tbuckley/cabot-search huggingface dataset:
Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics
Authors: Bryan T. Hennessy, Ana-Maria Gonzalez-Angulo, Katherine Stemke-Hale, Michael Z. Gilcrease, Savitri Krishnamurthy, Ju-Seog Lee, Jane Fridlyand, Aysegul Sahin, Roshan Agarwal, Corwin Joy, Wenbin Liu, David Stivers, Keith Baggerly, Mark Carey, Ana Lluch, Carlos Monteagudo, Xiaping He, Victor Weigman, Cheng Fan, Juan Palazzo, Gabriel N. Hortobagyi, Laura K. Nolden, Nicholas J. Wang, Vicente Valero, Joe W. Gray, Charles M. Perou, Gordon B. Mills
Journal: Cancer Research (2009)

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.
Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli
Authors: M M Heimesaat, A Fischer, H-K Jahn, J Niebergall, M Freudenberg, M Blaut, O Liesenfeld, R R Schumann, U B Gobel, S Bereswill
Journal: Gut (2007)

In the course of inflammatory bowel diseases (IBD) and acute murine ileitis following peroral Toxoplasma gondii infection, commensal Escherichia coli accumulate at inflamed mucosal sites and aggravate small intestinal immunopathology.To unravel the molecular mechanisms by which commensal E coli exacerbate ileitis.Ileitis was investigated in mice that lack Toll-like receptors (TLR) 2 or 4, specific for bacterial lipoproteins (LP) or lipopolysaccharide (LPS), respectively. Gnotobiotic mice, in which any cultivable gut bacteria were eradicated by antibiotic treatment, were used to study the role of LPS in ileitis.Microbiological analyses revealed that E coli increase in the inflamed ileum. TLR4(-/-), but not TLR2(-/-), mice displayed reduced mortality and small intestinal immunopathology. Decreased interferon (IFN)-gamma and nitric oxide (NO) levels in the inflamed terminal ileum of TLR4(-/-) mice indicated that TLR4 signalling aggravates ileitis via local mediator release from immune cells. E coli strains isolated from the inflamed ileum activated cultured mouse macrophages and induced TLR4-dependent nuclear factor kappaB activation and NO production in human embryonic kidney 293 cells and in peritoneal macrophages, respectively. Most strikingly, in contrast with wild-type mice, gnotobiotic TLR4(-/-) mice were protected from induction of ileitis by treatment with purified E coli lipid A or colonisation with live E coli. Finally, prophylactic treatment with the LPS scavenger polymyxin B ameliorated T gondii-induced ileitis.These findings highlight the innate immune system as a key player in T gondii-induced ileal immunopathology. Treatment with LPS or TLR4 antagonists may represent a novel strategy for prophylaxis and/or therapy of small intestinal inflammation in IBD.
Lupus-specific antibodies reveal an altered pattern of somatic mutation.
Authors: A J Manheimer-Lory, G Zandman-Goddard, A Davidson, C Aranow, B Diamond
Journal: Journal of Clinical Investigation (1997)

The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4+ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4+ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent VH gene restriction. Furthermore, VH gene segments encoding these antibodies are also used in protective immune responses. An examination of the process of somatic mutation in F4+ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection.
Eburnamine derivatives and the brain
Authors: Ádám Vas, Balázs Gulyás
Journal: Medicinal Research Reviews (2005)

Abstract The Apocynaceae plant family contains a great number of so called eburnamine–vincamine alkaloids. Quite a few of these alkaloids exert varied pharmacological activities on the cell multiplication, cardiovascular system, and brain functions. Many derviatives were also synthesized to find pharmacologically active compunds better characterized and safer to be administered than the natural plant alkaloids themselves. We concentrate on the eburnamine structures with cerebral activities in this review. Vincamine, vinburnine, vindeburnol, apovincaminate, and vinpocetine (cis‐ethyl‐apovincaminate) all share modulatory effects on brain circulation and neuronal homeostasis, bear antihypoxic and neuroprotective potencies to various degrees. The most eminent compound of this class of alkaloids is vinpocetine. Since its introduction to the market as a neuroprotective agent many non clinical and clinical studies proved vinpocetine's effects on calmodulin dependent phosphodiesterase E1, on sodium, calcium channels, peripheral benzodiazepine receptor, and glutamate receptors as well as its clinical usefulness in the treatment of post‐ischaemic stroke disease states and various disorders of cerebrovascular origin. Lately, positron emission tomography studies proved that vinpocetine has a rapid uptake in the primate and human brain with a heterogenous distribution pattern (preference areas: thalamus, basal ganglia, and visual cortex) both after intravenous and oral administration. Vinpocetine exerts beneficial effects in cerebral glucose metabolism and regional cerebral blood flow in chronic post‐stroke patients. © 2005 Wiley Periodicals, Inc. Med Res Rev
Delayed pneumothorax after CT-guided percutaneous fine needle aspiration lung biopsy
Authors: Z. C. Traill, F. V. Gleeson
Journal: Thorax (1997)

Two patients are described who developed pneumothoraces more than 24 hours after computed tomography (CT) guided percutaneous fine needle aspiration lung biopsies. The pneumothoraces required treatment in both cases. Such delayed pneumothorax after lung biopsy is extremely unusual. Patients should be warned of the possible occurrence of this complication and instructed to seek medical help if they develop chest pain or breathlessness.
1352 IL28B-CC GENOTYPE-RELATED GENE EXPRESSION DURING TREATMENT OF CHRONIC HEPATITIS C (CH-C) WITH PEGYLATED INTERFERON-ALFA (PEG-IFN) AND RIBAVIRIN (RBV): POTENTIAL MECHANISMS FOR SUSTAINED VIROLOGIC RESPONSE (SVR)
Authors: Z.M. Younossi, J.M. Estep, A. Birerdinc, M. Stepanova, A. Baranova, I. Younossi, A. Afendy
Journal: Journal of Hepatology (2011)
Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes
Authors: Saïd El-Haou, Elise Balse, Nathalie Neyroud, Gilles Dilanian, Bruno Gavillet, Hugues Abriel, Alain Coulombe, Andreas Jeromin, Stéphane N. Hatem
Journal: Circulation Research (2009)

Membrane-associated guanylate kinase (MAGUK) proteins are major determinants of the organization of ion channels in the plasma membrane in various cell types. Here, we investigated the interaction between the MAGUK protein SAP97 and cardiac Kv4.2/3 channels, which account for a large part of the outward potassium current, I(to), in heart. We found that the Kv4.2 and Kv4.3 channels C termini interacted with SAP97 via a SAL amino acid sequence. SAP97 and Kv4.3 channels were colocalized in the sarcolemma of cardiomyocytes. In CHO cells, SAP97 clustered Kv4.3 channels in the plasma membrane and increased the current independently of the presence of KChIP and dipeptidyl peptidase-like protein-6. Suppression of SAP97 by using short hairpin RNA inhibited I(to) in cardiac myocytes, whereas its overexpression by using an adenovirus increased I(to). Kv4.3 channels without the SAL sequence were no longer regulated by Ca2+/calmodulin kinase (CaMK)II inhibitors. In cardiac myocytes, pull-down and coimmunoprecipitation assays showed that the Kv4 channel C terminus, SAP97, and CaMKII interact together, an interaction suppressed by SAP97 silencing and enhanced by SAP97 overexpression. In HEK293 cells, SAP97 silencing reproduced the effects of CaMKII inhibition on current kinetics and suppressed Kv4/CaMKII interactions. In conclusion, SAP97 is a major partner for surface expression and CaMKII-dependent regulation of cardiac Kv4 channels.
Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial
Authors: Bruce A. Arnow, Christine Blasey, Leanne M. Williams, Donna M. Palmer, William Rekshan, Alan F. Schatzberg, Amit Etkin, Jayashri Kulkarni, James F. Luther, A. John Rush
Journal: American Journal of Psychiatry (2015)

Objective: The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications. Method: Participants 18–65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report). Results: Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect. Conclusions: There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.
Acceleration of idioventricular rhythms by histamine in guinea pig heart: mediation by H2 receptors.
Authors: R Levi, J H Zavecz
Journal: Circulation Research (1979)

To evaluate the ability of histamine to induce ventricular arrhythmias, we studied the effects of histamine on ventricular rhythmicity in the isolated guinea pig heart with complete atrioventricular conduction block. As a function of dose (0.1-30 microgram), histamine enhanced the idioventricular rate by increasing the rate of firing of the original pacemaker and also by causing the sudden appearance of faster idioventricular rhythms that coincided with changes in pacemaker site. Anaphylaxis in the isolated guinea pig heart with complete atrioventricular conduction block caused histamine release and acceleration of idioventricular rate. The effects of histamine on idioventricular rhythmicity were not attenuated by the histamine H1 receptor antagonist chlorpheniramine, but were antagonized by the H2 receptor antagonist cimetidine. Moreover, the selective H2 agonist 4-methylhistamine (4MeH) accelerated the idioventricular rate, whereas 2-(2-thiazolyl) ethylamine (ThEA), at doses selective for H1 receptor activation, did not. The effects of histamine on idioventricular rhythmicity were not modified by the beta-adrenergic blocker pindolol. The mechanism by which histamine increases idioventricular rate probably involves two components: (1) an enhancement in automaticity of the original pacemaker, and (2) the induction of faster rhythms via reentry and/or afterdepolarizations. Whatever the mechanism, both components of the ventricular chronotropic action of histamine appear to involve exclusively histamine receptors of the H2 type. Thus, our results suggest that H2 receptor antagonists may have a role as specific antiarrhythmic agents in the treatment of cardiac dysfunctions caused by histamine release.
Acute effects of ethanol on hepatic uptake and distribution of narcotics in the isolated perfused rabbit liver
Authors: Mary Jeanne Kreek, Marcus A. Rothschild, Murray Oratz, Joseph Mongelli, Anne C. Handley
Journal: Hepatology (1981)

This study was performed as an initial step in systematically defining the hepatic interactions between ethanol and opioids using a controlled in vitro system. The acute effects of ethanol on the initial uptake and distribution of long- and short-acting narcotics were studied using isolated rabbit liver perfused with rabbit blood without or with ethanol. A pulse injection of 1.5 mg of 14C-labeled narcotic [methadone, 1-alpha-acetylmethadol (LAAM), morphine, or meperidine] was made into the portal vein cannula followed by perfusion for 2 min. Radioactivity was determined in liver homogenates and subcellular fractions; methadone and its metabolites were measured by thin-layer chromatography with zonal scanning in each fraction. Ethanol preperfusion and concomitant ethanol perfusion did not effect hepatic uptake of methadone, LAAM, morphine, or meperidine. Although subcellular localization of morphine and meperidine differed from that of methadone and LAAM, perfusion with ethanol did not alter the acute hepatic uptake and distribution of any of the narcotics. These findings suggest that acute exposure to ethanol does not alter the acute hepatic disposition of narcotics.
Near misses of ACR/EULAR criteria for remission: effects of patient global assessment in Boolean and index-based definitions
Authors: Paul Studenic, Josef S Smolen, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The American College of Rheumatology/European League Against Rheumatism remission criteria for rheumatoid arthritis (RA) have been published recently. <h3>Objective</h3> To quantify the proportions of patients fulfilling only three of the four Boolean criteria and the relevance of patient global assessment (PGA) in context of remission. <h3>Methods</h3> From an observational prospective RA database the first visit of patients, fulfilling just three of the four Boolean criteria was identified. Logistic regression and descriptive analyses were processed, also defining remission by index-based (Simplified Disease Activity Index (SDAI)) definition and comparing outcomes with the evaluator global assessment (EGA). <h3>Results</h3> 52% had at least one visit, fulfilling just three criteria (not fulfilled were: PGA 61%; swollen joints 20%; tender joints 13%; C-reactive-protein 7%). 67% of patients not fulfilling the PGA criterion had an EGA≤1 cm, 25% of those fulfilled the SDAI definition. Increased pain (OR=1.28), EGA (OR=1.10) and discrepancy towards higher PGA than EGA (OR=1.28) could explain PGA failure to reach remission. <h3>Conclusions</h3> PGA is often the limiting factor for reaching remission; index-based remission showed balancing effects by adjusting for elevated variables in the summative score.
Field, Genetic, and Modeling Approaches Show Strong Positive Selection Acting upon an Insecticide Resistance Mutation in Anopheles gambiae s.s.
Authors: A. Lynd, D. Weetman, S. Barbosa, A. Egyir Yawson, S. Mitchell, J. Pinto, I. Hastings, M. J. Donnelly
Journal: Molecular Biology and Evolution (2010)

Alleles subject to strong, recent positive selection will be swept toward fixation together with contiguous sections of the genome. Whether the genomic signatures of such selection will be readily detectable in outbred wild populations is unclear. In this study, we employ haplotype diversity analysis to examine evidence for selective sweeps around knockdown resistance (kdr) mutations associated with resistance to dichlorodiphenyltrichloroethane and pyrethroid insecticides in the mosquito Anopheles gambiae. Both kdr mutations have significantly lower haplotype diversity than the wild-type (nonresistant) allele, with kdr L1014F showing the most pronounced footprint of selection. We complement these data with a time series of collections showing that the L1014F allele has increased in frequency from 0.05 to 0.54 in 5 years, consistent with a maximum likelihood-fitted selection coefficient of 0.16 and a dominance coefficient of 0.25. Our data show that strong, recent positive selective events, such as those caused by insecticide resistance, can be identified in wild insect populations.
Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation.
Authors: M Ots, H S Mackenzie, J L Troy, H G Rennke, B M Brenner
Journal: Journal of the American Society of Nephrology (1998)

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AT1RA) slow the rate of progression of experimental renal disease. Although the end result of both classes of drugs is to block the renin-angiotensin system (RAS), ACEI and AT1RA act at different sites in the RAS cascade. The aim of this study was to compare the effects of an ACEI (enalapril) and AT1RA (losartan), alone or in combination, in slowing the progression of experimental renal disease in a model of reduced renal mass. Two weeks after 5/6 renal ablation, rats were divided into five groups matched for body weight, systolic BP (SBP), and urinary protein excretion rate (UprotV). The effects on SBP and UprotV of treatment with 25 and 40 mg/L enalapril (groups I and II; both n = 7), 180 mg/L losartan (group III, n = 8), or a combination of enalapril (25 mg/L) + losartan (180 mg/L) (group IV, n = 9) versus vehicle (group V, n = 9) were studied for 12 wk. Remnant kidneys were then assessed histologically for evidence of focal and segmental glomerulosclerosis and hyalinosis (FSGS), and interstitial fibrosis. There were no significant differences (NSD) in body weight among the groups at any time. Combination therapy reduced SBP (122 +/- 8 mmHg) significantly at 12 wk to levels similar to losartan (127 +/- 3 mmHg) or enalapril (40 mg/L) alone (124 +/- 5 mmHg) (P < 0.05 versus vehicle controls). With equivalent antihypertensive effects, no differences in frequency of FSGS were discerned among the treatment groups (groups II through IV; F = 1.7, NSD). Tubulointerstitial injury scores followed a similar pattern. BP was highly correlated with the extent of FSGS, both among individual rats (r = 0.68, P = 0.05) and the group means (r = 0.99, P = 0.001). We conclude that the renoprotective effects of enalapril, losartan, or combination therapy are similar in this model over the 12 wk of the study, and are closely related to the magnitude of their antihypertensive effects.
Side Effects of Short-Term 10,000-Lux Light Therapy
Authors: A O Kogan, P M Guilford
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: Previous reports of side effects from light therapy were mostly based on administration of 2,500-lux treatments. It has become common practice to use brighter, 10,000-lux exposure when treating seasonal affective disorder. The authors studied side effects produced by short-term 10,000-lux light therapy. METHOD: Seventy subjects with seasonal affective disorder who underwent brief 10,000-lux light therapy were asked to report side effects. RESULTS: Of the 70 subjects, 32 (45.7%) experienced side effects, and nine (12.9%) reported two or more apiece. Headaches and eye or vision problems were the most common. Almost all were mild, were transient, and did not interfere with treatment. CONCLUSIONS: Short-term 10,000-lux light therapy often produces side effects early in treatment. These are not serious or prolonged, however, confirming findings from earlier studies that used dimmer light. (Am J Psychiatry 1998; 155:293–294)
British Thoracic Society national bronchiectasis audit 2010 and 2011: Figure 1
Authors: Adam T Hill, Sally Welham, Kerry Reid, C E Bucknall
Journal: Thorax (2012)

There have been two national British Thoracic Society (BTS) bronchiectasis audits from 1 October to 30 November in 2010 and 2011 in patients with non-cystic fibrosis attending secondary care. The first audit was soon after the publication of the BTS guidelines in July 2010 and both audits were based on the BTS guideline recommendations. We had 1460 and 2404 records in the 2 years respectively. The national audits highlight that the majority of guideline recommendations were not currently being adhered to and demonstrate the need for national quality standards, which are currently in preparation.