tbuckley/cabot-search huggingface dataset:
Identification of Essential Amino Acid Changes in Paired Domain Evolution Using a Novel Combination of Evolutionary Analysis and In Vitro and In Vivo Studies
Authors: Hongmin Sun, Srinivas Merugu, Xun Gu, Yuan Yuan Kang, Douglas P. Dickinson, Patrick Callaerts, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2002)

Pax genes are defined by the presence of a paired box that encodes a DNA-binding domain of 128 amino acids. They are involved in the development of the central nervous system, organogenesis, and oncogenesis. The known Pax genes are divided into five groups within two supergroups. By means of a novel combination of evolutionary analysis, in vitro binding assays and in vivo functional analyses, we have identified the key residues that determine the differing DNA-binding properties of the two supergroups and of the Pax-2, 5, 8 and Pax-6 subgroups within supergroup I. The differences in binding properties between the two supergroups are largely caused by amino acid changes at residues 20 and 121 of the paired domain. Although the paired domains of the Pax-2, 5, 8 and the Pax-6 group differ by >19 amino acids, their distinct DNA-binding properties are determined almost completely by a single amino acid change. Thus, a small number of amino acid changes can account in large part for the divergence in binding properties among the known paired domains. Our approach for selecting candidate sites responsible for the functional divergence between genes should also be useful for studying other gene families.
Drug Approval and Drug Effectiveness
Authors: Glen I. Spielmans, Irving Kirsch
Journal: Annual Review of Clinical Psychology (2013)

Data on the efficacy and safety of psychiatric medicines should form the foundation of evidence-based treatment practices. The US Food and Drug Administration (FDA) reviews such data in determining whether to approve new treatments, and the published literature serves as a repository for evidence on treatment benefits and harms. We describe the FDA review of clinical trials, examining the underlying logic and legal guidelines. Several FDA reviews provide evidence that the agency requires only minimal efficacy for psychiatric drugs. Further, in some instances, the FDA has relied on secondary rather than primary outcomes and has discounted the findings of negative studies in its review of antidepressant and antipsychotic medications. The published literature provides another lens into the safety and efficacy of treatments. We describe how treatment efficacy is systematically overstated and treatment-related harms are understated in the scientific literature. Suggestions are provided to improve public access to underlying safety and efficacy data and for the FDA to potentially improve its review process.
Audit on Myocardial Infarction in a District General Hospital: Is There Room for Improvement in Diagnostic Accuracy?
Authors: Wilson Wong, Adam Jones, Timothy J Goodwin
Journal: Journal of the Royal Society of Medicine (1994)

The proportion of patients with an acute myocardial infarction (MI) whose diagnosis was missed on admission was accessed. The admitting consultants were then tested to see if they could diagnose the patients correctly when they were shown the admission histories and electrocardiograms (ECGs). Twenty-six per cent of patients with a final diagnosis of MI were not correctly diagnosed on admission. Fifty-one per cent of all patients did not receive thrombolytic therapy (TT) mainly because the diagnosis was not made on admission. A smaller proportion of these patients were admitted to the coronary care unit (CCU). The consultants only correctly diagnosed an average of 7.3 of the 20 patients who were mis-diagnosed on admission and would have prescribed TT to an average of 4.3 of these 20 patients. A significant proportion of patients had a diagnosis of MI missed on admission and therefore did not receive TT. Therefore, another aid to diagnosis such as serum creatinine phosphokinase (CPK) measurement should be available as an emergency test.
Electron Microscopic Alterations at the Alveolar Level in Pulmonary Edema
Authors: THOMAS S. COTTRELL, O. ROBERT LEVINE, ROBERT M. SENIOR, JOSEPH WIENER, DAVID SPIRO, ALFRED P. FISHMAN
Journal: Circulation Research (1967)

The electron microscopic alterations of the alveolar septum in advanced hemodynamin and alloxan-induced pulmonary edema were compared. Pulmonary edema was produced in anesthetized dogs by means of increased lefy atrial pressure and hemodilution and by allocan administration. Sections of pulmonary tissue from these dogs and similarly anesthetized controls were processed for and examined by light and electron microscopy. In the hemodynamic form of edema the interstitial fluid collects only in the collagen-containing portions of the septum. The endothelium, epithelium, their respective basement membranes and large portions of the air-blood barrier are unaffected. Alloxaninduced edema, in contrast, is characterized by degeneration of both endothelium and epithelium and by the appearance of fibrin within the alveoli. The hemodynamic type of pulmonary edema appears to result from an accentuation of the normal process of fluid exchange within the lung. Allocan-induced edema, on the other hand, is a pathologic process. The functional implications of these results are discussed.
Antibiotic Rotation and Development of Gram-Negative Antibiotic Resistance
Authors: Harald J. van Loon, Menno R. Vriens, Ad C. Fluit, Annet Troelstra, Christiaan van der Werken, Jan Verhoef, Marc J. M. Bonten
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

To attain a better understanding of antibiotic cycling and its effects on the epidemiology of antibiotic resistance in gram-negative microorganisms, two different antibiotic classes (quinolone and beta-lactam) were cycled during four 4-month periods in a surgical intensive care unit. Respiratory aspirates and rectal swabs were obtained and DNA fingerprinting was performed. Primary endpoint of the study was the acquisition rate with gram-negative bacteria resistant to the antibiotic of choice during each cycle. Secondary endpoints were changes in endemic prevalence of resistant bacteria and the relative importance of cross-transmission. In all, 388 patients were included and 2,520 cultures analyzed. Adherence to antibiotic protocol was 96%. Overall antibiotic use increased with 24%. Acquisition rates with resistant bacteria were highest during levofloxacin exposure (relative risk [RR] 3.2; 95% confidence interval [CI]: 1.4-7.1) and piperacillin/tazobactam exposure (RR 2.4; 95% CI 1.2-4.8). The relative importance of cross-transmission decreased during the study. For individual patients, treatment with levofloxacin was the only independent risk factor for acquisition of levofloxacin-resistant bacteria (hazard ratio 12.6; 95% CI 3.8-41.6). Potential for selection of antibiotic-resistant gram-negative bacteria during periods of homogeneous exposure increased from cefpirome to piperacillin/tazobactam to levofloxacin. Cycling of homogeneous antibiotic exposure is unlikely to control the emergence of gram-negative antimicrobial resistance in intensive care units.
Effect of Concomitant CYP2D6 Inhibitor Use and Tamoxifen Adherence on Breast Cancer Recurrence in Early-Stage Breast Cancer
Authors: Vincent O. Dezentjé, Nico J.C. van Blijderveen, Hans Gelderblom, Hein Putter, Myrthe P.P. van Herk-Sukel, Mariel K. Casparie, Antoine C.G. Egberts, Johan W.R. Nortier, Henk-Jan Guchelaar
Journal: Journal of Clinical Oncology (2010)

The use of cytochrome P450 2D6-inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer. The objectives of this study were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time (EFT).Data were from PHARMO and included a community pharmacy dispensing database; PALGA, a nationwide pathology database; and the Dutch Medical Register in the Netherlands. Patients with breast cancer treated with adjuvant tamoxifen between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for concomitant CYP2D6 inhibitor exposure was used. Adherence calculated over the first year after tamoxifen initiation was related to breast cancer events in the following period.In total, 1,962 patients with breast cancer using tamoxifen were included, among whom 150 (7.6%) frequently used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed (adjusted hazard ratio [HR], 0.87; 95% CI, 0.42 to 1.79; P = .69). Poor tamoxifen adherence was associated with lower EFT (adjusted HR, 0.987; 95% CI, 0.975 to 0.999; P = .029).This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen despite the strong biologic rationale. This study shows, to the best of our knowledge for the first time, that poor tamoxifen adherence is associated with an increased risk of breast cancer events.
Advanced Seminoma: The Role of Chemotherapy and Adjunctive Surgery
Authors: ROBERT J. MOTZER
Journal: Annals of Internal Medicine (1988)

Study Objective: To determine the effectiveness of chemotherapy and adjunctive surgery in managing patients with advanced seminoma. Design: Nonrandomized prospective clinical trial of chemotherapy in a cohort of patients with advanced seminoma. Setting: Referral cancer hospital. Patients: Consecutive sample of 62 patients with primary extragonadal, stage IIC (> 5-cm retroperitoneal adenopathy) and stage III seminoma; 45 patients were previously untreated, 13 had received radiotherapy, and 4 had previously received radiotherapy and chemotherapy. Intervention: Cisplatin-based chemotherapy (100 to 120 mg/m2 body surface area per cycle of treatment); 45 patients received vinblastine, bleomycin, cisplatin, dactinomycin, and cyclophosphamide; 15, etoposide and cisplatin; and 2, both regimens. Measurements and Main Results: Fifty-three of the sixty (88%) evaluable patients achieved a complete remission, and only 6 patients had relapses. Fifty-three of the sixty-two patients (85%) remain alive and disease-free. The regimen of etoposide and cisplatin was equivalent to regimens using more drugs. An elevated level of human chorionic gonadotropin at the initiation of treatment was associated with a worse prognosis. Conclusions: Cisplatin-based chemotherapy is effective treatment for patients with extragonadal, stage IIC, and stage III seminoma and should be considered as initial therapy.
Sonication of Removed Hip and Knee Prostheses for Diagnosis of Infection
Authors: Andrej Trampuz, Kerryl E. Piper, Melissa J. Jacobson, Arlen D. Hanssen, Krishnan K. Unni, Douglas R. Osmon, Jayawant N. Mandrekar, Franklin R. Cockerill, James M. Steckelberg, James F. Greenleaf, Robin Patel
Journal: New England Journal of Medicine (2007)

Culturing of samples of periprosthetic tissue is the standard method used for the microbiologic diagnosis of prosthetic-joint infection, but this method is neither sensitive nor specific. In prosthetic-joint infection, microorganisms are typically present in a biofilm on the surface of the prosthesis. We hypothesized that culturing of samples obtained from the prosthesis would improve the microbiologic diagnosis of prosthetic-joint infection.
Irritant susceptibility and weal and flare reactions to bioactive agents in atopic dermatitis. I. Influence of disease severity
Authors: R.A. TUPKER, P.J. COENRAADS, V. FIDLER, M.C.J.M. JONG, J.B. MEER, J.G.R. MONCHY
Journal: British Journal of Dermatology (1995)

The two main pathogenetic characteristics of atopic dermatitis (AD) are: (i) antigen-dependent 'specific' reactivity, and (ii) altered non-immunological 'non-specific' reactivity. Our understanding of the role of non-specific reactivity is hampered by the fact that methods available for its quantification are limited. The aim of the present study was to assess the usefulness of two parameters as quantitative measures of non-specific skin reactivity in AD: (i) susceptibility to repeated epicutaneous exposure to an irritant (sodium lauryl sulphate, SLS), assessed by visual scoring and transepidermal water loss (TEWL) measurement, and (ii) reactivity to intracutaneously injected bioactive agents (codeine, FMLP, histamine, methacholine, substance P, trypsin), assessed by measurement of weal and flare size. These two parameters were tested in a group of AD patients, subdivided according to the severity of their dermatitis, and a control group. The visual score and TEWL after SLS exposure tended to be higher in the AD group than in the control group. Furthermore, visual score and post-exposure TEWL were positively correlated with the dermatitis severity score. Weal size following injection of codeine, histamine and substance P, and flare size following injection of all agents, except methacholine, were significantly lower in the AD group than in the control group. Negative correlations were found between weal and flare sizes and the dermatitis severity score. These findings can be explained by down-regulation of structures involved in weal and flare reactions. In conclusion, we propose that epicutaneous irritant susceptibility and reactivity to intracutaneous bioactive agents may be useful indicators of non-specific skin reactivity in AD.
Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review
Authors: D. Chambers, A.-M. Bagnall, S. Hempel, C. Forbes
Journal: Journal of the Royal Society of Medicine (2006)

Objectives To determine whether any particular intervention or combination of interventions is effective in the treatment, management and rehabilitation of adults and children with a diagnosis of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).Design Substantive update of a systematic review published in 2002.Randomized (RCTs) and non-randomized controlled trials of any intervention or combination of interventions were eligible for inclusion.Study participants could be adults or children with a diagnosis of CFS/ME based on any criteria.We searched eleven electronic databases, reference lists of articles and reviews, and textbooks on CFS/ME.Additional references were sought by contact with experts.Results Seventy studies met the inclusion criteria.Studies on behavioural, immunological, pharmacological and complementary therapies, nutritional supplements and miscellaneous other interventions were identified.Graded exercise therapy and cognitive behaviour therapy appeared to reduce symptoms and improve function based on evidence from RCTs.For most other interventions, evidence of effectiveness was inconclusive and some interventions were associated with significant adverse effects.Conclusions Over the last five years, there has been a marked increase in the size and quality of the evidence base on interventions for CFS/ME.Some behavioural interventions have shown promising results in reducing the symptoms of CFS/ME and improving physical functioning.There is a need for research to define the characteristics of patients who would benefit from specific interventions and to develop clinically relevant objective outcome measures.
A Peptide-binding Motif for I-Ag7, the Class II Major Histocompatibility Complex (MHC) Molecule of NOD and Biozzi AB/H Mice
Authors: Leonard C. Harrison, Margo C. Honeyman, Sylvie Trembleau, Silvia Gregori, Fabio Gallazzi, Petra Augstein, Vladimir Brusic, Juergen Hammer, Luciano Adorini
Journal: The Journal of Experimental Medicine (1997)

The class II major histocompatibility complex molecule I-Ag7 is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its β chain. To identify the requirements for peptide binding to I-Ag7 and thereby potentially pathogenic T cell epitopes, we analyzed a known I-Ag7-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9–27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-Ag7 M12-Y20/ K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-Ag7 deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-Ag7–restricted T cell epitopes or eluted from I-Ag7. Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.
Suppression of p21Rac Signaling and Increased Innate Immunity Mediate Remission in Crohn’s Disease
Authors: Kaushal Parikh, Lu Zhou, Rajesh Somasundaram, Gwenny M. Fuhler, J. Jasper Deuring, Tjasso Blokzijl, Anouk Regeling, Ernst J. Kuipers, Rinse K. Weersma, Veerle J. Nuij, Maria Alves, Lauran Vogelaar, Lydia Visser, Colin de Haar, Kausilia K. Krishnadath, C. Janneke van der Woude, Gerard Dijkstra, Klaas Nico Faber, Maikel P. Peppelenbosch
Journal: Science Translational Medicine (2014)

Overactivation of p21Rac1 is a rate-limiting step for innate immune function in Crohn’s disease and prevents remission.
The Inhibitor of Cyclin-Dependent Kinase 4a/Alternative Reading Frame (<b> <i>INK4a/ARF</i> </b>) Locus Encoded Proteins p16INK4a and p19ARF Repress Cyclin D1 Transcription through Distinct <b> <i>cis</i> </b> Elements
Authors: Mark D’Amico, Kongming Wu, Maofu Fu, Mahadev Rao, Chris Albanese, Robert G. Russell, Hanzhou Lian, David Bregman, Michael A. White, Richard G. Pestell
Journal: Cancer Research (2004)

Abstract The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16INK4a and p14ARF (murine p19ARF). Invariant inactivation of either the p16INK4a-cyclin D/CDK-pRb pathway and/or p53-p14ARF pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16INK4a/pRb pathway. Targeted overexpression of cyclin D1 to the mammary gland is sufficient for tumorigenesis, and cyclin D1−/− mice are resistant to Ras-induced mammary tumors. Recent studies suggest cyclin D1 and p16INK4a expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16INK4a was observed in tissues of mice mutant for the Ink4a/Arf locus. p16INK4a and p19ARF inhibited DNA synthesis in MCF7 cells. p16INK4a repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16INK4a occurred independently of the p16INK4a-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19ARF repressed cyclin D1 through a novel distal cis-element at −1137, which bound p53 in chromatin-immunoprecipitation assays. Transcriptional repression of the cyclin D1 gene through distinct DNA sequences may contribute to the tumor suppressor function of the Ink4a/Arf locus.
Nitric Oxide and Mechanisms of Redox Signaling
Authors: Josef Pfeilschifter, Wolfgang Eberhardt, Andrea Huwiler
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Regulation of signal transduction and gene expression is a multifaceted process involving ligands, receptors, and second messengers that trigger cascades of protein kinases and phosphatases and propagate the signal to the nucleus to alter gene expression. Reduction-oxidation (redox)-based regulatory pathways provide additional means of gating signal transduction, and redox-based regulation of gene expression emerges as a fundamental regulatory mechanism in living cells. The cellular redox state is reflected by the degree of oxidation (or reduction) of various redox-active molecules at a specific cellular location at any given time point. The ratio of oxidized/reduced redox species determines the redox potential, which may vary dramatically in time and in different compartments of a cell and consequently alter in a temporally and spatially dynamic process the activity of signaling enzymes that carry redox-active functional groups. Generation and action of free radicals such as nitric oxide, superoxide, and H2O2 that paradigmatically highlight the impact of redox regulation on cellular signal transduction and gene expression are discussed with a special focus on the renal glomerular response to injury. E-mail: [email protected]
Up-regulation of EGFR gene family in COPD patients: Correlation with airway obstruction
Authors: Eirini Neofytou, Aristotelis Anagnostis, Nikolaos Soulitzis, Dimitris Kampas, Ioannis Tzortzakis, Despoina Dermitzaki, Eleni Tzortzaki, Nikolaos Siafakas
Journal: European Respiratory Journal (2013)

Background : Growth factors receptors mediate a variety of cellular responses to the environment. Specifically, exposure of lung epithelium to oxidative stress induced by cigarette smoke stimulates aberrant Epidermal Growth Factor Receptor (ERBB) family activation.

Aim : As a part of a genome-wide microarray screening analysis, this study’s objective was to evaluate the expression of ERBB1-4 receptors in smokers with or without COPD.

Methods : Lung tissue samples from selected patients were subjected to microarray analysis, and confirmed by Quantitative Real-Time PCR in 45 male subjects: A ) 20 COPD patients (GOLD stage II), B) 15 non-COPD smokers and C ) 10 non-smokers.

Results : Microarray data analysis revealed that ERBB receptors were elevated, from 1.62-fold to 2.45-fold, in COPD patients compared to non-COPD smokers (p<0.01). Real-Time qPCR verified that COPD patients had higher ERBB1-3 expression levels compared to non-COPD smokers ( PERBB1 <0.001; PERBB2 =0.003; PERBB3 =0.003) and non-smokers ( PERBB1 =0.019; PERBB2 =0.005; PERBB3 =0.011). On the other hand, ERBB4 mRNA levels gradually increased from non-smokers (0.74±0.19) to non-COPD smokers (1.11±0.05) to COPD patients (1.57±0.28), and were correlated with the degree of airflow obstruction ( P FEV1<0.001).

Conclusions : These data suggest that ERBB1-3 overexpression is possibly related to COPD pathogenesis and not to smoking exposure, while the gradual increase of ERBB4 expression could indicate a direct link between ERBB4 and disease severity.