tbuckley/cabot-search huggingface dataset:
MUTANT EGFR SUPPRESSION OF MICRORNA-9 INDUCES FOXP1 TO ENHANCE GLIOBLASTOMA TUMORIGENICITY
Authors: F. Furnari, G. Gomez, S. Volinia, C. Croce, C. Zanca, M. Li, D. Gutmann, C. Brennan, W. Cavenee
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma (GBM) frequently displays amplification and/or mutation of the epidermal growth factor receptor (EGFR) gene. Highlighting the importance of EGFR in the pathogenesis of GBM, aberrant EGFR (ΔEGFR, also known as EGFRvIII) confers a variety of biological effects upon its expression, including resistance to radiation and chemotherapeutic agents, promotion of tumor cell motility and invasion, enhancement of tumorigenicity in vivo, and maintenance of GBM growth and heterogeneity. We hypothesized that this diverse oncogenic pathophysiology exerted by ΔEGFR is regulated, in part, through the modulation of microRNA (miR) activity, widely shown to be involved in many biological processes including cancer initiation, maintenance and progression. METHODS: To test this hypothesis, we used miR microarrays to compare miR profiles of GBM cells with activated wild type EGFR (wtEGFR) and ΔEGFR, to cells with non-activated wtEGFR or kinase-dead ΔEGFR. miRs demonstrating differential expression were validated by northern blot analysis and qRT-PCR and potential pathways regulating miR expression were interrogated by pharmacological and genetic analysis. Candidate miR targets were validated by luciferase reporter assays and western blot analysis. The role of validated miRs and targets, in modulating ΔEGFR-mediated tumorgenicity, was analyzed by overexpression and knockdown studies in engineered glioma cell lines engrafted in athymic nude mice. Validated target significance was determined by survival-association expression analysis in a patient cohort of 67 newly diagnosed and 64 recurrent GBM cases. RESULTS: We observed and validated that ΔEGFR suppresses miR-9. The repression of miR-9 was due to the negative regulation of the primary miR-9 encoding transcript, pri-miR-9-2, by ΔEGFR. Downstream of ΔEGFR, the Ras/PI3K/AKT axis was required to suppress miR-9. We identified the transcription factor, FOXP1, to be a bona-fide miR-9 target. Upregulation of miR-9 decreased expression of FOXP1 in ΔEGFR cells, suggesting that miR-9 and FOXP1 may regulate, in part, ΔEGFR-dependent GBM growth. Consistent with this, miR-9 antagonized the tumor growth advantage conferred by ΔEGFR while FOXP1 knock-down inhibited the growth of ΔEGFR-driven tumors. Upregulation of FOXP1, as a consequence of inhibiting miR-9 activity, increased the tumorigenicity of GBM cells, suggesting that miR-9 is a tumor suppressor while FOXP1 likely functions as an oncogenic factor in GBM. Finally, high FOXP1 expression was significantly associated with poor survival in GBM patients, further supporting the notion that FOXP1 is an oncogenic factor. CONCLUSIONS: Collectively, these data reveal a novel regulatory mechanism by which ΔEGFR signaling through the Ras-PI3K-Akt pathway suppresses miR-9, resulting in FOXP1 expression and increased tumorigenicity. SECONDARY CATEGORY: n/a.
Particulate air pollution and respiratory disease in Anchorage, Alaska.
Authors: M E Gordian, H Ozkaynak, J Xue, S S Morris, J D Spengler
Journal: Environmental Health Perspectives (1996)

This paper examines the associations between average daily particulate matter less than 10 microns in diameter (PM10) and temperature with daily outpatient visits for respiratory disease including asthma, bronchitis, and upper respiratory illness in Anchorage, Alaska, where there are few industrial sources of air pollution. In Anchorage, PM10 is composed primarily of earth crustal material and volcanic ash. Carbon monoxide is measured only during the winter months. The number of outpatients visits for respiratory diagnoses during the period 1 May 1992 to 1 March 1994 were derived from medical insurance claims for state and municipal employees and their dependents covered by Aetna insurance. The data were filtered to reduce seasonal trends and serial autocorrelation and adjusted for day of the week. The results show that an increase of 10 micrograms/m3 in PM10 resulted in a 3-6% increase in visits for asthma and a 1-3% increase in visits for upper respiratory diseases. Winter CO concentrations were significantly associated with bronchitis and upper respiratory illness, but not with asthma. Winter CO was highly correlated with automobile exhaust emissions. These findings are consistent with the results of previous studies of particulate pollution in other urban areas and provide evidence that the coarse fraction of PM10 may affect the health of working people.
Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats
Authors: Yoichi Kurebayashi, Yuko Honda
Journal: Hepatology (1991)

16,16-Dimethyl prostaglandin E2, a known cytoprotective agent, was examined for its ability to protect the liver against complement-mediated necrosis induced by an intravenous injection of a monoclonal antibody against a rat liver-specific antigen in rats. The hepatic injury induced by the antibody was characterized by (a) rapid development of numerous massive hemorrhagic foci of necrotic liver cells, (b) marked increases in serum liver enzyme activities and (c) pronounced reduction in the CH50 level, presumably as a result of complement consumption in the liver. Pretreatment with 16,16-dimethyl prostaglandin E2 at intraperitoneal doses of 20 and 100 micrograms/kg suppressed the hepatic injury, as evidenced by markedly mitigated liver-cell necrosis and much smaller increases in the serum-enzyme activities compared with the values in diseased control animals. The prostaglandin analogue failed to prevent serum complement consumption in response to the antibody injection or affect the CH50 level at the preinjury stage, indicating that neither complement inactivation nor interference with the antigen-antibody reaction was involved in the hepatic protection. The hepatoprotective doses of 16,16-dimethyl prostaglandin E2 produced a significant increase in liver cyclic AMP content in a dose-related manner. In addition, intravenous dibutyryl cyclic AMP at 3 and 10 mg/kg dose-dependently prevented histological and biochemical changes in the hepatic damage without altering the rate of reduction in serum complement activity. Like 16,16-dimethyl prostaglandin E2, dibutyryl cyclic AMP did not affect the preinjury CH50 level.(ABSTRACT TRUNCATED AT 250 WORDS)
Hungarian geneticists call for prosecution of firm that carried out tests to prove politician's racial origin
Authors: S. Mayor
Journal: BMJ (2012)

The European Society of Human Genetics has issued a statement strongly condemning the use of genetic testing to establish racial origins for political purposes after reports that a Hungarian politician used a genetic test to attempt to demonstrate his “ethnic purity” before local elections.

“The use of genetic testing to establish racial origins for political purposes is not only scientifically foolish, but also unethical and should be condemned,” the society said. It was criticising the use of a genetic test by an unnamed member of the Hungarian far right Jobbik party to demonstrate his ethnic origins. The society is a non-profit organisation that promotes research in medical genetics and high standards in clinical genetics.

Joerg Schmidtke, president of the society, said, “This is …
DENTAL CARIES, AND ITS RELATIONS TO THE GERM THEORY OF DISEASE.
Authors: G. V. BLACK
Journal: JAMA (1885)

Read in the Section on Oral and Dental Surgery of American Medical Association, May, 1884. Caries of the teeth has been defined as a molecular disintegration of the tooth substance; or a breaking down of the chemical constituents of the tooth, molecule by molecule. This destruction always has its beginning on the surface of the tooth, or in some pit, crevice, or other imperfection in the enamel. And it spreads from this point, as the focus, in every direction, the dentine being destroyed more rapidly than the enamel; hence it usually happens that the cavity is larger within than on the surface of the tooth. Caries does not seem to be a simple solution of the tooth's substance; sometimes we find nearly all of the material removed from the cavity, in other cases we find the dentine reduced to a pulpy, or semi-glutinous mass, in which the structure of the
DEATH FROM FOOD POISONING DUE TO BACILLUS BOTULINUS
Authors: James B. Cutter
Journal: JAMA (1922)

P. A. A. and T. P., two men, ate tomato-onion-chili sauce at noon, June 16, taken from the last of twelve bottles, home made, that had been used during the winter. While acrid and hot, its taste was not much different from that eaten previously. Slight gastro-enteric symptoms followed within a few hours, not sufficient to cause alarm. When I saw them next noon the patients complained of slight dizziness, vertigo and dryness of the throat, which was attributed to cider that they had drunk. When I was called the following morning, further inquiry elicited the information that the men had eaten the sauce described and that the housewife, thinking it "smelled too strong," had thrown it out. The symptoms at this time were diplopia, weakness, loss of accommodation, ptosis, dryness of the mouth and pharynx, constriction of the throat with difficulty in speaking and swallowing, and still slight gastro-intestinal
High Baseline Vitamin C Levels Do Not Prevent a Positive Outcome of a Lifestyle Intervention
Authors: Claus Thamer, Fausto Machicao, Norbert Stefan, Andreas Fritsche, Hans-Ulrich Häring
Journal: Diabetes Care (2009)

Reactive oxygen species (ROS) generated by oxidative stress induced by physical activity are important mediators responsible for adaptive processes in skeletal muscle (1). ROS induce the production of myokines (muscle-derived cytokines) that mediate systemic metabolic effects (1) and induce an increase in the expression of genes involved in mitochondrial biogenesis (2). Therefore, the oxidative stress induced by exercise may play an important role in the cellular responses occurring within skeletal muscle after training.

Supplementation with the antioxidant vitamin C pharmacologically inhibits positive effects of exercise on the parameters of glucose metabolism (3). However, these data conflict with the finding that high levels of vitamin C also reduce the risk of type 2 diabetes (4). Therefore, we …
Pathogenic Escherichia coli increase Cl– secretion from intestinal epithelia by upregulating galanin-1 receptor expression
Authors: Gail Hecht, Jorge A. Marrero, Alexey Danilkovich, Kristina A. Matkowskyj, Suzanna D. Savkovic, Athanasia Koutsouris, Richard V. Benya
Journal: Journal of Clinical Investigation (1999)

Galanin is widely distributed in enteric nerve terminals lining the human gastrointestinal (GI) tract. We have shown previously that galanin-1 receptors (Gal1-R) are expressed by epithelial cells lining the human GI tract, and upon activation cause Cl- secretion. Because expression of this receptor is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B), which is activated by enteric pathogens as a part of the host epithelial response to infection, we investigated whether such bacterial pathogens could directly increase Gal1-R expression in the T84-cell model system. Pathogenic Escherichia coli, but not nonpathogenic E. coli, activate a p50/p65 NF-kappa B complex that binds to oligonucleotides corresponding to a recognition site located within the 5' flanking region of the human GAL1R gene. Pathogenic E. coli, but not normal commensal organisms, increase Gal1-R mRNA synthesis and [(125)I]galanin binding sites. Whereas galanin increases short-circuit current (Isc) approximately 5-fold in uninfected T84 cells, exposure to pathogenic, but not nonpathogenic, E. coli results in galanin increasing Isc approximately 20-fold. To confirm the validity of these in vitro observations, we also studied C57BL/6J mice infected with enterohemorrhagic E. coli (EHEC) by gavage. Infection caused a progressive increase in both NF-kappa B activation and Gal1-R expression, with maximal levels of both observed 3 days after gavage. Ussing chamber studies revealed that colons infected with EHEC, but not those exposed to normal colonic flora, markedly increased Isc in response to galanin. These data indicate that pathogen-induced increases in Gal1-R expression by epithelial cells lining the colon may represent a novel unifying pathway responsible for at least a portion of the excessive fluid secretion observed during infectious diarrhea.
Investigate death of British doctor in Syria, say campaigners
Authors: S. Arie
Journal: BMJ (2013)

The death of a British doctor detained in Syria after he tried to give medical assistance to war victims has caused outrage just as the United Nations attempts to negotiate safer access for humanitarian aid in the country.

Abbas Khan, a 32 year old trainee orthopaedic surgeon from south London, died in jail more than a year after he was arrested in Aleppo, where he had gone without a visa to help in a hospital. His mother had tracked him down after the Foreign Office failed to do so,1 and he told her he had been held in an underground cell for months and tortured. He was due to be released within days when authorities announced …
The genesis of cystic fibrosis lung disease
Authors: Jeffrey J. Wine
Journal: Journal of Clinical Investigation (1999)

Cystic fibrosis (CF), as Bals et al. discuss in the other Perspective in this issue (1), is one of the most thoroughly understood genetic diseases. Thus it is frustrating that CF lung disease has been refractory to the onslaught of molecular/cellular research that has clarified so many other aspects of CF. But after many false starts, recent experiments are finally beginning to crack the shell of ignorance that surrounds CF lung disease. A series of innovative experiments, mainly from two laboratories, has revealed fascinating new aspects of normal and CF lung biology. Yet despite the care and resourcefulness of each group, their findings generate sharply contrasting views of CF lung disease that lead to opposite treatment strategies! Fortunately, this controversy is generating more light than heat and is illuminating the field to the ultimate benefit of CF clinical care.
Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Authors: Daniel I. Feig, Beth Soletsky, Richard J. Johnson
Journal: JAMA (2008)

Hyperuricemia is a predictor for the development of hypertension and is commonly present in new-onset essential hypertension. Experimentally increasing uric acid levels using a uricase inhibitor causes systemic hypertension in animal models.To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension.Randomized, double-blind, placebo-controlled, crossover trial (September 2004-March 2007) involving 30 adolescents (aged 11-17 years) who had newly diagnosed, never-treated stage 1 essential hypertension and serum uric acid levels > or = 6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Children's Hospital in Houston. Patients were excluded if they had stage 2 hypertension or known renal, cardiovascular, gastrointestinal tract, hepatic, or endocrine disease.Allopurinol, 200 mg twice daily for 4 weeks, and placebo, twice daily for 4 weeks, with a 2-week washout period between treatments. The order of the treatments was randomized.Change in casual and ambulatory blood pressure.For casual BP, the mean change in systolic BP for allopurinol was -6.9 mm Hg (95% confidence interval [CI], -4.5 to -9.3 mm Hg) vs -2.0 mm Hg (95% CI, 0.3 to -4.3 mm Hg; P = .009) for placebo, and the mean change in diastolic BP for allopurinol was -5.1 mm Hg (95% CI, -2.5 to -7.8 mm Hg) vs -2.4 (95% CI, 0.2 to -4.1; P = .05) for placebo. Mean change in mean 24-hour ambulatory systolic BP for allopurinol was -6.3 mm Hg (95% CI, -3.8 to -8.9 mm Hg) vs 0.8 mm Hg (95% CI, 3.4 to -2.9 mm Hg; P = .001) for placebo and mean 24-hour ambulatory diastolic BP for allopurinol was -4.6 mm Hg (-2.4 to -6.8 mm Hg) vs -0.3 mm Hg (95% CI, 2.3 to -2.1 mm Hg; P = .004) for placebo. Twenty of the 30 participants achieved normal BP by casual and ambulatory criteria while taking allopurinol vs 1 participant while taking placebo (P < .001).In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP. The results represent a new potential therapeutic approach, although not a fully developed therapeutic strategy due to potential adverse effects. These preliminary findings require confirmation in larger clinical trials.clinicaltrials.gov Identifier: NCT00288184.
Book Review The Ethics of Surgical Practice: Cases, Dilemmas, and Resolutions By James W. Jones, Laurence B. McCullough, and Bruce W. Richman. 340 pp. New York, Oxford University Press, 2008. $99 (cloth); $24.95 (paper). 978-0-19-532108-1 (cloth); 978-0-19-532109-8 (paper).
Authors: Peter M. Black
Journal: New England Journal of Medicine (2009)
Response to Comment on: Jones et al. Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study). Diabetes Care 2011;34:828–837
Authors: T. Hugh Jones, Julian D. Howell, Kevin S. Channer
Journal: Diabetes Care (2011)

The primary outcome of the TIMES2 study was to determine if testosterone replacement improved insulin resistance in hypogonadal men with metabolic syndrome and/or type 2 diabetes. There is substantial evidence that hypogonadism is associated with reduced insulin sensitivity and that testosterone replacement increases sensitivity as assessed by hyperinsulinemic-euglycemic clamp and homeostasis model assessment of insulin (HOMA-IR). TIMES2 showed a significant benefit on reduction in insulin resistance (−15%), similar to that reported with metformin. Changes in HOMA-IR in the per-protocol group did not reach significance, but in the type 2 diabetes cohort after 12 months approached significance ( P = 0.067; n = 50). In the total modified per-protocol population, changes in HOMA-IR almost reached significance at 6 ( P …
Open your eyes
Authors: Tariq Hussain
Journal: BMJ (2005)

entitled "When enough is enough."This two hour course aims to assist hospital doctors develop communication skills so that they can better explore their patients' wishes and are therefore better prepared to help their patients make decisions when confronted by major illness at the end of life.The course includes written material, video footage, and interaction with actors.We believe that discussing treatment options with patients is a vitally important skill for which training can be improved.Medical education is mainly focused on understanding disease.A move towards educating doctors to better understand people has potential to improve patient outcomes considerably.We acknowledge the efforts of Ruth Clark, who arranged and coordinated the interviews.We also thank all those doctors who participated in the study.Further details of the "When enough is enough" course can be obtained from charliec@ barwonhealth.org.
Severe Hypersensitivity Reactions Associated With Allopurinol
Authors: Roger M. Mills
Journal: JAMA (1971)

Two patients developed fever, dermatitis, renal insufficiency, and eosinophilia, three and five weeks after beginning therapy with allopurinol. The clinical, laboratory, and histologic findings were compatible with a severe hypersensitivity reaction. Both patients required long-term corticosteroid therapy (more than six and four months, respectively) to control their symptoms. These observations suggest that hypersensitivity to allopurinol can produce a severe, prolonged, or potentially fatal illness.
Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia
Authors: Oliver Goodyear, Angelo Agathanggelou, Igor Novitzky-Basso, Shamyla Siddique, Tina McSkeane, Gordon Ryan, Paresh Vyas, Jamie Cavenagh, Tanja Stankovic, Paul Moss, Charles Craddock
Journal: Blood (2010)
'The Wheel Within a Wheel': Meningococcal Trends
Authors: George W. Counts
Journal: JAMA (1980)

The meningococcus has occupied a special position among bacteria causing disease in humans. Epidemiologic data in this country, available since 1920 and reported by the Center for Disease Control (CDC), show that three major epidemics have occurred, with peaks in 1929, 1936, and 1943. At those times the case rate per 100,000 population was 8.6, 5.7, and 13.6, respectively.<sup>1</sup>The most recent sizable epidemic occurred in the early 1950s, with a peak incidence of 3.2 cases per 100,000 population in 1953. In the ten-year period beginning in 1968, disease rates compiled by the CDC have ranged from a low of 0.64 per 100,000 population (1,323 cases in 1972) to 1.46 cases per 100,000 (2,951 cases in 1969). Both the reported total number of cases and rate have increased slightly since 1974.<sup>2</sup> Like the revolving of an outer wheel, epidemics of meningococcal disease have come in waves or cycles.
Screening for Hepatocellular Carcinoma in Alaska Natives Infected With Chronic Hepatitis B: A 16-Year Population-Based Study
Authors: Brian J. McMahon, Lisa Bulkow, Annette Harpster, Mary Snowball, Anne Lanier, Frank Sacco, Eitel Dunaway, James Williams
Journal: Hepatology (2000)

The benefits of screening hepatitis B surface antigen (HBsAg)-positive carriers for hepatocellular carcinoma (HCC) in terms of long-term survival have not been established. We conducted a prospective 16-year, population-based cohort study to determine the impact of screening for HCC in 1,487 HBsAg-positive Alaska native carriers with alpha-fetoprotein (AFP) determinations every 6 months. Men and nonpregnant women with an elevated AFP level were evaluated for the presence of HCC by ultrasound (US) examination. The long-term survival rate for patients whose HCC was detected by the screening program was compared with a historical control group of Alaska native patients with HCC from the same population who were clinically diagnosed with HCC between 1969 and October 1982, through a National Cancer Institute-sponsored Cancer Registry. Between October 1982 and December 1998, 26,752 AFP determinations in HBsAg carriers were performed. One or more AFP elevations were found in 61 men and 39 nonpregnant women. HCC was diagnosed in 32 patients (24 men and 8 women). HCC tumors less than 6 cm were found in 23 patients; 22 patients had resections, and 1 patient refused a resection. Compared with 12 patients with hepatitis B virus (HBV)-related HCC diagnosed from 1969 to October 1982, before this program, the 5- and 10-year survival rate for the 32 patients with HCC were 42% ( P = .008) and 30% ( P = .07), respectively. Five- and 10-year tumor-free survival rates for carriers who had a normal AFP level on initial screening and subsequently developed HCC were 29% ( P = .004) and 24% ( P = .024), respectively. Screening of HBsAg carriers with semiannual AFP was effective in detecting most HCC tumors at a resectable stage and significantly prolonged survival rates when compared with historical controls in this population.
Three-year follow-up of the argentine randomized trial of percutaneous transluminal coronary angioplasty versus coronary artery bypass surgery in multivessel disease (ERACI)
Authors: Alfredo Rodriguez, Eduardo Mele, Ernesto Peyregne, Fernando Bullon, Nestor Perez-Baliño, Maria I. Sosa Liprandi, Igor F. Palacios
Journal: Journal of the American College of Cardiology (1996)