tbuckley/cabot-search huggingface dataset:
The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology
Authors: Charlotte Esser, Agneta Rannug
Journal: Pharmacological Reviews (2015)

The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim–basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views—namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance.
Spanish chemists will offer HIV tests to members of public in pilot project
Authors: M. de Lago
Journal: BMJ (2008)

Thirty five pharmacies in the province of Barcelona will carry out rapid HIV tests for free, in a pilot project aiming to increase access to tests for people from vulnerable groups and to avoid delay in diagnosis.

The project, to start in the first quarter of 2009, will run for at least six months in 23 municipalities with populations from 30 000 to 50 000, most of them around Barcelona city. It is being organised by Rafael Borras, a member of the governing council of the Barcelona …
Overexpression of Ecdysoneless in Pancreatic Cancer and Its Role in Oncogenesis by Regulating Glycolysis
Authors: Parama Dey, Satyanarayana Rachagani, Subhankar Chakraborty, Pankaj K. Singh, Xiangshan Zhao, Channabasavaiah Basavaraju Gurumurthy, Judy M. Anderson, Subodh Lele, Michael A. Hollingsworth, Vimla Band, Surinder K. Batra
Journal: Clinical Cancer Research (2012)

To study the expression and function of a novel cell-cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer pathogenesis.Immunohistochemical expression profiling of Ecd was done in nonneoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in pancreatic cancer progression, Ecd was stably knocked down in pancreatic cancer cell line followed by in vitro and in vivo functional assays.Normal pancreatic ducts showed very weak to no Ecd expression compared to significant positive expression in pancreatic cancer tissues (mean ± SE composite score: 0.3 ± 0.2 and 3.8 ± 0.2 respectively, P < 0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1-PanIN-3). Analysis of matched primary tumors and metastases from patients with pancreatic cancer revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Furthermore, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of pancreatic cancer cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in pancreatic cancer cells and was subsequently shown to modulate glucose uptake, lactate production, and ATP generation by pancreatic cancer cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells.Ecd is a novel tumor-promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells.
Effects of Losartan or Atenolol in Hypertensive Patients without Clinically Evident Vascular Disease: A Substudy of the LIFE Randomized Trial
Authors: Richard B. Devereux
Journal: Annals of Internal Medicine (2003)

Background: Cardiovascular morbidity and mortality are reduced by treatment with the angiotensin II AT1-receptor antagonist losartan compared with conventional treatment with the -blocker atenolol in patients with hypertension and electrocardiogram-defined left ventricular hypertrophy, many of whom had known vascular disease. Objective: To determine whether losartan reduces cardiovascular event rates in lower-risk hypertensive patients without clinically evident vascular disease. Design: Subgroup analysis of a randomized trial. Setting: The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study. Patients: 6886 men and women (57% women) 55 to 80 years of age (average, 66 years) with essential hypertension (sitting blood pressure, 160 to 200/95 to 115 mm Hg [average, 174/98 mm Hg]) and electrocardiogram-defined left ventricular hypertrophy who did not have clinically evident vascular disease. Intervention: Patients were randomly assigned to once-daily double-blind treatment with losartan or atenolol. Measurements: An end point committee ascertained end points (cardiovascular death, stroke, or myocardial infarction). Results: Blood pressure was reduced similarly by losartan and atenolol. The primary composite end point occurred in 282 losartan-treated patients (17.5 per 1000 patient-years) and 355 atenolol-treated patients (21.8 per 1000 patient-years; relative risk, 0.81 [95% CI, 0.69 to 0.95]; P = 0.008). Cardiovascular death occurred in 103 losartan-treated patients and 132 atenolol-treated patients (relative risk, 0.80 [CI, 0.62 to 1.04]; P = 0.092), stroke (nonfatal and fatal) occurred in 125 losartan-treated patients and 193 atenolol-treated patients (relative risk, 0.66 [CI, 0.53 to 0.82]; P < 0.001), and myocardial infarction (nonfatal and fatal) occurred in 110 losartan-treated patients and 100 atenolol-treated patients (relative risk, 1.14 [CI, 0.87 to 1.49]; P > 0.2). New-onset diabetes occurred less often in patients treated with losartan (n = 173) than in patients treated with atenolol (n = 254) (relative risk, 0.69 [CI, 0.57 to 0.84]; P < 0.001). Benefits of losartan treatment were numerically smaller, but not significantly so, in patients with preexisting vascular disease. Conclusion: In hypertensive patients without clinically evident vascular disease, losartan was more effective than atenolol in preventing cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. *For a list of investigators in the LIFE study, see the Appendix.
The Heymann nephritis antigenic complex
Authors: M G Farquhar, A Saito, D Kerjaschki, R A Orlando
Journal: Journal of the American Society of Nephrology (1995)

Heymann nephritis (HN) has been extensively studied as a model of human membranous nephropathy since it was first described by Heymann in 1959. HN was induced in active form by the immunization of rats with antigens derived from the proximal tubule brush border, resulting in subepithelial glomerular immune deposits. HN was also induced passively by the injection of antibrush border antibodies into normal rats. A breakthrough in the understanding of the pathogenesis of HN was made in the 1970s, when it was established that the disease was due to the binding of circulating antibodies to glomerular components. This in turn led to a search to identify the endogenous antigen(s). In 1982, gp330 (now called megalin), a glycoprotein located in clathrin-coated pits of glomerular and proximal tubular epithelia, was identified as a target antigen. In 1990, a second protein (44 kd), now known as RAP (for receptor associated protein), that binds to megalin was also shown to be a target antigen. Both molecules have been cloned and sequenced, and their role in normal epithelial cells has been explored. It has come to light that megalin (gp330) is a member of the low-density lipoprotein receptor gene family and functions as a multiligand receptor for the uptake of a variety of macromolecules (plasminogen, protease: protease inhibitor complexes, apolipoprotein E-enriched very low-density lipoproteins, lactoferrin, among others). RAP associates with megalin and appears to function as a chaperone assisting in the folding of megalin in the endoplasmic reticulum and its transport to the cell surface. This review considers what is now known about the structure, function, and trafficking of megalin and RAP and the role of these two molecules in the pathogenesis of HN.
PHENOMENON OF LOCAL SKIN REACTIVITY TO BACTERIAL FILTRATES: AN ANTIBODY AUXILIARY TO SERUM NEUTRALIZATION OF MENINGOCOCCUS REACTING FACTORS
Authors: G. Shwartzman
Journal: The Journal of Experimental Medicine (1931)

In. this paper there is described an antibody auxiliary to the neutralization of meningococcus reacting factors. The presence of the antibody facilitates studies on neutralizing potency of antimeningococcus sera.
A general strategy for the generation of hypoallergenic molecules for the immunotherapy of fish allergy
Authors: Ines Swoboda, Nadja Balic, Christoph Klug, Margit Focke, Milena Weber, Susanne Spitzauer, Angela Neubauer, Santiago Quirce, Nikolaos Douladiris, Nikolaos G. Papadopoulos, Rudolf Valenta
Journal: Journal of Allergy and Clinical Immunology (2013)
Regulation of megakaryocyte phenotype in human erythroleukemia cells.
Authors: M W Long, C H Heffner, J L Williams, C Peters, E V Prochownik
Journal: Journal of Clinical Investigation (1990)

Induction of human erythroleukemia (HEL) cells with nanomolar tumor-promoting phorbol myristate acetate (PMA) diesters results in the synchronous acquisition of multiple markers of the megakaryocyte phenotype. Induced cells markedly increase their content of cytoplasm and show features of morphological maturation. At the ultrastructural level, PMA-treated cells show increases in cytoplasm, nuclear lobulation and nucleolar content, and free ribosomes. Limited numbers of cells also express alpha-granules and nascent demarcation membrane systems. Functionally, PMA-stimulated HEL cells express increased amounts of the megakaryocyte/platelet proteins: glycoprotein IIb/IIIa, platelet factor 4, von Willebrand factor, glycoprotein Ib, and thrombospondin. No changes are observed in antigenic markers of the erythroid (glycophorin A) or macrophage lineages (MO-1 or MO-2). The increases in antigenic expression are rapid, reaching maximum levels within 3-4 d under serum-free conditions. Treatment with PMA also abruptly (within 1-2 d) inhibits cellular division in these cells. Washout studies indicate that phorbols exert their effect within 18-24 h, the approximate cell cycle time for these cells. Consistent with proliferative arrest, c-myc proto-oncogene transcripts begin to decline within 8 h of PMA treatment, although transcripts of c-myb are unaffected. Importantly, megakaryocyte differentiation is associated with endomitotic DNA synthesis (i.e., continued DNA synthesis in the absence of mitosis and cytokinesis), with HEL cells reaching a DNA content of 3-12 times that of unstimulated cells. Endomitosis is coordinately regulated with changes in antigenic expression and cell size such that those cells having the highest DNA content are the largest and also express the greatest levels of antigen.
<i>Epidermal Growth Factor Receptor</i>Mutation Testing in the Care of Lung Cancer Patients
Authors: Lecia V. Sequist, Victoria A. Joshi, Pasi A. Jänne, Daphne W. Bell, Panos Fidias, Neal I. Lindeman, David N. Louis, Jeffrey C. Lee, Eugene J. Mark, Janina Longtine, Peter Verlander, Raju Kucherlapati, Matthew Meyerson, Daniel A. Haber, Bruce E. Johnson, Thomas J. Lynch
Journal: Clinical Cancer Research (2006)

Abstract As the literature about epidermal growth factor receptor (EGFR) mutations grows and screening for mutations becomes increasingly integrated into clinical care, it is important to examine how best to do somatic mutational analyses and how best to use the test results in clinical decision making. We began offering mutation screening by comprehensive direct sequence analysis of exons 18 to 24 of the tyrosine kinase domain of EGFR in August 2004 as part of clinical cancer care and protocol therapy at our institutions. All identified potential mutations are confirmed with three to five independent PCRs of the original genomic DNA sample and, if not previously noted in the literature, are compared with the patient's germ-line DNA to ensure the finding is somatic. We formally analyzed the first 100 patients to undergo EGFR sequence analysis and found that testing was feasible and significantly affected the treatment of patients with non–small cell lung cancer (NSCLC). Patients harboring EGFR mutations were significantly more likely to receive recommendations for therapy with EGFR tyrosine kinase inhibitors (i.e., gefitinib or erlotinib) than patients without mutations. However, negative EGFR test results did not prevent physicians from administering these agents to selected patients. Ideally, a standardized technique for mutation testing could be developed, with demonstrated reproducibility and validity. Clinical trials incorporating molecular diagnostics are ongoing to assess the efficacy of EGFR tyrosine kinase inhibitors as first-line therapy for metastatic NSCLC and as adjuvant therapy for early-stage resected NSCLC. It is likely that mutation testing and other molecular analyses will be most useful in these two clinical situations.
419 THE CORRELATION OF LIVER STIFFNESS WITH PORTAL PRESSURE AND FIBROSIS STAGE IS INFLUENCED BY VASOACTIVE TREATMENT AND ETIOLOGY OF LIVER DISEASE
Authors: T. Reiberger, A. Ferltisch, M. Pinter, M. Homoncik, G. Ulbrich, M. Peck-Radosavljevic
Journal: Journal of Hepatology (2010)
Statin Drugs and Risk of Advanced Prostate Cancer
Authors: Elizabeth A. Platz, Michael F. Leitzmann, Kala Visvanathan, Eric B. Rimm, Meir J. Stampfer, Walter C. Willett, Edward Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2006)

Statins are commonly used cholesterol-lowering drugs that have proapoptotic and antimetastatic activities that could affect cancer risk or progression. Results from previous epidemiologic studies of the association between statin use and cancer have been inconsistent. We investigated the association of statin use with total and advanced prostate cancer, the latter being the most important endpoint to prevent.We analyzed data from an ongoing prospective cohort study of 34,989 US male health professionals who were cancer free in 1990 and were followed to 2002. Participants reported their use of cholesterol-lowering drugs on biennial questionnaires. Prostate cancer diagnosis was confirmed by medical record review. Multivariable-adjusted relative risks (RRs) were estimated from Cox proportional hazards regression models. Statistical tests were two-sided.During 376,939 person-years of follow-up, we ascertained 2579 prostate cancer cases, 316 of which were advanced (regionally invasive, metastatic, or fatal). The age-standardized incidence rates of advanced prostate cancer were 38 and 89 per 100,000 person-years in current statin users and in past or never users, respectively. The multivariable-adjusted relative risk of advanced disease was 0.51 (95% confidence interval [CI] = 0.30 to 0.86) and of metastatic or fatal disease was 0.39 (95% CI = 0.19 to 0.77) for current statin use compared with no current use. The associations remained after adjusting for prostate-specific antigen screening history (advanced disease: RR = 0.57, 95% CI = 0.30 to 1.11; metastatic or fatal disease: RR = 0.35, 95% CI = 0.14 to 0.92). Risk of advanced disease was lower with longer statin use (P(trend) = .003); compared with never use, the relative risk for less than 5 years of use was 0.60 (95% CI = 0.35 to 1.03) and for 5 or more years of use was 0.26 (95% CI = 0.08 to 0.83). We found no association between statin use and risk of total prostate cancer (RR = 0.96, 95% CI = 0.85 to 1.09).In this cohort of male health professionals, use of statin drugs was not associated with risk of prostate cancer overall but was associated with a reduced risk of advanced (especially metastatic or fatal) prostate cancer.
Reduced repolarization reserve in ventricular myocytes from female mice
Authors: Y Wu
Journal: Cardiovascular Research (2002)

Objective: Cardiac repolarization is prolonged and repolarization reserve (RR) is diminished in female rabbits and humans, compared to males. Reduced RR is evidenced by the relatively greater increase in ventricular action potential duration (APD) in myocytes from females in response to drugs that block repolarizing K+ currents. Mice are an increasingly important experimental model animal for cardiovascular research, but gender-dependent differences have not been reported for repolarization in murine ventricular myocytes. Methods: APD and repolarizing K+ currents were measured in isolated ventricular myocytes from adult littermate male and female mice. Repolarizing K+ currents were dissected into transient (Ito) and sustained (Isus) components and the selective Isus antagonist FK506 was used to probe for differences in RR. Results: Under control conditions APD at 50% (APD50) and at 90% (APD90) repolarization was significantly longer in females (APD50=15±3 ms, n=6 and APD90=63±6 ms, n=6) compared to males (APD50=8±2 ms, n=7 and APD90=42±9 ms, n=7) at 1.0 Hz. At 0.3 Hz stimulation frequency APD90, but not APD50, was significantly longer in females (APD50=12±2 ms and APD90=54±5 ms, n=10) compared to males (APD50=11±2 ms and APD90=47±7 ms, n=10). FK506 treatment (25 μM) selectively and equally inhibited Isus in all cells, and significantly increased APD50 and APD90 in males and females at 0.3 and 1.0 Hz. However, increases in APD50 and APD90 (0.3 and 1.0 Hz) in response to FK506 were significantly greater in myocytes from females compared to males. Voltage clamp measurement of Ito and Isus revealed that males had a relatively more prominent Ito while females exhibited a more prominent Isus. Conclusions: Ventricular action potential repolarization is prolonged in myocytes from female compared to male mice. Female mice have reduced RR that is unmasked by FK506. These findings suggest that gender is an important variable for cardiovascular studies using mice.
Grading quality of evidence and strength of recommendations in clinical practice guidelines Part 3 of 3. The GRADE approach to developing recommendations
Authors: J. L. Brożek, E. A. Akl, E. Compalati, J. Kreis, L. Terracciano, A. Fiocchi, E. Ueffing, J. Andrews, P. Alonso-Coello, J. J. Meerpohl, D. M. Lang, R. Jaeschke, J. W. Williams Jr, B. Phillips, A. Lethaby, P. Bossuyt, P. Glasziou, M. Helfand, J. Watine, M. Afilalo, V. Welch, A. Montedori, I. Abraha, A. R. Horvath, J. Bousquet, G. H. Guyatt, H. J. Schünemann
Journal: Allergy (2011)

To cite this article: Brożek JL, Akl EA, Compalati E, Kreis J, Terracciano L, Fiocchi A, Ueffing E, Andrews J, Alonso-Coello P, Meerpohl JJ, Lang DM, Jaeschke R, Williams JW Jr, Phillips B, Lethaby A, Bossuyt P, Glasziou P, Helfand M, Watine J, Afilalo M, Welch V, Montedori A, Abraha I, Horvath AR, Bousquet J, Guyatt GH, Schünemann HJ, for the GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 3 of 3. The GRADE approach to developing recommendations. Allergy 2011; 66: 588–595. This is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients’ values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients’ values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices.
Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome
Authors: Piero Ruggenenti, Barbara Ruggiero, Paolo Cravedi, Marina Vivarelli, Laura Massella, Maddalena Marasà, Antonietta Chianca, Nadia Rubis, Bogdan Ene-Iordache, Michael Rudnicki, Rosa Maria Pollastro, Giovambattista Capasso, Antonio Pisani, Marco Pennesi, Francesco Emma, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2014)

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.