gebhart/patrepeval huggingface dataset:
Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants (1993)

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.
Autonomous replication of a DNA fragment containing the chromosomal replication origin of the human c-myc gene (1990)

The c-myc genes of HeLa cells are preferentially replicated in the transcriptional direction, from chromosomal origin sequences which display cell type-specific activity. Using a run-off replication assay involving in vitro extension of replication forks initiated in intact HeLa cells, bidirectional replication was observed to begin within a 3.5 kb domain 5' to the c-myc gene. To characterize the replication origin further a 2.4 HindIII-Xhol subfragment of the c-myc 5' flanking DNA was cloned in a selectable vector and transfected into HeLa cells. The resulting pNeo.Myc-2.4 construct persisted as a circular extrachromosomal element for more than 300 cell generations under selection, with recovery of approximately 500-1000 times the mass of plasmid initially introduced into the cells. Extrachromosomal circular pNeo.Myc-2.4 monomer was reisolated in supercoiled form, along with oligomeric and miniplasmid variants which had been generated in vivo; however, chromosomally integrated copies of the plasmid were not detectable in cultures containing extrachromosomal pNeo.Myc-2.4. The recovered pNeo.Myc-2.4 plasmid was resistant to Dpnl digestion and sensitive to Mbol digestion. After transfection with pNeo.Myc-2.4 BrUdR pulse labeling of long-term or short-term cultures demonstrated that the plasmid replicated semiconservatively, under controls similar to those imposed on chromosome replication. Bisection of the pNeo.Myc-2.4 insert suggested that c-myc 5' flanking DNA within 1.2 kb 5' to promoter P1 was sufficient to confer autonomously replicating sequence activity on the plasmid vector in transient replication assays.
Liquid‐Phase Synthesis of 2′‐Methyl‐RNA on a Homostar Support through Organic‐Solvent Nanofiltration (2015)

Due to the discovery of RNAi, oligonucleotides (oligos) have re-emerged as a major pharmaceutical target that may soon be required in ton quantities. However, it is questionable whether solid-phase oligo synthesis (SPOS) methods can provide a scalable synthesis. Liquid-phase oligo synthesis (LPOS) is intrinsically scalable and amenable to standard industrial batch synthesis techniques. However, most reported LPOS strategies rely upon at least one precipitation per chain extension cycle to separate the growing oligonucleotide from reaction debris. Precipitation can be difficult to develop and control on an industrial scale and, because many precipitations would be required to prepare a therapeutic oligonucleotide, we contend that this approach is not viable for large-scale industrial preparation. We are developing an LPOS synthetic strategy for 2'-methyl RNA phosphorothioate that is more amenable to standard batch production techniques, using organic solvent nanofiltration (OSN) as the critical scalable separation technology. We report the first LPOS-OSN preparation of a 2'-Me RNA phosphorothioate 9-mer, using commercial phosphoramidite monomers, and monitoring all reactions by HPLC, (31)P NMR spectroscopy and MS.
Pacemaker-mediated tachycardia with varying cycle length: what is the mechanism? (2009)

As new algorithms are being developed to promote intrinsic atrioventricular conduction in preventing the deleterious effects of right ventricular pacing, more complex rhythm strips can be encountered. In our patient with a dual-chamber implantable cardioverter-defibrillator, such an algorithm resulted in a pacemaker-mediated tachycardia with several changes in cycle length.
Data Fusion for Visual Tracking With Particles (2004)

The effectiveness of probabilistic tracking of objects in image sequences has been revolutionized by the development of particle filtering. Whereas Kalman filters are restricted to Gaussian distributions, particle filters can propagate more general distributions, albeit only approximately. This is of particular benefit in visual tracking because of the inherent ambiguity of the visual world that stems from its richness and complexity. One important advantage of the particle filtering framework is that it allows the information from different measurement sources to be fused in a principled manner. Although this fact has been acknowledged before, it has not been fully exploited within a visual tracking context. Here we introduce generic importance sampling mechanisms for data fusion and discuss them for fusing color with either stereo sound, for teleconferencing, or with motion, for surveillance with a still camera. We show how each of the three cues can be modeled by an appropriate data likelihood function, and how the intermittent cues (sound or motion) are best handled by generating proposal distributions from their likelihood functions. Finally, the effective fusion of the cues by particle filtering is demonstrated on real teleconference and surveillance data.
Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in People With Type 1 Diabetes (2004)

The aim of this randomized double-blind study was to compare the within-subject variability of the glucose-lowering effect of a novel insulin analog, insulin detemir, with that of insulin glargine and NPH insulin in people with type 1 diabetes. Fifty-four subjects (32 males and 22 females, age 38 +/- 10 years [mean +/- SD], BMI 24 +/- 2 kg/m(2), HbA(1c) 7.5 +/- 1.2%, diabetes duration 18 +/- 9 years) participated in this parallel group comparison. Each subject received four single subcutaneous doses of 0.4 units/kg of either insulin detemir (n = 18), insulin glargine (n = 16), or human NPH insulin (n = 17) under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/l) on four identical study days. The pharmacodynamic (glucose infusion rates [GIRs]) and pharmacokinetic (serum concentrations of insulin detemir, human insulin, and insulin glargine) properties of the basal insulin preparations were recorded for 24 h postdosing. Insulin detemir was associated with significantly less within-subject variability than both NPH insulin and insulin glargine, as assessed by the coefficient of variation (CV) for the pharmacodynamic end points studied [GIR-AUC((0-12 h)) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine); GIR-AUC((0-24 h)) 27 vs. 68 vs. 48%; GIR(max) 23 vs. 46 vs. 36%; P < 0.001 for all comparisons]. Insulin detemir also provided less within-subject variability in the pharmacokinetic end points: maximal concentration (C(max)) 18 vs. 24 vs. 34%; INS-AUC((0- infinity )) 14 vs. 28 vs. 33%. The results suggest that insulin detemir has a significantly more predictable glucose-lowering effect than both NPH insulin and insulin glargine.
Therapeutic vaccines and cancer: focus on DPX-0907 (2014)

In an attempt to significantly enhance immunogenicity of peptide cancer vaccines, we developed a novel non-emulsion depot-forming vaccine platform called DepoVax™ (DPX). Human leukocyte antigen (HLA)-A2 restricted peptides naturally presented by cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. In a phase I clinical study, the safety and immune-activating potential of DPX-0907 in advanced-stage breast, ovarian, and prostate cancer patients were examined, following encouraging results in HLA-A2 transgenic mice. The DPX-0907 vaccine was shown to be safe and well tolerated, with injection-site reactions being the most commonly reported adverse event. Vaccinated cancer patients exhibited a 61% immune response rate, with higher response rates in the breast and ovarian cancer patient cohorts. In keeping with the higher immune efficacy of this vaccine platform, antigen-specific responses were detected in 73% of immune responders after just one vaccination. In 83% of responders, peptide-specific T-cells were detected at two or more time points post-vaccination, with 64% of these patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory, with the ability to secrete multiple type 1 cytokines. The novel DPX formulation promotes multifunctional effector/memory responses to peptide-based tumor-associated antigens. The data support the capacity of DPX-0907 to elicit type-1 biased immune responses, warranting further clinical development of the vaccine. In this review, we discuss the rationale for developing DPX-based therapeutic cancer vaccine(s), with a focus on DPX-0907, aimed at inducing efficient anti-tumor immunity that may eventually be shown to prolong patient survival.
Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer (2007)

Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, -2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.
A Wireless, Remote Query Glucose Biosensor Based on a pH-Sensitive Polymer (2004)

This paper describes a wireless, remote query glucose biosensor using a ribbonlike, mass-sensitive magnetoelastic sensor as the transducer. The glucose biosensor is fabricated by first coating the magnetoelastic sensor with a pH-sensitive polymer and upon it a layer of glucose oxidase (GOx). The pH-responsive polymer swells or shrinks, thereby changing mass, respectively, in response to increasing or decreasing pH values. The GOx-catalyzed oxidation of glucose produces gluconic acid, inducing the pH-responsive polymer to shrink, which in turn decreases the polymer mass. In response to a time-varying magnetic field, a magnetoelastic sensor mechanically vibrates at a characteristic resonance frequency, the value of which inversely depends on sensor mass loading. As the magnetoelastic films are magnetostrictive, the vibrations launch magnetic flux that can be remotely detected using a pickup coil. Hence, changes in the resonance frequency of a passive magnetoelastic transducer are detected on a remote query basis, without the use of physical connections to the sensors.The sensitivity of the glucose biosensors decreases with increasing ionic strength; at physiological salt concentrations, 0.6 mmol/L of glucose can be measured. At glucose concentrations of 1-10 mmol/L, the biosensor response is reversible and linear, with the detection limit of 0.6 mmol/L corresponding to an error in resonance frequency determination of 20 Hz. Since no physical connections between the sensor and the monitoring instrument are required, this sensor can potentially be applied to in vivo and in situ measurement of glucose concentrations.
IL7 signaling confers polyfunctionality to antitumor CD4+ T cells (2014)

Meeting abstracts Mounting evidence indicates that polyfunctional T cells, effector T cells capable of simultaneously producing multiple pro-inflammatory cytokines, are more efficacious in controlling infection and cancer. Our previous study reported that adoptive transfer of tumor-specific CD4+ T
Interferometric Methods for Label-Free Molecular Interaction Studies (2011)

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTInterferometric Methods for Label-Free Molecular Interaction StudiesAmanda Kussrow, Carolyn S. Enders, and Darryl J. Bornhop*View Author Information Department of Chemistry and Vanderbilt Institute of Chemical Biology Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States*Phone: 1.615.322.4404. Fax: 1.615.322.2861. E-mail: [email protected]Cite this: Anal. Chem. 2012, 84, 2, 779–792Publication Date (Web):November 7, 2011Publication History Published online7 November 2011Published inissue 17 January 2012https://pubs.acs.org/doi/10.1021/ac202812hhttps://doi.org/10.1021/ac202812hreview-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views2818Altmetric-Citations57LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Light,Molecular interactions,Optical properties,Peptides and proteins,Sensors Get e-Alerts
<title>Molecular DNA switches and DNA chips</title> (1999)

We present an assay to detect single-nucleotide polymorphisms on a chip using molecular DNA switches and isothermal rolling- circle amplification. The basic principle behind the switch is an allele-specific oligonucleotide circularization, mediated by DNA ligase. A DNA switch is closed when perfect hybridization between the probe oligonucleotide and target DNA allows ligase to covalently circularize the probe. Mismatches around the ligation site prevent probe circularization, resulting in an open switch. DNA polymerase is then used to preferentially amplify the closed switches, via rolling-circle amplification. The stringency of the molecular switches yields 10<SUP>2</SUP> - 10<SUP>3</SUP> fold discrimination between matched and mismatched sequences.
Glucose contribution to nucleic acid base synthesis in proliferating hepatoma cells: a glycine-biosynthesis-mediated pathway (1995)

The coupling of glycolysis to serine and glycine metabolism was studied in fast-growing Zajdela hepatoma cultured cells. During the exponential phase of growth, occurring between 12 and 72 h, cells exhibited a decreased glycogen content together with a high glycolytic activity. Glycogen labelling, evaluated by 1 h-pulse experiments with [U-14C]glucose (5.5 mM), was minimal during the first 48 h and increased 2.5-fold at 72 h and 8-fold at 96 h, at which times it was also stimulated 2-fold by 10 nM insulin. [U-14C]Glucose carbons were incorporated into nucleic acid bases, with maximal incorporation at 72 h, the rate of nucleotide base labelling exceeding that of glycogen during the first 2 days of culture. Incubation of the cells with [U-14C]glucose resulted in the release into the medium of 14C-labelled glycine, the first intermediate formed on the route from serine to DNA. The rate of release per cell decreased as a function of cell growth, concomitantly with an increased rate of glucose carbon incorporation into nucleotide bases. The latter implied the intermediary formation of amino acids since the transaminase inhibitor cycloserine (10 mM), which totally inhibited [14C]glycine release, decreased by 65% nucleotide labelling from [U-14C]glucose. A dose-dependent inhibition by serine of the rate of [U-14C]glucose carbon incorporation into nucleotide bases was observed, which was maximal at 5 mM serine. These metabolic flux measurements indicate that glucose can be used as a precursor of nucleic acid synthesis. These results strongly suggest that this process is to a large extent mediated by a serine/glycine-biosynthesis-mediated pathway, and reinforce the hypothesis that glycolysis contributes to enhancing the provision of precursors required for cell proliferation.
A causal role for uric acid in fructose-induced metabolic syndrome (2005)

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
A 25-Year Prospective Mortality Study in the Spinal Cord Injured Patient: Comparison with the Long-Term Living Paraplegic (1977)

Herein we combine 2 studies: a 25-year prospective followup on 270 spinal cord injury patients and a more than 20-year (average 24.2 years) evaluation of 175 paraplegics. The mortality rate was 49 per cent after 25 years, with renal disease as the major cause of death (43 per cent). Vascular deaths were just as prevalent during the last 5 years of spinal cord life. There are probably several reasons why some patients have long-term survival (more than 20 years), including patient motivation (better followup), less vascular problems, less chronic decubitus and a higher percentage of lower motor neuron lesions. Patients with lower motor neuron lesions had the best bladder status associated with less upper tract deterioration.
Validating UML models against architectural profiles (2003)

The Unified Modeling Language (UML) has become a widely adopted standard in the software industry. While UML has established itself in detailed software design, its usage as an architecture description language is still taking its shape. In particular, there is a growing need for techniques to define domain specific architectural constraints and conventions in UML. We address this issue by adopting the concept of UML profiles for architectural design. Architectural profiles are specialized for describing and constraining software architecture descriptions for a given domain. We argue that these profiles represent an appropriate abstraction level to elaborate architectural constraints and conventions. We present a general schema for arranging architectural profiles and a set of conformance rules that define how these profiles are interpreted, constituting a profile definition language for validating architectural design. We introduce a tool for performing architectural validation and discuss the results of our initial case studies.
Kelley's essentials of internal medicine (2001)

Part 1: General Medicine Part 2: CardiologySection I: Approach to the Patient with Cardiovascular DisordersSection II: Disorders of the Cardiovascular System Part 3: GastroenterologySection I: Approach to the Diagnosis and Management of Gastrointestinal DisordersSection II: Disorders of the Gastrointestinal Tract and Hepatobiliary System Part 4: NephrologySection I: Approach to the Patient with Renal and Electrolyte DisordersSection II: Disorders of the Kidney Part 5: Rheumatologic, Allergic, and Dermatologic DiseasesSection I: Approach to the Patient with Rheumatologic DisordersSection II: RheumatologicSection III: Allergic and Immunologic DisordersSection IV: Approach to the Patient with Dematologic Disorders Part 6: Hematology and OncologySection I: General principlesSection II: Hematologic MalignanciesSection III: Bone Marrow FailureSection IV: Miscellaneous Disorders of LeukocytesSection V: Solid TumorsSecton VI: Disorders of Hemostasis and ThrombosisSection VII: Approach to the Patient with Red Blood Cell DisordersSection VIII: Red Blood Cell DisordersSection IX: Approach to the Patient with ErythrocytosisSection X: Blood Groups, Tissue Typing, and Transfusion of Blood Products Part 7: Infectious DiseasesSection I: Scientific Basis of Infectious DiseasesSection II: Approach to the Patient with Infectious Diseases Part 8: Pulmonary and Critical Care MedicineSection II: Disorders of the Pulmonary System Part 9: Endocrinology, Metabolism, and GeneticsSecton I: Approach to the Patient with Endocrinologic, Metabolic, and Genetic DisordersSection II: Disorders of Endocrinology, Metabolism, and Genetics Part 10: Neurologysection I: Approach to the Patient with Neurologic DisordersSection II: Disorders of the Nervous System Part 11: GeriatricsSection I: Approach to the Diagnosis and Management of Classic Geriatric SyndromesSection II: Diseases Common in the Geriatric PopulationSection III: Other Topics Importnat in Expert Care of the ElderlyInde