gebhart/patrepeval huggingface dataset:
The pharmacodynamics and pharmacokinetics of conventional and long‐ acting propranolol in patients with moderate hypertension. (1983)

1 The effects on heart rate and blood pressure after single and multiple dosing (1 month) of a long acting formulation of propranolol 160 mg daily, and conventional propranolol, 80 mg twice daily, or 160 mg daily were compared in 11 moderately hypertensive subjects previously shown to respond to propranolol. 2 After acute dosing all three treatments produced significant reduction in blood pressure. After multiple dosing all three treatments maintained significant reductions in lying, standing and exercise heart rate and blood pressure throughout the 24 h. At 24 h, after multiple dosing, the fall in resting and standing systolic BP was significantly greater with LA propranolol than with conventional propranolol 80 mg twice daily or conventional propranolol 160 mg once daily (P at least less than 0.05). 3 The plasma propranolol concentration time curve after LA propranolol showed slowed absorption, and the area under the curve was significantly lower than after conventional propranolol (acute dosing; LA propranolol 160 mg 560 mg ml-1 h, conventional propranolol 80 mg twice daily 1135 mg ml-1 h, conventional propranolol 160 mg daily 1414 mg ml-1 h).
Polysaccharide intercellular adhesin (PIA) protects Staphylococcus epidermidis against major components of the human innate immune system (2004)

The skin commensal and opportunistic pathogen Staphylococcus epidermidis is the leading cause of nosocomial and biofilm-associated infections. Little is known about the mechanisms by which S. epidermidis protects itself against the innate human immune system during colonization and infection. We used scanning electron microscopy to demonstrate that the exopolysaccharide intercellular adhesin (PIA) resides in fibrous strands on the bacterial cell surface, and that lack of PIA production results in complete loss of the extracellular matrix material that has been suggested to mediate immune evasion. Phagocytosis and killing by human polymorphonuclear leucocytes was significantly increased in a mutant strain lacking PIA production compared with the wild-type strain. The mutant strain was also significantly more susceptible to killing by major antibacterial peptides of human skin, cationic human beta-defensin 3 and LL-37, and anionic dermcidin. PIA represents the first defined factor of the staphylococcal biofilm matrix that protects against major components of human innate host defence.
A probabilistic approach to fault diagnosis in linear lightwave networks (1993)

The application of probabilistic reasoning to fault diagnosis in linear lightwave networks (LLNs) is investigated. The LLN inference model is represented by a Bayesian network (or causal network). An inference algorithm is proposed that is capable of conducting fault diagnosis (inference) with incomplete evidence and on an interactive basis. Two belief updating algorithms are presented which are used by the inference algorithm for performing fault diagnosis. The first belief updating algorithm is a simplified version of the one proposed by Pearl (1988) for singly connected inference models. The second belief updating algorithm applies to multiply connected inference models and is more general than the first. The authors also introduce a t-fault diagnosis system and an adaptive diagnosis system to further reduce the computational complexity of the fault diagnosis process.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor (2016)

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del<sub>746-750,</sub> T790M/L858R, and T790M/del<sub>746-750</sub>) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del<sub>746-750</sub>) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del<sub>746-750</sub>) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.
Device Factors Affecting Pulmonary Delivery of Dry Powders (2013)

The use of orally inhaled dry powder technologies is one way of delivering medicines to the lung for treating local conditions or for achieving systemic effect. These involve dry powder formulations containing an active pharmaceutical ingredient together with inhaler devices. These powder/device systems enable patients to inhale and aerosolize the medicine into suitably sized particles that deposit in the lung. Several inhaler centric aspects of these delivery systems are presented and discussed in context of new product development. Case examples are provided to highlight several inhaler aspects and to guide development of powder/inhaler systems.
Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33. (2001)

Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.
The role of neurotrophic factors in nerve regeneration (2009)

This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.
Multiple frequency bioelectrical impedance analysis: a cross-validation study of the inductor circuit and Cole models (1999)

It has been proposed that multiple frequency bioelectrical impedance models of the human body should include an inductive property for the circulatory system, the inductor circuit model (ICM), and that such a model, when coupled with a new method of data analysis, can improve the predictive power of multiple frequency bioelectrical impedance analysis (MFBIA). This hypothesis was tested using MFBIA measurements and gold standard measures of total body and extracellular water volumes in a cross-validation study in two subject groups (viz. controls and HIV). The MFBIA measurements were analysed using the current, widely accepted Cole model and the alternative ICM model which includes an inductive component. Correlations in the range 0.75 to 0.92 (for TBW) and 0.46 to 0.79 (for ECW) for impedance quotients versus gold standard measures within the subject groups were observed. These decreased, to as low as r = 0.50 for TBW and r = 0.29 for ECW, when the derived algorithms were applied to the alternative subject group. These results suggest that lack of portability of MFBIA algorithms between subject groups is not due to an inadequacy of the analogue circuit model per se but is possibly due more to fundamental flaws in the principles associated with its application. These include assuming a constant proportionality of body segment geometries and tissue fluid resistivities. This study has also demonstrated that this inadequacy cannot be overcome by simply introducing an inductive component into the analogue electrical circuit.
Absolute electronegativity and hardness: application to inorganic chemistry (1988)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAbsolute electronegativity and hardness: application to inorganic chemistryRalph G. PearsonCite this: Inorg. Chem. 1988, 27, 4, 734–740Publication Date (Print):February 1, 1988Publication History Published online1 May 2002Published inissue 1 February 1988https://pubs.acs.org/doi/10.1021/ic00277a030https://doi.org/10.1021/ic00277a030research-articleACS PublicationsRequest reuse permissionsArticle Views9114Altmetric-Citations2537LEARN 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 Get e-Alerts
Gα12 and Gα13 Stimulate Rho-dependent Stress Fiber Formation and Focal Adhesion Assembly (1995)

Rho, a member of the Ras superfamily of GTP-binding proteins, regulates actin polymerization resulting in the formation of stress fibers and the assembly of focal adhesions. In Swiss 3T3 cells, heterotrimeric G protein-coupled receptors for lysophosphatidic acid and gastrin releasing peptide stimulate Rho-dependent stress fiber and focal adhesion formation. The specific heterotrimeric G protein subunits mediating Rho-dependent stress fiber and focal adhesion formation have not been defined previously. We have expressed GTPase-deficient, constitutively activated G protein alpha subunits and mixtures of beta and gamma subunits in Swiss 3T3 cells. Measurement of actin polymerization and focal adhesion formation indicated that GTPase-deficient alpha 12 and alpha 13, but not the activated forms of alpha 12 or alpha q stimulated stress fiber and focal adhesion assembly. Combinations of beta and gamma subunits were unable to stimulate stress fiber or focal adhesion formation. G alpha 12- and alpha 13-mediated stress fiber and focal adhesion assembly was inhibited by botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho, indicating that alpha 12 and alpha 13, but not other G protein alpha subunits or beta gamma complexes, regulate Rho-dependent responses. The results define the integration of G12 and G13 with the regulation of the actin cytoskeleton.
Role of Polyamines Derived from Arginine in Differentiation and Proliferation of Human Blood Cells (2006)

L-Arginine is a precursor of polyamine, nitric oxide (NO), creatine, and agmatine and is essential for the differentiation and proliferation of blood cells, although the precise biological role of L-arginine is unclear. We have recently reported that the depletion of L-arginine in cultured medium prevented both proliferation and differentiation of blood cells (Shima et al., Blood First Edition Paper, October 6, 2005; DOI 10.1182). Since one of metabolic products of L-arginine in the cells is polyamine that associates with cell differentiation and proliferation, the effects of L-arginine on the human K562 cell line and human cord blood-derived CD34 positive cells were investigated by focusing on polyamines such as putrescine, spermidine, and spermine in the present study. When polyamines were added to the culture medium in the absence of L-arginine, the cells did not grow or differentiate well. However, when intracellular polyamines were depleted using ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), the proliferation and differentiation of K562 cells to erythrocytes were reduced even in the presence of L-arginine. Moreover, in the presence of DFMO, cell differentiation and proliferation were recovered by the addition of putrescine or spermidine in the presence of L-arginine. Accordingly, it was demonstrated that polyamines are essential for the proliferation and differentiation of the blood cells as the metabolites of L-arginine and the externally added polyamines are also effective by being taken up through polyamine transporter.
Immunology and Adjuvant Chemoimmunotherapy of Breast Cancer (1976)

Antibody against a breast carcinoma antigen was present in patients with breast carcinoma and other cancer more often (P less than .05) than in normal women. The incidence of antibody in women with breast carcinoma correlated with the presence or absence of gross tumor, and the titer of antibody paralleled the clinical course. These results suggest importance of a host-immune response to breast carcinoma. Fifty-seven patients with stage II carcinoma of the breast were entered into a prospective randomized adjuvant chemoimmunotherapy program of cyclophosphamide, methotrexate, and fluorouracil, and BCG vaccine +/- an irradiated allogeneic tumor cell vaccine. After 24 months of study, metastases occurred in two patients (3.5%) and a new primary carcinoma developed in the contralateral breast in two others, for an overall treatment failure rate of 7%. Adjuvant chemoimmunotherapy can delay early recurrence. Long-term follow-up is needed to assess the significance of these results.
Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia (2013)

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.
Pentalenene Synthase. Purification, Molecular Cloning, Sequencing, and High-Level Expression in Escherichia coli of a Terpenoid Cyclase from Streptomyces UC5319 (1994)

Pentalenene synthase, which catalyzes the cyclization of farnesyl diphosphate (1) to the tricyclic sesquiterpene hydrocarbon pentalenene (2), was purified from Streptomyces UC5319. A 450-bp hybridization probe, generated by PCR amplification of genomic DNA using primers based on N-terminal and internal tryptic peptide sequence data for pentalenene synthase, was used to screen both plasmid and phage DNA libraries of Streptomyces genomic DNA, resulting in the isolation and sequencing of the complete pentalenene synthase gene. PCR was used to insert the pentalenene synthase gene into the T7 expression vector pLM1. Cloning of the resulting construct in the expression host Escherichia coli BL21 (DE3) gave transformants that expressed pentalenene synthase as greater than 10% of soluble protein. The recombinant enzyme has been purified, and initial physical and kinetic characterization has been performed. The recombinant enzyme appears to be identical in every respect with the native Streptomyces synthase and exhibits the following steady-state kinetic parameters: Km = 0.31 +/- 0.05 microM, kcat = 0.32 +/- s-1, KI(PPi) = 3.2 +/- 0.6 microM. Both enzymes have an absolute requirement of Mg2+ for catalysis and an optimum pH of 8.2-8.4. Both proteins have M(r) values of 41-42 kDa, as determined by SDS-PAGE.
Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients (2008)

These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis.
The relevance of bacterial mutators to understanding human cancer. (1996)

The study of mutator strains of bacteria has elucidated new systems and pathways of mutagenesis and led to the defining of human counterparts to these systems. In addition to previous work that defined the mismatch repair system, newer studies have revealed a repair pathway for oxidative lesions, as well as demonstrating that mistranslation can increase mutation rates. Defects in the human repair pathways are involved in increased cancer susceptibility as well as a mutator character.
Bloom filtering cache misses for accurate data speculation and prefetching (2014)

A processor must know a load instruction's latency to schedule the load's dependent instructions at the correct time. Unfortunately, modern processors do not know this latency until well after the dependent instructions should have been scheduled to avoid pipeline bubbles between themselves and the load. One solution to this problem is to predict the load's latency, by predicting whether the load will hit or miss in the data cache. Existing cache hit/miss predictors, however, can only correctly predict about 50% of cache misses.This paper introduces a new hit/miss predictor that uses a Bloom Filter to identify cache misses early in the pipeline. This early identification of cache misses allows the processor to more accurately schedule instructions that are dependent on loads and to more precisely prefetch data into the cache. Simulations using a modified SimpleScalar model show that the proposed Bloom Filter is nearly perfect, with a prediction accuracy greater than 99% for the SPECint2000 benchmarks. IPC (Instructions Per Cycle) performance improved by 19% over a processor that delayed the scheduling of instructions dependent on a load until the load latency was known, and by 6% and 7% over a processor that always predicted a load would hit the cache and with a counter-based hit/miss predictor respectively. This IPC reaches 99.7% of the IPC of a processor with perfect scheduling.