tbuckley/cabot-search huggingface dataset:
Maternal Atopic Disease Modifies Effects of Prenatal Risk Factors on Exhaled Nitric Oxide in Infants
Authors: Urs Frey, Claudia Kuehni, Hanna Roiha, Mateja Cernelc, Benjamin Reinmann, Johannes H. Wildhaber, Graham L. Hall
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

In a prospective healthy birth cohort, we determined whether levels of exhaled nitric oxide (eNO) in healthy unselected infants at the age of 1 month were associated with maternal atopic disease and prenatal and early postnatal environmental exposures. Tidal eNO was measured in 98 healthy, unsedated infants (35 from mothers with atopy) (mean age ± SD, 36.0 ± 6.2 days) and was compared with histories taken in standardized interviews. eNO was higher in males compared with females (17.7 vs. 14.6 ppb, p = 0.042) and infants exposed to postnatal maternal smoking (+4.4 ppb, p = 0.027), adjusting for weight and tidal breathing parameters. Prenatal tobacco exposure was associated with higher eNO (+12.0 ppb, p = 0.01) in infants of mothers with asthma and lower eNO (−5.7 ppb) in infants of mothers without asthma (p for interaction < 0.0001). Coffee consumption in pregnancy decreased eNO (−6.0 ppb, p = 0.008) only in children of mothers with atopy (p for interaction = 0.015). Paternal atopy had no influence. In the early phase of immunologic development, before the onset of infections and allergic disease, the effect of prenatal or early postnatal environmental factors on eNO was modified by the presence of maternal atopic disease. This underlines the complex interaction of maternal and environmental factors in the development of airway disease.
Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma
Authors: David A. Rizzieri, Gamal Akabani, Michael R. Zalutsky, R. Edward Coleman, Scott D. Metzler, James E. Bowsher, Bonnie Toaso, Elizabeth Anderson, Anand Lagoo, Steve Clayton, Charles N. Pegram, Joseph O. Moore, Jon P. Gockerman, Carlos DeCastro, Cristina Gasparetto, Nelson J. Chao, Darell D. Bigner
Journal: Blood (2004)
Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes With Prognosis
Authors: Karen Dybkær, Martin Bøgsted, Steffen Falgreen, Julie S. Bødker, Malene K. Kjeldsen, Alexander Schmitz, Anders E. Bilgrau, Zijun Y. Xu-Monette, Ling Li, Kim S. Bergkvist, Maria B. Laursen, Maria Rodrigo-Domingo, Sara C. Marques, Sophie B. Rasmussen, Mette Nyegaard, Michael Gaihede, Michael B. Møller, Richard J. Samworth, Rajen D. Shah, Preben Johansen, Tarec C. El-Galaly, Ken H. Young, Hans E. Johnsen
Journal: Journal of Clinical Oncology (2015)

Purpose Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell–associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. Patients and Methods We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. Results Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP–treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell–like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1–signature and major histocompatibility complex class II–signature genes, which are known to have a positive impact on prognosis. Conclusion Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.
A Randomized, Double-Blind, Placebo-Controlled Trial of Rifaximin To Prevent Travelers' Diarrhea
Authors: Herbert L. DuPont, Zhi-Dong Jiang, Pablo C. Okhuysen, Charles D. Ericsson, Francisco Javier de la Cabada, Shi Ke, Margaret W. DuPont, Francisco Martinez-Sandoval
Journal: Annals of Internal Medicine (2005)

Travelers' diarrhea causes substantial morbidity and postinfectious irritable bowel syndrome.To evaluate nonabsorbable rifaximin for prevention of travelers' diarrhea.Randomized, double-blind, placebo-controlled clinical trial.Guadalajara, Mexico.U.S. students.On arrival in Guadalajara, Mexico, 210 U.S. adults received rifaximin (200 mg/d, 200 mg twice daily, or 200 mg 3 times daily) or placebo for 2 weeks.Participants were followed daily for 3 weeks for enteric disease and symptoms and daily for 5 weeks for drug side effects. Changes in intestinal coliform flora were studied.Travelers' diarrhea developed in 14.74% of participants taking rifaximin and 53.70% of those taking placebo (rate ratio, 0.27 [95% CI, 0.17 to 0.43]). Rifaximin provided 72% and 77% protection against travelers' diarrhea and antibiotic-treated travelers' diarrhea, respectively (P < 0.001 for both), and all rifaximin doses were superior to placebo. In the groups that did not report travelers' diarrhea, rifaximin significantly reduced the occurrence of mild diarrhea (P = 0.02) and moderate and severe intestinal problems (P = 0.009 for pain or cramps; P = 0.02 for excessive gas). Rates of adverse events were comparable in the rifaximin and placebo groups. Minimal changes in coliform flora were found during rifaximin therapy.Rifaximin safely prevented travelers' diarrhea in Mexico, where most cases are caused by diarrhea-producing Escherichia coli. A study is needed in Asia to determine whether rifaximin can prevent diarrhea caused by invasive bacterial pathogens.Rifaximin prevents travelers' diarrhea with minimal changes in fecal flora, and more liberal chemoprophylaxis against this disease should be considered. Future studies should evaluate whether rifaximin is effective in preventing postinfectious irritable bowel syndrome.
Inflamed Joints and Stiff Arteries
Authors: Arshed A. Quyyumi
Journal: Circulation (2006)

atients with rheumatoid arthritis (RA) are at increased risk of cardiovascular events, with an estimated 70% excess mortality rate that can be ascribed to cardiovascular causes in up to 50% of cases. 1,2A 3-fold-increased adjusted risk of myocardial infarction has been reported, particularly in subjects with longer disease duration. 3This has prompted recommendations that RA be considered an independent risk factor for atherosclerosis. 2 Mechanisms underlying this increased susceptibility remain uncertain and range from exposure to traditional cardiovascular risk factors to enhanced inflammation and oxidative stress emanating from the synovium leading to early vascular disease, 4 and extend to adverse cardiovascular effects of medications.
VARIATIONS IN THE PNEUMOCOCCUS INDUCED BY GROWTH IN IMMUNE SERUM
Authors: Laura M. Stryker
Journal: The Journal of Experimental Medicine (1916)

1. The growth of virulent pneumococci in homologous immune serum produces (a) variations in agglutinability, (b) decrease in virulence, (c) inhibition of capsule formation, (d) increase in phagocytability with normal serum, and (e) change in absorption power and antigenic properties. 2. Reversion to the original type in these changed forms takes place upon animal passage.
Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials
Authors: M R Law
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. <b>Design</b> Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. <b>Subjects</b> 40 000 treated patients and 16 000 patients given placebo. <b>Main outcome measures</b> Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. <b>Results</b> All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. <b>Conclusions</b> Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.
Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis. Does diltiazem induce its regression?
Authors: M Vayssairat, D Hidouche, N Abdoucheli-Baudot, J P Gaitz
Journal: Annals of the Rheumatic Diseases (1998)

To establish whether diltiazem reduces subcutaneous calcinosis (SCC) in patients with systemic sclerosis (SSc), and whether this calcinosis is related to other signs or symptoms.47 patients with SSc were evaluated and divided into two groups according to the presence or absence of SCC.Among the 12 patients with SCC who were treated with diltiazem and had sequential hand radiographs (differential time between the two radiographs: 7.8+/-4 years), there was a slight radiological improvement in three patients only. More patients with SCC had anticentromere antibodies than patients without (p = 0.003), fewer had anti-Scl 70 antibodies (p = 0.01), more had telangiectasia and giant capillaries ( p + 0.04 and 0.048 respectively), and SCC patients had significantly fewer capillaries at the nailfold (p = 0.03).These results do not clearly indicate that diltiazem is effective in calcinosis associated with SSc. Among the patients with SSc, those who also had SCC exhibited a distinctive autoimmune profile and more severe cutaneous capillary injury than those without SCC.
Gene Expression Profiling of Breast Cancer in Relation to Estrogen Receptor Status and Estrogen-Metabolizing Enzymes: Clinical Implications
Authors: Vessela N. Kristensen, Therese Sørlie, Jurgen Geisler, Anita Langerød, Noriko Yoshimura, Rolf Kåresen, Nobuhiro Harada, P.E. Lønning, Anne-Lise Børresen-Dale
Journal: Clinical Cancer Research (2005)

Abstract Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER− and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.
DNA rearrangement can account for in vitro switching to IgG1.
Authors: C C Chu, E E Max, W E Paul
Journal: The Journal of Experimental Medicine (1993)

During immune responses, B lymphocytes may switch from the expression of immunoglobulin M (IgM) to the expression of another isotype (e.g., IgG, IgE, IgA). In stable hybridomas and myelomas expressing a "switched" (S) isotype, DNA deletions between S mu and a "downstream" S region (S region recombination) have been found. In primary B cells, studies of the molecular basis of switching have been limited by the ability to sensitively quantitate the amount of DNA deletion; such studies would be of interest because other nondeletional mechanisms (trans-splicing, alternative processing of a long transcript) have been proposed to account for isotype switching in certain circumstances. We have applied the digestion-circularization polymerase chain reaction (DC-PCR) technique to measure the amount of S region recombination that occurs in the course of class switching in primary B lymphocytes. Resting B cells were cultured in lipopolysaccharide (LPS) and interleukin 4 (IL-4) to stimulate switching to IgG1. These cells begin to express membrane IgG1 at day 2.5 of culture and reach maximum expression by day 4.5. DNA was prepared from cultured cells and analyzed for S mu-S gamma 1 rearrangement by DC-PCR. Chimeric switch regions, indicating S mu-S gamma 1 recombination, were detected in amounts that, in most cases, correlated with surface expression. Furthermore, when cells were sorted on the basis of surface IgG1 expression, a mean of at least one S mu-S gamma 1 rearrangement per cell was seen in five out of seven experiments. In general, the IgG1+ cells obtained at 4.5 and 5.5 d of culture had close to 2 S mu-S gamma 1 rearrangements per cell. In IgG1- cells, S mu-S gamma 1 rearrangements were detectable, but at frequencies substantially lower that in IgG1+ cells. Thus, these results indicate that DNA deletion accompanies class switching in normal B cells stimulated with LPS and IL-4.
Peroxiredoxin 6 attenuates lipopolysaccharide-induced plasminogen activatro inhibitor 1 expression by regulating autophagy
Authors: Dong Yang, Yuanlin Song, Jiayuan Sun, Tong Lin, Jing Bi, Chunxue Bai
Journal: European Respiratory Journal (2012)

Objective: To evaluate the roles of Peroxiredoxin(Prdx)6 in the expression of plasminogen activator inhibitor(PAI)-1 in lipopolysaccharide(LPS) induced acute lung injury(ALI). Methods and Results: ALI was induced in Prdx6(-/-) and C57BL/6J mice 4hrs or 24hrs after intratracheal instillation of LPS(5mg/kg), characterized by inflammation in morphology, higher wet/dry ratio, elevated protein concentration and increased neutrophils in bronchial alveolar lavage fluid(BALF), which were more significantly in Prdx6(-/-) mice. After LPS administration, PAI-1 mRNAexpressions were markedly increased in a time-dependant manner and the PAI-1 concentration in BALF were markedly increased at 4hrs and decreased nearly to baseline at 24hrs in Prdx6(-/-) mice compared to C57BL/6J mice. Autophagy was significantly enhenced with higher expression of LC3B in Prdx6(-/-) mice compared to C57BL/6J mice. Primary cultured macrophages were stimulated by LPS (10ug/ml) for 4hrs. The level of reactive oxygen species(ROS) in macrophages from Prdx6 (-/-) mice was significantly higher than that from C57BL/6J mice. The release of PAI-1 was significantly increased in macrophages from Prdx6(-/-) mice compared to wildtype mice after LPS instillation. PAI-1 release was partially suppressed by extracellular signal–regulated kinase(ERK) and p38 mitogen-activated protein kinase inhibitor(MAPK) but not by c-Jun N-terminal kinase inhibitors. Conclusions: In LPS-induced ALI, Prdx6(-/-) mice increased PAI-1 expressions of partially dependent on enhanced autophagy in lungs and p38 MAPK and ERK in macrophages. Thus, Prdx6 possesses anti-fibrinolytic activity under inflammation by regulating autophagy.
Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials
Authors: J. Drevs, U. Zirrgiebel, C.I.M. Schmidt-Gersbach, K. Mross, M. Medinger, L. Lee, J. Pinheiro, J. Wood, A.L. Thomas, C. Unger, A. Henry, W.P. Steward, D. Laurent, D. Lebwohl, M. Dugan, D. Marmé
Journal: Annals of Oncology (2005)
Genomic landscape of non-small-cell lung cancer in smokers and never-smokers
Authors: Niruthika Sritharan
Journal: Thorax (2013)

Genomic landscape of non-small-cell lung cancer in smokers and never-smokers Whole-genome and transcriptome sequencing studies were performed on 17 tumour and adjacent normal tissue samples from smokers, former light smokers and never-smokers diagnosed with non-small-cell lung cancer.This sequencing-based study revealed a markedly distinct genomic landscape in smokers and never-smokers.Smokers had an average mutation frequency 10-fold higher than neversmokers and a significantly higher number of point mutations of the cancer genome LUC9, involving DNA repair genes.A positive correlation was found to exist between the amount of smoking exposure and mutational burden.The mutation spectrum differed significantly with C:G→A:T transversions being the most predominant point mutation in smokers and C:G→T:A transitions in never-smokers.Each group had distinctive sets of mutations: KRAS, TP53, BRAF, JAK2 and JAK3 in smokers and EGFR mutations, ROS1 and ALK fusions in never-smokers-all potential novel therapeutic targets.The EGFR and KRAS mutations were identified in founder clones, suggesting a role in cancer initiation.Most of the samples had diverse clonality patterns and no correlation was found between smoking status and tumour clonality.Further analysis revealed a total of 3726 point mutations including kinase genes, chromatin-associated genes and significant alterations of DACH1, RELN and ABCB5 genes in both smokers and non-smokers.Mutations in 54 genes were identified that could be targeted with existing drugs.This study has identified a vast number of potential therapeutic targets that require further exploration.Further studies that confirm dominant genetic alterations in founder clones need to be targeted to develop potentially curative treatment.
Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803
Authors: Monica M. Bertagnolli, Donna Niedzwiecki, Carolyn C. Compton, Hejin P. Hahn, Margaret Hall, Beatrice Damas, Scott D. Jewell, Robert J. Mayer, Richard M. Goldberg, Leonard B. Saltz, Robert S. Warren, Mark Redston
Journal: Journal of Clinical Oncology (2009)

Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.
Loss of Synchronized Retinal Phagocytosis and Age-related Blindness in Mice Lacking αvβ5 Integrin
Authors: Emeline F. Nandrot, Yoonhee Kim, Scott E. Brodie, Xiaozhu Huang, Dean Sheppard, Silvia C. Finnemann
Journal: The Journal of Experimental Medicine (2004)

Daily phagocytosis by the retinal pigment epithelium (RPE) of spent photoreceptor outer segment fragments is critical for vision. In the retina, early morning circadian photoreceptor rod shedding precedes synchronized uptake of shed photoreceptor particles by RPE cells. In vitro, RPE cells use the integrin receptor αvβ5 for particle binding. Here, we tested RPE phagocytosis and retinal function in β5 integrin–deficient mice, which specifically lack αvβ5 receptors. Retinal photoresponses severely declined with age in β5−/− mice, whose RPE accumulated autofluorescent storage bodies that are hallmarks of human retinal aging and disease. β5−/− RPE in culture failed to take up isolated photoreceptor particles. β5−/− RPE in vivo retained basal uptake levels but lacked the burst of phagocytic activity that followed circadian photoreceptor shedding in wild-type RPE. Rhythmic activation of focal adhesion and Mer tyrosine kinases that mediate wild-type retinal phagocytosis was also completely absent in β5−/− retina. These results demonstrate an essential role for αvβ5 integrin receptors and their downstream signaling pathways in synchronizing retinal phagocytosis. Furthermore, they identify the β5−/− integrin mouse strain as a new animal model of age-related retinal dysfunction.