly but not entirely be explained by differences in the characteristics considered to be important in a professional context by selectors during shortlisting of candidates: academic ability, interests, and contribution to the community. No differences in the success rate of applicants from ethnic minority groups to individual medical schools could be identified. More research is needed to discover how perceptions of professional suitability are assessed from application forms and interviews.
Comparison of Serum Cytokine, Chemokine, and Growth Factor Profiles in Crohn's Disease and Food Allergy in Children
Authors: J. Cohn, Y. Song, D. Dunkin, J. Wang, C. Ceballos, K. Hoffstadter-Thal, J. Ross, K. Benkov, X. Li
Journal: Journal of Allergy and Clinical Immunology (2012)
Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds.
Authors: I Lascombe, D Beffa, U Rüegg, J Tarradellas, W Wahli
Journal: Environmental Health Perspectives (2000)

Environmental chemicals with estrogenic activities have been suggested to be associated with deleterious effects in animals and humans. To characterize estrogenic chemicals and their mechanisms of action, we established in vitro and cell culture assays that detect human estrogen receptor [alpha] (hER[alpha])-mediated estrogenicity. First, we assayed chemicals to determine their ability to modulate direct interaction between the hER[alpha] and the steroid receptor coactivator-1 (SRC-1) and in a competition binding assay to displace 17ss-estradiol (E(2)). Second, we tested the chemicals for estrogen-associated transcriptional activity in the yeast estrogen screen and in the estrogen-responsive MCF-7 human breast cancer cell line. The chemicals investigated in this study were o,p'-DDT (racemic mixture and enantiomers), nonylphenol mixture (NPm), and two poorly analyzed compounds in the environment, namely, tris-4-(chlorophenyl)methane (Tris-H) and tris-4-(chlorophenyl)methanol (Tris-OH). In both yeast and MCF-7 cells, we determined estrogenic activity via the estrogen receptor (ER) for o,p'-DDT, NPm, and for the very first time, Tris-H and Tris-OH. However, unlike estrogens, none of these xenobiotics seemed to be able to induce ER/SRC-1 interactions, most likely because the conformation of the activated receptor would not allow direct contacts with this coactivator. However, these compounds were able to inhibit [(3)H]-E(2) binding to hER, which reveals a direct interaction with the receptor. In conclusion, the test compounds are estrogen mimics, but their molecular mechanism of action appears to be different from that of the natural hormone as revealed by the receptor/coactivator interaction analysis.
Abstract 3290: REGN910, a fully-human, Ang2-specific monoclonal antibody, inhibits tumor growth as a monotherapy and dramatically potentiates the effects of VEGF Trap (aflibercept)
Authors: Christopher Daly, Carla Castanaro, Alexander P. Adler, Alexandra Eichten, Alshad S. Lalani, Nicholas J. Papadopoulos, Gavin Thurston
Journal: Cancer Research (2011)

Abstract Inhibition of tumor angiogenesis via blockade of vascular endothelial growth factor (VEGF) has proven to be beneficial in several solid tumors. However, anti-VEGF therapies are not curative; thus, there is a significant opportunity to improve efficacy through combination therapy with agents that target other essential angiogenic pathways. Angiopoietin-2 (Ang2), a ligand for the endothelial cell-specific receptor Tie2, is selectively expressed in remodeling blood vessels such as those found in tumors. Furthermore, genetic and pharmacologic data indicate that Ang2 is essential for angiogenesis in several settings. These properties make Ang2 an attractive target for specific inhibition of tumor angiogenesis. We generated a fully-human, Ang2-specific IgG1 monoclonal antibody (REGN910) using VelocImmune technology. REGN910 binds human Ang2 with very high affinity (KD ∼ 18 pM), and potently blocks its interaction with Tie2 (IC50 ∼ 50 pM), thereby inhibiting downstream signaling. In contrast, REGN910 exhibits no binding to Ang1, a Tie2 ligand that is broadly-expressed in normal tissues, and has no effect on Ang1/Tie2 signaling. In tumor xenograft models, REGN910 significantly inhibited the growth of several tumor types in a dose-dependent manner, including PC3 (prostate), Colo205 (colorectal) and A431 (epidermoid carcinoma). Furthermore, the combination of REGN910 plus the potent VEGF blocker aflibercept (VEGF Trap) inhibited tumor growth significantly better than the single agents in both the Colo205 and MMT models, promoting significant regression of Colo205 tumors. Consistent with the potent effect of this combination on tumor growth, REGN910 plus aflibercept reduced Colo205 tumor vascularity and tumor perfusion much more dramatically than the single agents, as monitored by histological and micro-ultrasound analyses. Thus, REGN910 significantly potentiates the effect of VEGF blockade on the function of tumor blood vessels, even in a tumor model (Colo205) that is very sensitive to anti-VEGF therapy. These results indicate that REGN910 is a promising candidate to selectively inhibit tumor angiogenesis, both as a single agent and in combination with anti-VEGF therapies. 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 3290. doi:10.1158/1538-7445.AM2011-3290
Extraction of Vitamin D Metabolites by Bones of Normal Adult Dogs
Authors: K. Olgaard, J. Schwartz, D. Finco, M. Arbelaez, J. Haddad, L. Avioli, S. Klahr, E. Slatopolsky
Journal: Journal of Clinical Investigation (1982)

Using the isolated perfused canine tibia we examined the extraction of [3H]25(OH)D3, [3H]1,25(OH)2D3 and [3H]24,25(OH)2D3 by bone of normal adult dogs. The studies were performed with and without vitamin D binding protein (DBP) in the perfusate to examine the effect of protein binding on the extraction of the vitamin D metabolites. An average of 48±2% of [3H]25(OH)D3 was extracted by bone, when no DBP was present. However, addition of only a small amount of DBP (∼720 ng/ml of perfusate) nearly completely abolished the extraction of [3H]25(OH)D3 by bone. No degradation and/or transformation of the labeled 25(OH)D3 could be demonstrated during passage through the isolated perfused bone. The extraction of [3H]24,25(OH)2D3 in a DBP-free medium averaged 33±5%. Addition of 720 ng of DBP/ml of perfusate completely inhibited the extraction of this metabolite. The extraction of [3H]1,25(OH)2D3 averaged 30±3% in a DBP free medium and no inhibition of the extraction was demonstrated after addition of DBP (720 ng/ml of perfusate). However, addition of DBP in a concentration of 14.4 μg/ml of perfusate reduced the extraction of 1,25(OH)2D3 to 8±2%, a value still significantly higher than that seen after addition of 20 times less DBP to perfusions with 25(OH)D3 and 24,25(OH)2D3. It is concluded that the isolated perfused bone of normal dogs can extract significant amounts of 25(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3. Small concentrations of DBP (720 ng/ml) in the perfusate significantly inhibited the extraction of 25(OH)D3 and 24,25(OH)2D3. A carrier role for DBP is suggested and it is proposed that the levels of free vitamin D are important for extraction of the metabolites by bone. Therefore, due to the different affinities of DBP for the various metabolites of vitamin D, only 1,25(OH)2D3 is extracted in vitro in significant amounts by bone of normal adult dogs, in the presence of DBP.
Pathogenesis of Esophageal Varix Rupture
Authors: Hirsch R. Liebowitz
Journal: JAMA (1961)

Clinical, pathological, and hemodynamic studies indicate that peak elevations in portal blood pressure, coupled with flooding of the cardioesophageal pathways by blood precipitously mobilized from the stagnant splanchnic basin, underlie the pathogenesis of varix rupture. Retching, vomiting, straining, coughing, etc., influence the magnitude and integrity of the varicosities and are often the mechanisms that trigger such vascular accidents. Several facts argue against the hypothesis of erosion by acid and pepsin, especially when the site of hemorrhage is located out of range of the corrosive gastric juice. Prophylactic and therapeutic considerations of the patient with esophageal varices must take into account all of the varied factors which determine blood flow in that region.
Perforating Gunshot-Wound of Abdomen Implicating Kidney: Profuse Secondary Haematuria: Recovery
Authors: A. Hayes
Journal: BMJ (1886)

For the next few days his condition was nearly unaltered.All the parnlyse remained, but the numbness gave place to a feeling of " pins and needles," especially in the feet and left hand.April 2nd.The pain in the head was less persistent.He had a feeble grip of the left hand.There was very slight discharge from the wound He was giddy when sittint up in bed.The wound was nearly healed.April 5th.The sisht of the right eye was niow fairly good, when he could get an object in the dlirect line of vision ; he could also hear a watch at a distance of one inch from the right ear.From this date he began to improve steadily, the various paral-ses gradually diminishing, and, for the most part, in the inverse order to that in which they had appeared.On Apnil 15th, he was up a little, but was rather unsteady on his legs The grip of the left hand was much stroniger.Hypertsthesia in the frontal and temporal regions was still well mnarked.April 27th.The sight was now good; he could see the second-hand of a watch at 12 or 15 inches' distance.The hearing of the right er was almost perfect.The ocular muscles were still completely paralysed.May 2nd.He had slight power of movement of the right eyeball, in all directions except outwards.lie could raise the tipper lid slightly.Mray 7th.He walked the length of the ward (100 feet) in a straight line without a stick.He was discharged from hospital.June 20th.He was seen at Armlsy Gaol, and was in excellent health.The grip of the left hand was natural.Ptosis was almost gone.He could read minion type at 18 inches.The ocular move- ments were all right, except the external rectus, which was atill com- pletely paralysed.He Yet complained of slight pain in the head at a single point near the middle of the right half ot the coronal suture, but said it caused him little inconvenience.REIhIARKS.-I.What was the path of the bullet?and where is it now lodged!I think it must evidently have traversed the whole thickness of the anterior lobe, in a nearly vertical direction, probably invading the fissure ol Sylvius also, and be now lying encysted beneath the bone at the point indicate(d by the pain. 2. What caused the