gebhart/patrepeval huggingface dataset:
Therapeutic Drug Monitoring of Antifungals: Pharmacokinetic and Pharmacodynamic Considerations (2008)

Therapeutic drug monitoring of any pharmacologic agent should be considered when there is both significant pharmacokinetic variability and strong, clinically relevant, exposure-effect relationships. Many antifungal drugs exhibit marked variability in drug concentration as a result of inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. For each of the available antifungal drugs, both preclinical and clinical trials have exhibited a relationship between serum concentrations and treatment efficacy. For a smaller subset of compounds, a similar relationship has been identified for the toxicity. The kinetic variability among patients falls outside the therapeutic window for a group of four antifungal compounds. This review summarizes the current literature on therapeutic drug monitoring for these antifungal agents.
Yeast genes involved in response to lactic acid and acetic acid: acidic conditions caused by the organic acids inSaccharomyces cerevisiaecultures induce expression of intracellular metal metabolism genes regulated by Aft1p (2006)

Using two types of genome-wide analysis to investigate yeast genes involved in response to lactic acid and acetic acid, we found that the acidic condition affects metal metabolism. The first type is an expression analysis using DNA microarrays to investigate 'acid shock response' as the first step to adapt to an acidic condition, and 'acid adaptation' by maintaining integrity in the acidic condition. The other is a functional screening using the nonessential genes deletion collection of Saccharomyces cerevisiae. The expression analysis showed that genes involved in stress response, such as YGP1, TPS1 and HSP150, were induced under the acid shock response. Genes such as FIT2, ARN1 and ARN2, involved in metal metabolism regulated by Aft1p, were induced under the acid adaptation. AFT1 was induced under acid shock response and under acid adaptation with lactic acid. Moreover, green fluorescent protein-fused Aft1p was localized to the nucleus in cells grown in media containing lactic acid, acetic acid, or hydrochloric acid. Both analyses suggested that the acidic condition affects cell wall architecture. The depletion of cell-wall components encoded by SED1, DSE2, CTS1, EGT2, SCW11, SUN4 and YNL300W and histone acetyltransferase complex proteins encoded by YID21, EAF3, EAF5, EAF6 and YAF9 increased resistance to lactic acid. Depletion of the cell-wall mannoprotein Sed1p provided resistance to lactic acid, although the expression of SED1 was induced by exposure to lactic acid. Depletion of vacuolar membrane H+-ATPase and high-osmolarity glycerol mitogen-activated protein kinase proteins caused acid sensitivity. Moreover, our quantitative PCR showed that expression of PDR12 increased under acid shock response with lactic acid and decreased under acid adaptation with hydrochloric acid.
MPEG-4 one-pass VBR rate control for digital storage (2003)

One-pass, variable bit-rate (VBR) rate control is ideally suited to the requirements of real-time video encoding for the purpose of digital storage. Previous MPEG one-pass VBR rate control algorithms have been based on appropriate selection of quantization scale parameters for controlling the bit rate and quality of the output bitstream. The major disadvantage of relying solely on quantization scales, for rate control, is the introduction of significant perceptual distortion when high quantization scales are used. We propose an MPEG-4, 1-pass, VBR rate control scheme that relies on the selective use of the MPEG-4 reduced resolution mode to supplement modulation of the quantization scale and provide an effective rate control strategy. Experimental results show that the proposed algorithm can encode high-complexity, standard definition (720 /spl times/ 480) video sequences at rates as low as 750 kbps without incurring significant perceptual artifacts.
DCIS grading schemes and clinical implications (1999)

The frequency with which ductal carcinoma in situ (DCIS) is detected has increased greatly since the introduction of mammographic screening. The number of treatment options has also increased and mastectomy has been extensively replaced by local excision with or without radiotherapy. DCIS is generally unicentric, as evidenced by the rarity with which it is bilateral and the location of recurrences at the site of previous surgery. Complete excision is thus curative but assessing adequacy of excision is beset with significant technical problems and consequently margin involvement does not correlate very well with the presence of residual disease in the breast or the development of clinical recurrence. Lesion size is related to recurrence but is also often difficult to measure. At the histological level, DCIS is a heterogeneous group of proliferations varying in cytological and architectural features, some of which are related to clinical outcome. The traditional method of classification was by growth pattern but was found to lack reproducibility and prognostic power. As a consequence, several new classifications have been proposed in recent years. Some have been assessed more rigorously than others in terms of the consistency with which they can be applied and their ability to predict clinical outcome. There is strong evidence, however, that nuclear grade is the best predictor of recurrence and the time scale over which it is likely to occur although presently it can be determined with only fair to moderate consistency. Necrosis is also a useful feature when used in combination with nuclear grade, but specifically recognizing a comedo pattern appears to have little clinical value and is associated with significant diagnostic inconsistency. No histological features to date have been found to predict the development of invasive disease. Histological assessment alone is insufficient to determine how patients with DCIS should be managed, which should also take account pathological assessment of excision margins and lesion size as well as radiological and clinical features.
New antiplatelet drugs: beyond aspirin and clopidogrel (2009)

Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX-4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.
Age-Related Reference Intervals of the Main Biochemical and Hematological Parameters in C57BL/6J, 129SV/EV and C3H/HeJ Mouse Strains (2008)

Our results indicate that metabolic variations in C57BL/6J, 129SV/EV and C3H/HeJ mice after therapeutic intervention should be evaluated against gender- and age-dependent reference intervals.
ATRP-based polymers with modular ligation points under thermal and thermomechanical stress (2015)

Functional modular ATRP polymers suffer from accelerated ester cleavage due to HBr release as well as the formation of triazolium salts <italic>via</italic> the reaction of triazole units with bromine terminal chain ends under thermal and thermomechanical insult.
Monte Carlo simulation of an optical coherence tomography signal in homogeneous turbid media (1999)

The Monte Carlo technique with angle biasing is used to simulate the optical coherence tomography (OCT) signal from homogeneous turbid media. The OCT signal is divided into two categories: one is from a target imaging layer in the medium (Class I); the other is from the rest of the medium (Class II). These two classes of signal are very different in their spatial distributions, angular distributions and the numbers of experienced scattering events. Multiply scattered light contributes to the Class I signal as well as the Class II signal. The average number of scattering events increases linearly with the probing depth. The Class II signal decays much more slowly than the Class I signal whose decay constant is close to the total attenuation coefficient of the turbid medium. The effect of the optical properties of the medium on the Class I signal decay is studied.
Glucose metabolism in cancer cells (2010)

The acquisition of a glycolytic phenotype by transformed cells confers a selective growth advantage to these cells. Interfering with aerobic glycolysis, therefore, represents a potentially effective strategy to selectively target cancer cells.
Efficient control plane for passive optical burst switching network (2013)

One of the main drawbacks of classical Optical Burst Switching (OBS) solutions is the loss of bursts when contentions occur. Time-domain Wavelength Interleaved Networking (TWIN) is a lossless solution with contention resolution in the edge nodes providing a simple and passive switching in the core nodes and satisfying both low-energy and efficient bandwidth use criteria. However, this solution requires an efficient control plane. In this paper, we compare three different control planes based on either centralized or distributed schemes. Moreover we use two different slot allocation strategies (contiguous or disjoint). The performances of the proposed solutions are compared in terms of total delay, jitter, queue length and bandwidth utilization. The simulation parameters are carefully chosen to take into account implementation constraints. We find that the centralized solution with contiguous slot allocation is the most efficient and it allows a throughput up to 7 Gb/s.
THE ALBUMIN-BINDING DOMAIN AS A SCAFFOLD FOR PROTEIN ENGINEERING (2013)

The albumin-binding domain is a small, three-helical protein domain found in various surface proteins expressed by gram-positive bacteria. Albumin binding is important in bacterial pathogenesis and several homologous domains have been identified. Such albumin-binding regions have been used for protein purification or immobilization. Moreover, improvement of the pharmacokinetics, through the non-covalent association to albumin, by fusing such domains to therapeutic proteins has been shown to be successful. Domains derived from streptococcal protein G and protein PAB from Finegoldia magna, which share a common origin and therefore represent an interesting evolutionary system, have been thoroughly studied structurally and functionally. Their albumin-binding sites have been mapped and these domains form the basis for a wide range of protein engineering approaches. By substitution-mutagenesis they have been engineered to achieve a broader specificity, an increased stability or an improved binding affinity, respectively. Furthermore, novel binding sites have been incorporated either by replacing the original albumin-binding surface, or by complementing it with a novel interaction interface. Combinatorial protein libraries, where several residues have been randomized simultaneously, have generated a large number of new variants with desired binding characteristics. The albumin-binding domain has also been utilized to explore the relationship between three-dimensional structure and amino acid sequence. Proteins with latent structural information built into their sequence, where a single amino acid substitution shifts the equilibrium in favor of a different fold with a new function, have been designed. Altogether, these examples illustrate the versatility of the albumin-binding domain as a scaffold for protein engineering.
Review of Nanomaterials in Dentistry: Interactions with the Oral Microenvironment, Clinical Applications, Hazards, and Benefits (2015)

Interest in the use of engineered nanomaterials (ENMs) as either nanomedicines or dental materials/devices in clinical dentistry is growing. This review aims to detail the ultrafine structure, chemical composition, and reactivity of dental tissues in the context of interactions with ENMs, including the saliva, pellicle layer, and oral biofilm; then describes the applications of ENMs in dentistry in context with beneficial clinical outcomes versus potential risks. The flow rate and quality of saliva are likely to influence the behavior of ENMs in the oral cavity, but how the protein corona formed on the ENMs will alter bioavailability, or interact with the structure and proteins of the pellicle layer, as well as microbes in the biofilm, remains unclear. The tooth enamel is a dense crystalline structure that is likely to act as a barrier to ENM penetration, but underlying dentinal tubules are not. Consequently, ENMs may be used to strengthen dentine or regenerate pulp tissue. ENMs have dental applications as antibacterials for infection control, as nanofillers to improve the mechanical and bioactive properties of restoration materials, and as novel coatings on dental implants. Dentifrices and some related personal care products are already available for oral health applications. Overall, the clinical benefits generally outweigh the hazards of using ENMs in the oral cavity, and the latter should not prevent the responsible innovation of nanotechnology in dentistry. However, the clinical safety regulations for dental materials have not been specifically updated for ENMs, and some guidance on occupational health for practitioners is also needed. Knowledge gaps for future research include the formation of protein corona in the oral cavity, ENM diffusion through clinically relevant biofilms, and mechanistic investigations on how ENMs strengthen the tooth structure.
Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis (2004)

The methylation profile of 31 genes was established in patients with colon cancer and colorectal adenomas, which provides new insights into the DNA methylation mediated mechanisms underlying the carcinogenesis of colorectal cancer and may be of prognostic values for colorectal cancer.
Quantitative Global Proteomics of Yeast PBP1 Deletion Mutants and Their Stress Responses Identifies Glucose Metabolism, Mitochondrial, and Stress Granule Changes (2016)

The yeast protein PBP1 is implicated in very diverse pathways. Intriguingly, its deletion mitigates the toxicity of human neurodegeneration factors. Here, we performed label-free quantitative global proteomics to identify crucial downstream factors, either without stress or under cell stress conditions (heat and NaN<sub>3</sub>). Compared to the wildtype BY4741 strain, PBP1 deletion always triggered downregulation of the key bioenergetics enzyme KGD2 and the prion protein RNQ1 as well as upregulation of the leucine biosynthesis enzyme LEU1. Without stress, enrichment of stress response factors was consistently detected for both deletion mutants; upon stress, these factors were more pronounced. The selective analysis of components of stress granules and P-bodies revealed a prominent downregulation of GIS2. Our yeast data are in good agreement with a global proteomics and metabolomics publication that the PBP1 ortholog ATAXIN-2 (ATXN2) knockout (KO) in mouse results in mitochondrial deficits in leucine/fatty acid catabolism and bioenergetics, with an obesity phenotype. Furthermore, our data provide the completely novel insight that PBP1 mutations in stress periods involve GIS2, a plausible scenario in view of previous data that both PBP1 and GIS2 relocalize from ribosomes to stress granules, interact with poly(A)-binding protein in translation regulation and prevent mitochondrial precursor overaccumulation stress (mPOS). This may be relevant for human diseases like spinocerebellar ataxias, amyotrophic lateral sclerosis, and the metabolic syndrome.
French Mischief: A Foxy Map of New Holland (2011)

The popular histories of nations are enmeshed in myths and misinformation. Australia is no exception. Witness the story of the curious switch in Australia's European 'possessors' and that of the equally curious changes in her cartographic labelling. The world's fifth continent was known as 'New Holland' for over 200 years, longer than it has been called 'Australia'. The latter name conjures up the legendary, but unrelated, Terra Australis Incognita and suggests a seamless continuance with that ancient, never-known land. Partly because of this, the era of Dutch possession has been squeezed from popular history and discarded. The myth is that Britain planted her colonies on an unnamed, unclaimed and unknown Terra Australis. This study examines two things. First, the misinformation which founded the myth: M. Thevenot's 1663 map. Second, the mischief which fed on it, a cartographic sleight-of-hand which would eventually permit Europe's island state to hijack from continental friends and foes alike, the great island-continent of the south.
Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. (2000)

Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.
Antiandrogens prevent stable DNA-binding of the androgen receptor (2005)

The androgen receptor (AR) is essential for development of the male gender and in the growth of the majority of prostate cancers. Agonists as well as most antagonists induce translocation of the receptor to the nucleus, whereas only agonists can activate AR function. Antagonists are therefore used in the therapy of metastasized prostate cancer. To obtain insight into the mechanism by which antagonists block AR function in living cells, we studied nuclear mobility and localization of green fluorescent protein (GFP)-tagged AR in the presence of either the agonist R1881 or the antagonists bicalutamide and hydroxyflutamide. As controls we investigated a non-DNA-binding AR mutant (A573D) and two mutants (W741C and T877A) with broadened ligand specificity. We demonstrate that in the presence of R1881, AR localizes in numerous intranuclear foci and, using complementary fluorescence recovery after photobleaching (FRAP) approaches and computer modelling, that a fraction of AR ( approximately 10-15%) is transiently immobilized in a DNA-binding-dependent manner (individual ARs being immobile for approximately 45 seconds). By contrast, antagonist-bound GFP-AR showed no detectable immobile fraction and the mobility was similar to that of the R1881-liganded non-DNA-binding mutant (A573D), indicating that antagonists do not induce the relatively stable DNA-binding-dependent immobilization observed with agonist-bound AR. Moreover, in the presence of bicalutamide and hydroxyflutamide GFP-AR was homogeneously distributed in the nucleus. Binding of bicalutamide and hydroxyflutamide to GFP-AR(W741C) and GFP-AR(T877A), respectively, resulted in similar mobility and heterogeneous nuclear distribution as observed for R1881-liganded GFP-AR. The live cell studies indicate that the investigated antagonists interfere with events early in the transactivation function of the AR.
Chemical Architecture and Applications of Nucleic Acid Derivatives Containing 1,2,3-Triazole Functionalities Synthesized via Click Chemistry (2012)

There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole-modified nucleic acid derivatives for potential downstream DNA- and RNA-based applications. This review will focus on highlighting representative novel nucleic acid molecular structures that have been synthesized via the &#8220;click&#8221; azide-alkyne cycloaddition. Many of these derivatives show compatibility for various applications that involve enzymatic transformation, nucleic acid hybridization, molecular tagging and purification, and gene silencing. The details of these applications are discussed. In conclusion, the future of nucleic acid analogues functionalized with triazoles is promising.
Enhancing the performance of a point-of-care CD4+ T-cell counting microchip through monocyte depletion for HIV/AIDS diagnostics (2009)

CD4+ T cell counts are important tests used to stage HIV-positive patients, enabling clinicians to make informed antiretroviral treatment decisions and to monitor the therapeutic outcomes. However, state-of-the-art CD4 counting methods based on flow cytometry are not applicable in resource-limited settings, due to their high cost and technical requirements. In previous work, we reported the development of a cell isolation microchip that can be used at the point of care for CD4 counts. In that microfluidic chip, CD4+ T cells were separated from 10 microL of whole blood, and enumerated via either light microscopy or impedance sensing. The microchip counts matched flow cytometry results in the intermediate CD4 count range, between 200-800 cells/microL, but displayed a positive bias at absolute CD4 counts below 200 cells/microL, due largely to monocyte contamination. To enhance the performance in the low CD4 count range, we report here an improved design of a two-stage microfluidic device to deplete monocytes from whole blood, followed by CD4+ T cell capture. Using the double-stage device combined with a high viscosity rinsing solution, we obtained microchip CD4 counts comparable to flow cytometry results in the full clinically relevant range. In addition to CD4 counting, the strategy of contaminant depletion prior to target cell isolation can be easily adapted to immunoaffinity capture of other cell types that lack a unique surface marker from a complex biological fluid.