tbuckley/cabot-search huggingface dataset:
Dose-limiting effects of neutropenic events in six European audits of adjuvant breast cancer chemotherapy
Authors: T. D. Szucs, R. Leonard, R. Pettengell, R. Paridaens, C. Jackisch, M. Constenla, A. Bosly, M. Schwenkglenks
Journal: Journal of Clinical Oncology (2004)

619 Background: Retrospective audits of adjuvant breast cancer chemotherapy (CT) were performed in several European countries. Results of a combined analysis of six audits from Austria, Belgium, Germany, Spain and the UK are reported. Methods: Variables available in all six datasets were merged into a dataset of individual observations and their definitions were harmonised. We assessed the incidence of neutropenic events (NE) and of low average relative CT dose intensity (ARDI). Adjusted odds ratios (ORs) of low ARDI occurrence were calculated by robust multiple logistic regression. NE were defined as neutropenia-related hospitalisation, dose reduction ≥ 15%, and/or dose delay ≥ 7 days. Low ARDI was defined as ARDI ≤ 85%. Results: A total of 2633 patients had a mean age at diagnosis ± SD of 51.0 ± 11.3 years (inter-audit range (IAR): 48.0 ± 10.9 to 52.5 ± 11.7 years). Patients were post-menopausal in 51% of cases and 64% were hormone receptor positive. The diagnostic spread was stage I 19%, II 65%, III 16%. Fifty-eight percent received CMF-based regimens, 39% anthracycline-containing, and 3% other regimens. Concomitant radiotherapy was reported in 32%, and use of colony-stimulating factors (CSF) in 12%. In 3%, CSF use started in cycle 1. NE were observed in 20% of patients (IAR: 14–27%). Repeated NE were seen in 8% (IAR 6–11%). Low ARDI was observed in 14%. In those without and with NE low ARDI was observed in 9% vs 34% (p < 0.005). Low ARDI was independently associated with NE occurrence (OR 4.9, 95% CI 3.6–6.7); use of a non-anthracycline regimen (OR 1.5, CI 1.1–1.9); concomitant radiotherapy (OR 1.3, CI 1.1–1.5); and disease stage. ORs for stages II and III, compared to stage I, were 1.5 (CI 1.2–2.0) and 1.6 (CI 1.2–2.3). A more restrictive NE definition based on the cell count data available lead to an OR of 2.6 (CI 1.7–3.7) for low ARDI, with the other coefficients stable. Conclusions: NE occurred in a relevant proportion of patients receiving breast cancer CT and showed a robust association with low ARDI, which may affect treatment outcomes. Ongoing prospective research should address the development of risk models to target preventive measures and optimise CT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration INC-EU Study Group: Research Grant from Amgen EU
Birefringent Property of Hypercholesterolemic Rabbit Serum
Authors: SILAS M. EVANS, KENNETH D. BROWN, HARRY K. IHRIG
Journal: Circulation Research (1957)

Serum of hypercholesterolemic rabbits, when pulsated for 72 hours at pressures of 300 mm. Hg/0 mm. Hg with a pulse rate of 80 produced a birefringent deposit in excised pieces of rabbit aortae. Serum from normal rabbits did not produce this deposit. The active component or components responsible for this deposit are in the β-lipoprotein fraction of serum. The birefringent material is detectable in serum by this method before lipoid degeneration of the arterial intima becomes apparent in the sacrificed animal.
Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue
Authors: Anna Aakula, Pekka Kohonen, Suvi-Katri Leivonen, Rami Mäkelä, Petteri Hintsanen, John Patrick Mpindi, Elena Martens-Uzunova, Tero Aittokallio, Guido Jenster, Merja Perälä, Olli Kallioniemi, Päivi Östling
Journal: European Urology (2015)
Chemotherapy Drug Shortages in the United States: Genesis and Potential Solutions
Authors: Michael P. Link, Karen Hagerty, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2012)

In October 2011, the US Food and Drug Administration (FDA) announced the end of the cytarabine shortage. Cytarabine is the key chemotherapy drug for the management of leukemia in children and adults, particularly acute myeloid leukemia, and the announcement by the FDA of an end to this 11-month crisis was good news. However, in July 2011, we started experiencing shortages of daunorubicin, another drug critical to the management of leukemia and the second most important drug used to treat acute myeloid leukemia. The daunorubicin shortage has been mitigated somewhat by the fact that it can be replaced with other anthracylines, albeit with different toxicity profiles. However, daunorubicin is an essential component of clinical trial protocols for leukemia in the United States, and its shortage has created serious challenges in conducting leukemia research.
Multicenter study on the treatment of chronic NANB hepatitis with recombinant human interferon alfa-2b
Authors: M Piazza, V Guadagnino, L Picciotto, G Borgia, R Orlando, N Abrescia, R Ciampi, F Cangiano, G Tosone, M D'Abbraccio, MF Faravelli
Journal: Journal of Hepatology (1990)
Adipocytokines and Insulin Resistance
Authors: Eduardo Esteve, Wifredo Ricart, José Manuel Fernández-Real
Journal: Diabetes Care (2009)

It is well known that adipocytes and resident macrophages that have migrated to adipose tissue produce and secrete a variety of biologically active mediators (adipocytokines), which are thought to contribute to the development of insulin resistance, type 2 diabetes, and cardiovascular disease (1).

The abnormal function of adipocytes may play an important role in the development of a chronic low-grade proinflammatory state associated with obesity (2). For example, adipocyte hypertrophy appears to lead to an imbalance between pro- and anti-inflammatory adipokines. The secretion of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and granulocyte colony–stimulating factor have been positively correlated with adipocyte size.

Adipose tissue is an important inflammatory source in obesity and type 2 diabetes, not only because of cytokines produced from the adipocyte itself, but also because of infiltration by proinflammatory macrophages (3). Not only do adipocytes, but also adipose tissue macrophage numbers, increase with obesity and participate in inflammatory pathways of obese individuals. Macrophages from adipose tissue are responsible for almost all adipose tissue tumor necrosis factor (TNF)-α and significant amounts of IL-6 production. Macrophages migrating to adipose tissue in response to high-fat feeding overexpress proinflammatory cytokines.

Different cytokines synthesized by adipocytes or by macrophages from adipose tissue may induce insulin resistance, such as IL-6, TNF-α, leptin, resistin, adiponectin, retinol binding protein-4 (RBP4), or lipocalin-2 (LCN2). This review focuses on the latter adipocytokines, hinting at their role in obesity-associated insulin resistance.

LCN2 (or neutrophil gelatinase-associated lipocalin) is a recently identified adipokine that belongs to the superfamily of lipocalins (such as RBP4), which seems to affect glucose metabolism and insulin sensitivity (4). LCN2 protein has been implicated in diverse actions, such as apoptosis and innate immunity, and is expressed in several tissues, including neutrophils, liver, kidney, adipocytes, and macrophages (5).

Lipocalins comprise a class of proteins that are …
MRSA as a cause of lung infection including airway infection, community-acquired pneumonia and hospital-acquired pneumonia
Authors: S. Defres, C. Marwick, D. Nathwani
Journal: European Respiratory Journal (2009)

Staphylococcus aureus has been recognised as a cause of community-acquired pneumonia, albeit uncommon, and an important cause of healthcare-associated (HA) pneumonia, including ventilator-associated pneumonia. Resistance of S. aureus to methicillin developed shortly after its introduction into clinical practice. Since then, methicillin-resistant S. aureus (MRSA) has predominantly been a feature of hospital-acquired, or latterly HA, infections as the boundaries became more blurred between the community and hospital environments. However, more recently true community-acquired (CA)-MRSA infections have been detected and are becoming increasingly common, especially in the USA. Europe has not been immune to the development of MRSA in healthcare settings and although the prevalence of CA-MRSA is currently relatively low, there is the risk of wider spread. These new CA-MRSA strains appear to behave differently to HA-MRSA strains. Although predominantly causing skin and soft tissue infections, mainly as boils and abscesses requiring drainage, life threatening invasive infections including necrotising pneumonia can also occur. This article summarises the pathogenesis and clinical presentations of MRSA-related lung infections.
Actin cytoskeleton dynamics linked to synovial fibroblast activation as a novel pathogenic principle in TNF-driven arthritis
Authors: Y Vasilopoulos, V Gkretsi, M Armaka, V Aidinis, G Kollias
Journal: Annals of the Rheumatic Diseases (2007)

Rheumatoid arthritis is a chronic inflammatory disorder whose origin of defect has been the subject of extensive research during the past few decades. While a number of immune and non-immune cell types participate in the development of chronic destructive inflammation in the arthritic joint, synovial fibroblasts have emerged as key effector cells capable of modulating both joint destruction and propagation of inflammation. Ample evidence of aberrant changes in the morphology and biochemical behaviour of rheumatoid arthritis synovial fibroblasts have established the tissue evading and "transformed" character of this cell type. We have recently demonstrated that actin cytoskeletal rearrangements determine the pathogenic activation of synovial fibroblasts in modelled TNF-mediated arthritis, a finding correlating with similar gene expression changes which we observed in human rheumatoid arthritis synovial fibroblasts. Here, we show that pharmacological inhibition of actin cytoskeleton dynamics alters potential pathogenic properties of the arthritogenic synovial fibroblast, such as proliferation, migration and resistance to apoptosis, indicating novel opportunities for therapeutic intervention in arthritis. Recent advances in this field of research are reviewed and discussed.
“Good Enough Solutions” and the Genetics of Complex Diseases
Authors: James N. Weiss, Alain Karma, W. Robb MacLellan, Mario Deng, Christoph D. Rau, Colin M. Rees, Jessica Wang, Nicholas Wisniewski, Eleazar Eskin, Steve Horvath, Zhilin Qu, Yibin Wang, Aldons J. Lusis
Journal: Circulation Research (2012)

In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks. Coexpression analysis typically groups 20 000 genes into 20 to 30 modules containing tens to hundreds of genes, whose aggregate behavior can be represented by the module's “eigengene.” The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of single nucleotide polymorphisms. The goal of the GMAS approach is to identify groups of coregulated genes that explain complex traits from a systems perspective. From an evolutionary standpoint, we hypothesize that variability in eigengene patterns reflects the “good enough solution” concept, that biological systems are sufficiently complex so that many possible combinations of the same elements (in this case eigengenes) can produce an equivalent output, that is, a “good enough solution” to accomplish normal biological functions. However, when faced with environmental stresses, some “good enough solutions” adapt better than others, explaining individual variability to disease and drug susceptibility. If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations.
Long-term prospective pilot study with tranilast for the prevention of stricture progression in patients with Crohn's disease
Authors: N. Oshitani, H. Yamagami, K. Watanabe, K. Higuchi, T. Arakawa
Journal: Gut (2007)

Fibrosis and strictures are common and irreversible complications of Crohn’s disease that potentially necessitate bowel resection. Tranilast, N-(3’,4’-dimethoxycinnamoyl) anthranilic acid, inhibits keloid scar formation through the inhibition of production of metalloproteinases and tissue inhibitor of metalloproteinase-1 from neutrophils.1 Please check the phrase “inhibition of … neutrophils” is OK Tranilast has been shown to inhibit fibrosis in various experimental models.2–4 Randomised, double-blind, placebo-controlled studies have shown substantial inhibition by tranilast of restenosis of coronary arteries.5–7 A case report has demonstrated the efficacy of long-term administration of tranilast in inflammatory endobronchial stenosis.8

Between June 2001 and July 2005, 24 patients with quiescent Crohn’s disease with non-symptomatic intestinal strictures were recruited. Baseline intestinal stricture was evaluated by small bowel barium enteroclysis, or …
Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Marina Cerrone, Sami F. Noujaim, Elena G. Tolkacheva, Arkadzi Talkachou, Ryan O’Connell, Omer Berenfeld, Justus Anumonwo, Sandeep V. Pandit, Karen Vikstrom, Carlo Napolitano, Silvia G. Priori, José Jalife
Journal: Circulation Research (2007)

Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca 2+ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol’s solution, and patch clamping in a knockin (RyR2/RyR2 R4496C ) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 R4496C and in 9% of 11 wild-type ( P =0.03) littermates perfused with Ca 2+ and isoproterenol; 66% of 12 RyR2/RyR2 R4496C and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias ( P =0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His–Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol’s solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2 R4496C mice. Under current clamp, single Purkinje cells from RyR2/RyR2 R4496C mouse hearts generated delayed afterdepolarization–induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His–Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
Protein and Amino Acid Metabolism in the Human Newborn
Authors: Satish C. Kalhan, Dennis M. Bier
Journal: Annual Review of Nutrition (2008)

Birth and adaptation to extrauterine life involve major shifts in the protein and energy metabolism of the human newborn. These include a shift from a state of continuous supply of nutrients including amino acids from the mother to cyclic periodic oral intake, a change in the redox state of organs, thermogenesis, and a significant change in the mobilization and use of oxidative substrates. The development of safe, stable isotopic tracer methods has allowed the study of protein and amino acid metabolism not only in the healthy newborn but also in those born prematurely and of low birth weight. These studies have identified the unique and quantitative aspects of amino acid/protein metabolism in the neonate, thus contributing to rational nutritional care of these babies. The present review summarizes the contemporary data on some of the significant developments in essential and dispensable amino acids and their relationship to overall protein metabolism. Specifically, the recent data of kinetics of leucine, phenylalanine, glutamine, sulfur amino acid, and threonine and their relation to whole-body protein turnover are presented. Finally, the physiological rationale and the impact of nutrient (amino acids) interventions on the dynamics of protein metabolism are discussed.
An Official American Thoracic Society Statement: The Importance of Healthy Sleep. Recommendations and Future Priorities
Authors: Sutapa Mukherjee, Sanjay R. Patel, Stefanos N. Kales, Najib T. Ayas, Kingman P. Strohl, David Gozal, Atul Malhotra
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Section:ChooseTop of pageAbstract <<ContentsOverviewIntroductionMethodsHow Much Sleep Is Enough ...Sleep in ChildrenShort Sleep DurationLong Sleep DurationDrowsy DrivingSleep and OccupationSleep DisordersFuture Directions: Resear...ConclusionsReferencesCITING ARTICLES
Dynamic diversity of the tryptophan pathway in chlamydiae: reductive evolution and a novel operon for tryptophan recapture
Authors: Gary Xie, Carol A Bonner, Roy A Jensen
Journal: Genome biology (2002)

Complete genomic sequences of closely related organisms, such as the chlamydiae, afford the opportunity to assess significant strain differences against a background of many shared characteristics. The chlamydiae are ubiquitous intracellular parasites that are important pathogens of humans and other organisms. Tryptophan limitation caused by production of interferon-γ by the host and subsequent induction of indoleamine dioxygenase is a key aspect of the host-parasite interaction. It appears that the chlamydiae have learned to recognize tryptophan depletion as a signal for developmental remodeling. The consequent non-cultivable state of persistence can be increasingly equated to chronic disease conditions. The genes encoding enzymes of tryptophan biosynthesis were the focal point of this study. Chlamydophila psittaci was found to possess a compact operon containing PRPP synthase, kynureninase, and genes encoding all but the first step of tryptophan biosynthesis. All but one of the genes exhibited translational coupling. Other chlamydiae (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae) lack genes encoding PRPP synthase, kynureninase, and either lack tryptophan-pathway genes altogether or exhibit various stages of reductive loss. The origin of the genes comprising the trp operon does not seem to have been from lateral gene transfer. The factors that accommodate the transition of different chlamydial species to the persistent (chronic) state of pathogenesis include marked differences in strategies deployed to obtain tryptophan from host resources. C. psittaci appears to have a novel mechanism for intercepting an early intermediate of tryptophan catabolism and recycling it back to tryptophan. In effect, a host-parasite metabolic mosaic has evolved for tryptophan recycling.
Comparisons of Men With Full or Partial Eating Disorders, Men Without Eating Disorders, and Women With Eating Disorders in the Community
Authors: D. Blake Woodside, Paul E. Garfinkel, Elizabeth Lin, Paula Goering, Allan S. Kaplan, David S. Goldbloom, Sidney H. Kennedy
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors compared 62 men who met all or most of the DSM-III-R criteria for eating disorders with 212 women who had similar eating disorders and 3,769 men who had no eating disorders on a wide variety of clinical and historical variables. METHOD: The groups of subjects were derived from a community epidemiologic survey performed in the province of Ontario that used the World Health Organization's Composite International Diagnostic Interview. RESULTS: Men with eating disorders were very similar to women with eating disorders on most variables. Men with eating disorders showed higher rates of psychiatric comorbidity and more psychosocial morbidity than men without eating disorders. CONCLUSIONS: These results confirm the clinical similarities between men with eating disorders and women with eating disorders. They also reveal that both groups suffer similar psychosocial morbidity. Men with eating disorders show a wide range of differences from men without eating disorders; the extent to which these differences are effects of the illness or possible risk factors for the occurrence of these illnesses in men is not clear.
Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature
Authors: Alexander C. Tsai, Nicholas Z. Rosenlicht, Jon N. Jureidini, Peter I. Parry, Glen I. Spielmans, David Healy
Journal: PLoS Medicine (2011)

Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin
Authors: Ana B. Herrero, Cristina Martín-Castellanos, Esther Marco, Federico Gago, Sergio Moreno
Journal: Cancer Research (2006)

Abstract Trabectedin (Yondelis) is a potent antitumor drug that has the unique characteristic of killing cells by poisoning the DNA nucleotide excision repair (NER) machinery. The basis for the NER-dependent toxicity has not yet been elucidated but it has been proposed as the major determinant for the drug's cytotoxicity. To study the in vivo mode of action of trabectedin and to explore the role of NER in its cytotoxicity, we used the fission yeast Schizosaccharomyces pombe as a model system. Treatment of S. pombe wild-type cells with trabectedin led to cell cycle delay and activation of the DNA damage checkpoint, indicating that the drug causes DNA damage in vivo. DNA damage induced by the drug is mostly caused by the NER protein, Rad13 (the fission yeast orthologue to human XPG), and is mainly repaired by homologous recombination. By constructing different rad13 mutants, we show that the DNA damage induced by trabectedin depends on a 46–amino acid region of Rad13 that is homologous to a DNA-binding region of human nuclease FEN-1. More specifically, an arginine residue in Rad13 (Arg961), conserved in FEN1 (Arg314), was found to be crucial for the drug's cytotoxicity. These results lead us to propose a model for the action of trabectedin in eukaryotic cells in which the formation of a Rad13/DNA-trabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)