tbuckley/cabot-search huggingface dataset:
Abstract A38: Optimization of whole-genome amplification for analysis of single cells using next-generation sequencing
Authors: Terry J. Amiss, Frances Tong, Eileen Snowden, Richard Kelly, Rainer Blaesius, Nick Herrmann, Friedrich Hahn, Warren Porter, Mitchell Ferguson, Chen Chang, Daphne Clancy, Stewart Jurgensen
Journal: Clinical Cancer Research (2015)

Abstract The accurate analysis of both genotypic variation in tumors and tumor evolution due to selective pressure is important in determining treatment options in the clinic. Next generation sequencing (NGS) of single cells from solid tumors and circulating tumor cells has the potential to dramatically increase the amount of genotypic detail obtained from these samples. For the analysis of single cells the challenge is to employ whole genome amplification (WGA) to obtain enough DNA for analysis while minimizing amplification bias and maintaining copy accuracy. We are developing tools for single cell sequencing to improve these parameters while also increasing sample throughput. Initially, three commercially available WGA methods were tested on 5-10 genome quantities of HCT-15 genomic DNA. Using the Ion Torrent AmpliSeq Cancer Hotspot Panel, the amplification accuracy, amplicon coverage and DNA yield were determined. When compared to controls significant differences were observed in the three WGA methods ability to accurately amplify DNA. The most accurate kit produced a specificity and sensitivity of 98.5% and 100% respectively. This protocol also produced a substantial DNA yield of 25 µgs and although, the average amplicon coverage indicated some bias, greater than 99% of the amplicons had at least 100-fold coverage. This WGA kit was then tested on single cells from a human breast cancer; an ER/PR/Her2 negative spindle cell metaplastic carcinoma. To obtain single cells the tumor was grown in a PDX mouse model and index sorted using a BD FACSAria II flow cytometer. The WGA produced an average DNA yield of 2.7± 0.8 µg, with 100-fold amplicon coverage of 92±7%. For the variants identified, the amplification bias differed by as much as 3,000 reads/variant. We are now taking steps to improve WGA of single cells and will report on these efforts in detail. To date when monitoring variant allele frequency and coverage depth in the triple negative tumor, KRAS and MET mutations were identified in single cells, as well as in the bulk sample. Interestingly, a TP53 mutation was identified only in single cells. This data supports the utility of WGA and single cell analysis to identify mutations, some having clinically relevant role for targeted therapy. Citation Format: Terry J. Amiss, Frances Tong, Eileen Snowden, Richard Kelly, Rainer Blaesius, Nick Herrmann, Friedrich Hahn, Warren Porter, Mitchell Ferguson, Chen Chang, Daphne Clancy, Stewart Jurgensen. Optimization of whole-genome amplification for analysis of single cells using next-generation sequencing. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A38.
Managing atrial fibrillation in elderly people
Authors: T. Lancaster, J. Mayet, B. Wasan, P. Kanagaratnam, K M English, K S Channer
Journal: BMJ (1999)

Editor—Factual errors require correction in English and Channer’s editorial on managing atrial fibrillation in elderly patients.1 The authors state that the Boston area anticoagulation trial for atrial fibrillation and the stroke prevention in atrial fibrillation III (SPAF III) trial showed that anticoagulation to an international normalised ratio of 1.5-3.0 is safe and effective, referencing a 1994 review article to support this statement. The SPAF III trial was not published until 1996,2 so the reference is presumably to the SPAF II trial.3

The target for anticoagulation in the Boston area anticoagulation trial for atrial fibrillation was a prothrombin time ratio of 1.2-1.5 (corresponding roughly to an international normalised ratio of 2.0-3.0),4 whereas in the SPAF II trial it was a prothrombin time ratio of 1.3-1.8 (roughly an international normalised ratio of 2.0-4.5). The SPAF III trial showed that in high risk patients fixed dose warfarin (initial international normalised ratio 1.2-1.5) plus aspirin was less effective than adjusted dose warfarin (international normalised ratio 2.0- 3.0). A subsequent trial of fixed dose warfarin was stopped early in the light of the results of the SPAF III trial. At stopping, there was a trend favouring adjusted dose warfarin.5

In patients with atrial fibrillation treated with warfarin, current evidence suggests that the best ratio of benefit to risk is achieved when the target international normalised ratio is 2.0-3.0.
Original article: Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines
Authors: P. J. Bousquet, C. Combescure, F. Neukirch, J. M. Klossek, H. Méchin, J.‐P. Daures, J. Bousquet
Journal: Allergy (2007)

Background: The allergic rhinitis and its impact on asthma (ARIA) guidelines provide a new classification of allergic rhinitis, but a quantitative analysis for severity assessment is lacking. Objective: To study whether a visual analog scale (VAS) for global rhinitis symptoms could be used to assess the disease severity according to ARIA. Methods: Three thousand fifty‐two allergic rhinitis patients seen in primary care were tested. Fifty three per cent had an objective diagnosis of allergy and 58% of the patients were treated. Patients were categorized according to ARIA guidelines. The severity of nasal symptoms was assessed using a VAS. Quality of life was measured using the rhinoconjunctivitis quality of life questionnaire (RQLQ). Results: Severity had more impact on VAS levels than duration: mild intermittent rhinitis (3.5, 2.4–5.0 cm), mild persistent rhinitis (4.5, 3.2–5.6 cm), moderate/severe intermittent rhinitis (6.7, 5.3–7.7 cm) and moderate/severe persistent rhinitis (7.2, 6.1–8.2 cm). The receiver operating characteristic curve results showed that patients with a VAS of under 5 cm could be classified as ‘mild’ rhinitis (negative predictive value: 93.5%) and those with a VAS of over 6 cm as ‘moderate/severe’ rhinitis (positive predictive value: 73.6%). Receiver operating characteristic curves and a logistic regression showed that current treatment and allergy diagnosis have no effect on the assessment of rhinitis severity using VAS. Visual analog scale and the RQLQ global score were significantly correlated ( ρ = 0.46; P &lt; 0.0001). Conclusion: A simple and quantitative method (VAS) can be used for the quantitative evaluation of severity of allergic rhinitis.
Şiddetli plak tipi psoriazisde infliksimab indüksiyon tedavisi: Randomize, çift-kör, plasebo kontrollü çalışma
Authors: Alice B. Gottlieb, Robert Evans, Shu Li, Lisa T. Dooley, Cynthia A. Guzzo, Daniel Baker, Mohan Bala, Colleen W. Marano, veAlan MenterNew Brunswick, New Jersey, Pennsylvania, Dallas, Texas
Journal: Journal of the American Academy of Dermatology (2004)
1031. Improved Anti-Brain Tumor Efficacy of Δγ134.5 HSV Expressing Cytosine Deaminase
Authors: James M. Markert, M. Brad Guffey, Debbie Della Manna, Donald J. Buchsbaum, Kathleen H. Price, Catherine P. Langford, G. Yancey Gillespie
Journal: Molecular Therapy (2004)
In vivo efficacy of cefotaxime and amoxicillin against penicillin-susceptible, penicillin-resistant and penicillin-cephalosporin-resistant strains of Streptococcus pneumoniae in a mouse pneumonia model
Authors: Pierre Moine, Colette Sauve, Eric Vallee, Jean-Pierre Bedos, Esther Azoulay-Dupuis
Journal: Clinical Microbiology and Infection (1997)
166. Induction of Immune Tolerance and Phenotypic Rescue of Hemophilic Mice by Stem Cell Mediated Gene Transfer
Authors: Brian W. Bigger, Elena K. Siapati, Ajay Mistry, Simon N. Waddington, Megha S. Nivsarkar, Maxine V. Holder, Chris Ridler, Geoff Kemball-Cook, Robyn R. Ali, Stuart Forbes, Charles Coutelle, Nick Wright, Malcolm Alison, Adrian Thrasher, Dominique Bonnet, Michael Themis
Journal: Molecular Therapy (2004)

Top of pageAbstract
Immune responses against an introduced transgene are a potential risk in many gene replacement strategies to treat genetic disease. Thus we have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells.

In both normal C57BL/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least 6 months in primary recipients with specific tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrated long-term production of therapeutic levels of human factor IX and tolerance. Furthermore, in hemophilic mice we have shown partial functional correction of treated mice and phenotypic rescue.

These data show the potential of using lineage depleted bone marrow transplantation, not only to tolerize recipients to a foreign transgene, but also as a potent method for obtaining efficient gene expression from the hematopoietic system.
Abstract 5349: Dual Effects of Nifekalant on I <sub>Kr</sub>
Authors: Mikio Morishima, Ryoko Niwa, Takahiro Yamaguchi, Sara Kato, Yukiomi Tsuji, Haruo Honjo, Ichiro Sakuma, Kaichiro Kamiya
Journal: Circulation (2008)

Purpose: Nifekalant, a potent and common antiarrhythmic drug, has been regarded to treat reentry arrhythmias through I Kr block (antagonist action). But, recently nifekalant was reported to increase I Kr at slight depolarizing level (agonist action) and details are still not known. In this study, profiles and molecular mechanisms of I Kr antagonist and agonist actions by nifekalant were comparatively investigated. Methods: I Kr was measured in rabbit ventricular myocytes. hERG currents were expressed in Xenopus oocytes . An Ala-scanning mutagenesis of hERG channel was performed in S4-S5 linker regions and S6 domain to seek for important amino acid residues to develop agonist action. Results: In I Kr of myocytes, nifekalant (0.3 μM) suppressed currents at all test voltages ranging from −60 mV to +40 mV and showed antagonist action. However, when a preceding depolarizing pulse (+20 mV for 2 sec) was applied, current amplitudes below −20 mV were transiently increased and showed agonist action. When repetitive short depolarizing pulses, mimic action potentials, were applied, agonist action was enhanced at higher frequency. When a preceding depolarizing pulses was prolonged, agonist action rapidly increased (+20 mV, time constant: 428±31 ms, n=4). When an interval at −90 mV between a preceding pulse and a tested depolarization to −50 mV was prolonged, currents were slowly decreased with time constant of 306±55 sec (n=4). These time constants were relatively similar to onset and offset time constant of current blocking by antagonist action (onset at 20 mV: 769±33 ms, offset at −90 mV: 218±44 sec, n=4). Nifekalant shifted activation curve to a hyperpolarizing direction by 28.0±2.5 mV (n=4), but did not affect inactivation curve. In 2 mutations made in the S4–S5 linker, which could affect activation gate, agonist action was abolished but antagonist action was maintained. Conclusions: Our results indicated that both antagonist and agonist actions on I Kr by nifekalant may exhibit continuously within normal range of heart rate, thereby contributing to antiarrhythmic effects. Agonist action may be derived by two factors; first, a binding to amino acid residues same as antagonist action and, second, an interaction with activation gate.
Propranolol in the treatment of rage and violent behavior associated with Korsakoff's psychosis
Authors: S C Yudofsky, L Stevens, J Silver, J Barsa, D Williams
Journal: American Journal of Psychiatry (1984)

Propranolol controlled the rage and violent behavior of a man with alcohol withdrawal, Korsakoff's psychosis, and seizures. The authors present evidence linking Korsakoff's psychosis and alcohol withdrawal to pathophysiologic alterations in CNS adrenergic amines and receptors.
Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes
Authors: A. Schaub, S. von Gunten, M. Vogel, S. Wymann, M. Rüegsegger, B. M. Stadler, M. Spycher, H.-U. Simon, S. Miescher
Journal: Allergy (2011)

Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of autoimmune and chronic inflammatory diseases. Naturally occurring autoantibodies against Siglec-9 and Fas are thought to contribute to the anti-inflammatory effects of IVIG via cell death regulation of leukocytes and tissue cells. Dimeric IVIG fractions are suspected to contain idiotypic (Id)-anti-idiotypic complexes of antibodies, which might also include anti-Siglec-9 and anti-Fas autoantibodies.Dimeric IVIG fractions were separated from monomeric IVIG by size-exclusion chromatography and remonomerized by low pH treatment. Binding studies of total, monomeric, and dimeric IVIG were performed using surface plasmon resonance and flow cytometry on primary human neutrophils.Anti-Siglec-9 and anti-Fas autoantibodies were contained in both monomeric and dimeric IVIG fractions, but anti-Siglec-9 antibodies were highly enriched in dimeric IVIG. The propensity to engage in dimer formation was paratope dependent. IVIG binding to Siglec-9 was specific and sialylation independent. Interestingly, we detected anti-idiotypic antibodies (anti-Ids) against anti-Siglec-9 autoantibodies in dimeric, but not in monomeric fractions of IVIG.Our study supports the concept that idiotype-anti-idiotype (Id-anti-Id) interactions contribute to the dimer formation in IVIG preparations. To our knowledge, this is the first description of Id-anti-Id dimers of death receptor-specific antibodies in IVIG. Such Id-anti-Id interactions might determine the activity of immunomodulatory antibodies present both in IVIG and the patient.
Abstract 4171: Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response
Authors: Jonathan R. Dry, Mark Wappett, Ron Yang
Journal: Cancer Research (2014)

Abstract Large cancer genome profiling efforts are releasing pan-molecular information for large numbers of patients into the public domain. A large proportion of novel oncogenic events discovered through these efforts are deleterious to gene/protein function. Recent clinical data from PARP inhibitors has highlighted the promise of tumor cell selective killing where loss of function of a tumor suppressor gene, in this case BRCA, results in a targetable dependency. We sought to take advantage of the pan-molecular information in these data sets to identify molecular patterns indicative of the mutually exclusive loss of function expected between synthetic lethal gene pairs. We have developed a toolkit comprising BiSEp (BImodality Subsetting ExPression) and SLinG (Synthetic Lethality in Genomics) with which we are able to identify instances of genetic and/or gene expression loss that are mutually exclusive between functionally redundant genes. We demonstrate the power of this toolkit to identify known synthetic lethal gene pairings from cancer literature and yeast based screens. We have also revealed a number of novel candidate synthetic lethal gene pairings, and highlight the value of paired biomarkers provided through this approach to select disease models for hypothesis testing. Through a further adaptation, BEEP (Bimodal Expression Exclusive with Pharmacology), we have gone on to identify biomarkers of response to a number of clinical drug candidates. Here we present these algorithms and supporting data for a number of candidate target and biomarker hypotheses discovered, and discuss rationale for their application in cancer drug research. Citation Format: Jonathan R. Dry, Mark Wappett, Ron Yang. Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4171. doi:10.1158/1538-7445.AM2014-4171
Evaluation of targeting c-Src by the RGT-containing peptide as a novel antithrombotic strategy
Authors: Jiansong Huang, Xiaofeng Shi, Wenda Xi, Ping Liu, Zhangbiao Long, Xiaodong Xi
Journal: Journal of Hematology & Oncology (2015)

Interaction of integrin β3 with c-Src plays critical roles in cellular signaling which is heavily implicated in platelet adhesion and aggregation, as well as in tumor cell proliferation and metastasis or in osteoclastic bone resorption. Selectively blocking integrin αIIbβ3 outside-in signaling in platelets has been a focus of attention because of its effective antithrombotic potential together with a sufficient hemostatic capacity. The myristoylated RGT peptide has been shown to achieve this blockade by targeting the association of c-Src with the integrin β3 tail, but the lack of key information regarding the mechanisms of action prevents this strategy from being further developed into practical antithrombotics. Therefore, in-depth knowledge of the precise mechanisms for RGT peptide in regulating platelet function is needed to establish the basis for a potential antithrombotic therapy by targeting c-Src.The reduction-sensitive peptides were applied to rule out the membrane anchorage after cytoplasmic delivery. The c-Src activity was assayed at living cell or at protein levels to assess the direct effect of RGT targeting on c-Src. Thrombus formation under flow in the presence of cytoplasmic RGT peptide was observed by perfusing whole blood through the collagen-coated micro-chamber.The RGT peptide did not depend on the membrane anchorage to inhibit outside-in signaling in platelets. The myr-AC ~ CRGT peptide readily blocked agonist-induced c-Src activation by disrupting the Src/β3 association and inhibited the RhoA activation and collagen-induced platelet aggregation in addition to the typical outside-in signaling events. The myr-AC ~ CRGT had no direct effect on the kinase activity of c-Src in living cells as evidenced by its inability to dissociate Csk from c-Src or to alter the phosphorylation level of c-Src Y(416) and Y(527), consistent results were also from in vitro kinase assays. Under flow conditions, the myr-AC~ CRGT peptide caused an inhibition of platelet thrombus formation predominantly at high shear rates.These findings provide novel insights into the molecular mechanisms by which the RGT peptide regulates integrin signaling and platelet function and reinforce the potential of the RGT peptide-induced disruption of Src/β3 association as a druggable target that would finally enable in vivo and clinical studies using the structure-based small molecular mimetics.
Abstract 2643: Preservation of Left Ventricular Myocardial Distensibility Using a Novel Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Markedly Enhances the Hemodynamic Efficacy of Chest Compression
Authors: Iyad M Ayoub, Madhav P Upadhyaya, Jeejabai Radhakrishnan, Raul J Gazmuri
Journal: Circulation (2009)

Objective: We previously reported that inhibition of the sodium-hydrogen exchanger isoform-1 (NHE-1) preserves left ventricular (LV) myocardial distensibility, enabling higher LV preload to enhance...
Chest Medicine: Essentials of Pulmonary and Critical Care Medicine.
Authors: Ronald B George
Journal: Annals of Internal Medicine (1991)

A favorite among residents and pulmonary fellows, this text provides all the information needed to evaluate and manage respiratory diseases and critically ill patients and to pass the American Board of Internal Medicine's subspecialty exam in pulmonary medicine. The Fifth Edition includes new information on ARDS, sedation of critically ill patients, rehabilitation for COPD, care of elderly patients, genetic testing for asthma, CTA and other diagnostic techniques for pulmonary thromboembolism, new antifungal drugs without renal toxicity, new treatment guidelines for pneumothorax, and ventilators and noninvasive ventilation for respiratory failure. This edition also includes more algorithms and differential diagnosis tables.
Defeating AIDS—advancing global health
Authors: Peter Piot, Salim S Abdool Karim, Robert Hecht, Helena Legido-Quigley, Kent Buse, John Stover, Stephen Resch, Theresa Ryckman, Sigrun Møgedal, Mark Dybul, Eric Goosby, Charlotte Watts, Nduku Kilonzo, Joanne McManus, Michel Sidibé
Journal: The Lancet (2015)
Increased prevalence of asthma associated with accidental peak exposures
Authors: Regine Abrahamsen, Anne Kristin Møller Fell, Paul Henneberger, Martin Veel Svendsen, Kjell Torén, Johny Kongerud
Journal: European Respiratory Journal (2014)

Introduction: In Northern Europe, approximately 10% of adults and 20% of children are diagnosed with asthma. Asthma incidence in Telemark has not been studied, but it is known that the use of respiratory medication is above the average level in Norway. In this prospective, population-based study we aim to estimate the occurrence of asthma in relation to gender, smoking habits and occupational exposures. We here report the first cross-sectional results.  Methods: In 2013, a random sample of 50.000 from the population of Telemark aged 16 to 50 years received a validated postal, self-administered questionnaire. Asthma was defined as asthma diagnosed by a physician.  Results: The response rate was approximately 33% and the mean age of the study sample 34 years. The prevalence of everyday smoking was similar for men and women (14%). Prevalence of physician-diagnosed asthma was 12% (men: 10%; women: 13%), and significantly higher in current smokers (14%) and past smokers (16%) compared to never-smokers (11%). The prevalence of asthma in non-responders contacted by telephone (n=183) was similar (12%), suggesting the study sample is representative. The overall prevalence of ever being occupational exposed to vapor, gas, dust or fumes (VGDF) was 48%, whereas 15% reported accidental peak exposures (APE) including APE at home. The risk of asthma was not increased for those reporting ever being exposed to VGDF, but was increased for those reporting APE (adjusted odds ratio 1.5 [95% Cl 1.3, 1.8]). Participants who report respiratory symptoms following an APE, were more likely to report physician-diagnosed asthma (21%).  Conclusion: Increased prevalence of asthma was observed in respondents reporting accidental peak exposures.
Spring Flowers in Two Panels
Authors: M. Therese Southgate
Journal: JAMA (1998)

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