gebhart/patrepeval huggingface dataset:
Playing Russian Roulette With Tyrosine Kinase Inhibitors (2012)

With the advent of molecularly “targeted therapies,” most notably the tyrosine kinase inhibitors (TKIs), there has been a significant shift in our formulary from intravenous to orally administered medications. The effect of food on bioavailability is a significant consideration for many drugs, especially those with a narrow therapeutic window. This article focuses on the complicated issue of oncology drug dosing with respect to food, highlighting the impact of food labeling on patient safety. Clinical Pharmacology & Therapeutics (2013); 93 3, 242–244. doi:10.1038/clpt.2012.245
Clinical Scale Expansion of Cryopreserved Small Volume Whole Bone Marrow Aspirates Produces Sufficient Cells for Clinical Use (1999)

Ex vivo expansion of bone marrow (BM) mononuclear cells (MNC) in a perfused culture system produces stem-progenitor cell type(s) in sufficient number(s) for hematopoietic reconstitution. The limitations in using fresh BM MNC for ex vivo expansion include additional cell processing and inflexibility in patient treatment. Cryopreservation of whole bone marrow (WBM) eliminates processing costs of MNC or CD34+ cell selection and allows for flexibility in patient treatment. We developed a convenient system to cryopreserve and thaw small volume WBM aspirations (n = 13) and then compared the expandability of unprocessed normal cryopreserved/thawed (C/T) WBM to that of fresh BM MNC cultured in the presence of erythropoietin, PIXY 321, and Flt3-ligand. Ex vivo expansion potential was retained in WBM aspirates after C/T. When initiated with 225 million viable nucleated cells, clinical scale expansion cultures (n = 6) yielded 9.7+/-2.8 x 10(8) total cells, which contained 10.4+/-5.8 x 10(6) colony-forming units-granulocyte-macrophage (CFU-GM), 1.3+/-1.4 x 10(4) LTCIC, and 2.2 x 10(6) CD34+Lin- cells, sufficient cell numbers for clinical use. These studies demonstrate that ex vivo perfusion culture expansion of unfractionated C/T WBM (< or =30 ml) provides doses of stem-progenitor cells similar in composition to expanded fresh BM MNC, previously demonstrated to achieve hematopoietic reconstitution.
Interaction with host SGS3 is required for suppression of RNA silencing by tomato yellow leaf curl virus V2 protein (2007)

The V2 protein of tomato yellow leaf curl geminivirus (TYLCV) functions as an RNA-silencing suppressor that counteracts the innate immune response of the host plant. The host-cell target of V2, however, remains unknown. Here we show that V2 interacts directly with SlSGS3, the tomato homolog of the Arabidopsis SGS3 protein (AtSGS3), which is known to be involved in the RNA-silencing pathway. SlSGS3 genetically complemented an AtSGS3 mutation and restored RNA silencing, indicating that SlSGS3 is indeed a functional homolog of AtSGS3. A point mutant of V2 that is unable to bind SlSGS3 also lost its ability to suppress RNA silencing, suggesting a correlation between the V2-SlSGS3 interaction in planta and the suppressor activity of V2.
Antiphlogistische 2,3 Dihydro‐1H‐pyrrolizine, 13. Mitt.: Stellungsisomere Diaryldihydropyrrolizinyl‐essigsäuren und ‐hydroxyethyl‐Derivate (1988)

Abstract Durch Umsetzung von 5,6‐, 6,7‐ und 5,7‐Diaryl‐2,3‐dihydro‐1H‐pyrrolizinen mit Diazoessigester und nachfolgende Esterverseifung werden die stellungsisomeren DADHP‐essigsäuren zugänglich. Unter den gewählten Reaktionsbedingungen wird keine oder nur sehr wenig Decarboxylierung der DADHP‐essigsäuren beobachtet. Die Reduktion der DADHP‐essigester mit LiAlH 4 ergibt die zugehörigen Hydroxyethylderivate.
Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development (2012)

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.
Destabilization of Ag nanoislands on Ag(100) by adsorbed sulfur (2011)

Sulfur accelerates coarsening of Ag nanoislands on Ag(100) at 300 K, and this effect is enhanced with increasing sulfur coverage over a range spanning a few hundredths of a monolayer, to nearly 0.25 monolayers. We propose that acceleration of coarsening in this system is tied to the formation of AgS(2) clusters primarily at step edges. These clusters can transport Ag more efficiently than can Ag adatoms (due to a lower diffusion barrier and comparable formation energy). The mobility of isolated sulfur on Ag(100) is very low so that formation of the complex is kinetically limited at low sulfur coverages, and thus enhancement is minimal. However, higher sulfur coverages force the population of sites adjacent to step edges, so that formation of the cluster is no longer limited by diffusion of sulfur across terraces. Sulfur exerts a much weaker effect on the rate of coarsening on Ag(100) than it does on Ag(111). This is consistent with theory, which shows that the difference between the total energy barrier for coarsening with and without sulfur is also much smaller on Ag(100) than on Ag(111).
Oxidative stress, male infertility and the role of carnitines. (2005)

Oxidative stress has been shown to be a major cause of male infertility; a large proportion of infertile men have elevated levels of seminal reactive oxygen species (ROS). High concentrations of ROS cause sperm pathology such as ATP depletion leading to insufficient axonemal phosphorylation, lipid peroxidation and loss of motility and viability. L-carnitine, a naturally occurring enzymatic antioxidant, is a necessary factor in the utilization of long chain fatty acids to produce energy. Furthermore, it plays a pivotal role in the maturation of spermatozoa within the male reproductive tract. Epididymal plasma contains the highest levels of L-carnitine found in the human body, and initiation of sperm motility occurs in parallel to L-carnitine increase in the epididymal lumen. It is known that L-carnitine prevents the formation of ROS, scavenges free radicals and protects cells from peroxidative stress. Moreover, it plays a key role in sperm metabolism by providing readily available energy for use by spermatozoa, which positively affects sperm motility, maturation and the spermatogenic process. L-carnitine and its derivatives have been proposed recently for treatment of male infertility, and a number of controlled and uncontrolled human and animal studies have been conducted to indicate their possible application. As a result, antioxidant therapy with carnitines may represent a new nonhormonal option within a broader therapeutic strategy in men with ROS-mediated infertility.
Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. (1999)

In an attempt to find the key to reducing the excessive morbidity and mortality seen with mood disorders, our laboratory has been extensively investigating lithium's mechanisms of action in an integrated series of clinical and preclinical studies. We have found that the chronic administration of the 2 structurally highly dissimilar agents, lithium and valproate, brings about a strikingly similar reduction in protein kinase C (PKC) alpha and epsilon isozymes in rat frontal cortex and hippocampus. In view of PKC's critical role in regulating neuronal excitability and neurotransmitter release, we have postulated that PKC inhibition may have antimanic efficacy. In a small study, we have found that tamoxifen (which, in addition to its estrogen receptor blockade, is also a PKC inhibitor) has marked antimanic efficacy. These exciting preliminary results suggest that PKC inhibitors may represent a novel class of improved therapeutic agents for bipolar disorder, and this is under further investigation. The beneficial effects of mood stabilizers require a lag period for onset of action and are generally not immediately reversed upon drug discontinuation; such patterns of effects suggest alterations at the genomic level. We have therefore undertaken a series of studies to investigate the effects of these agents on the AP-1 family of transcription factors and have found that both drugs increase AP-1 DNA binding activity in areas of rodent brain ex vivo and in human neuronal cells in culture. Both treatments also increase the expression of a reporter gene driven by an AP-1-containing promoter, and mutations in the AP-1 sites of the reporter gene promoter markedly attenuate these effects. Both treatments also increase the expression of several endogenous proteins, whose genes are known to be regulated by AP-1. Although the precise mechanisms have not been fully elucidated, preliminary results suggest that these effects may be mediated, in part, by mitogen-activating protein kinases and glycogen synthase kinase 3beta. We have also utilized mRNA reverse transcription-polymerase chain reaction (RT-PCR) differential display to identify concordant changes in gene expression induced by the chronic administration of both lithium and valproate. We have identified concordant changes in a number of cDNA bands by both lithium and valproate. Cloning and characterizing of these genes is currently underway. The identification of the functions of these genes offers the potential not only for improved therapeutics for reducing the morbidity and mortality associated with mood disorders, but may also provide important clues about the underlying pathophysiology.
Simulation of logarithmic time dependence of hot carrier degradation in PMOSFETs (1995)

10.1088/0268-1242/10/12/016
Differences between immunodeficient mice generated by classical gene targeting and CRISPR/Cas9-mediated gene knockout (2018)

Immunodeficient mice are widely used for pre-clinical studies to understand various human diseases. Here, we report the generation of four immunodeficient mouse models using CRISPR/Cas9 system without inserting any foreign gene sequences such as Neo<sup>R</sup> cassettes and their characterization. By eliminating any possible effects of adding a Neo<sup>R</sup> cassette, our mouse models may allow us to better elucidate the in vivo functions of each gene. Our FVB-Rag2<sup>-/-</sup>, B6-Rag2<sup>-/-</sup>, and BALB/c-Prkdc<sup>-/-</sup> mice showed phenotypes similar to those of the earlier immunodeficient mouse models, including a lack of mature B cells and T cells and an increase in the number of CD45<sup>+</sup>DX-5<sup>+</sup> natural killer cells. However, B6-Il2rg<sup>-/-</sup> mice had a unique phenotype, with a lack of mature B cells, increased number of T cells, and decreased number of natural killer cells. Additionally, serum immunoglobulin levels in all four immunodeficient mouse models were significantly reduced when compared to those in wild-type mice with the exception of IgM in B6-Il2rg<sup>-/-</sup> mice. These results indicate that our immunodeficient mouse models are a robust tool for in vivo studies of the immune system and will provide new insights into the variation in phenotypic outcomes resulting from different gene-targeting methodologies.
Opposite Action of Peroxisome Proliferator-activated Receptor-γ in Regulating Renal Inflammation (2010)

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists, a new class of antidiabetic agents, have been shown to possess antiinflammatory activity. In this study, we investigated the molecular mechanism by which PPARγ agonists inhibit proinflammatory cytokine expression in rat glomerular mesangial cells. Both natural and synthetic PPARγ agonists potently inhibited RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 expression induced by TNF-α in mesangial cells, which was dependent on NF-κB signaling. However, PPARγ agonists had little effect on TNF-α-triggered IκBα phosphorylation and its subsequent degradation, p65 phosphorylation, and nuclear translocation. In the absence of PPARγ ligand, TNF-α induced a physical interaction between nuclear p65 and PPARγ, as demonstrated by co-immunoprecipitation. Such an interaction was mediated by the C-terminal region of p65. Activation of PPARγ by its agonist prevented PPARγ·p65 complex formation. Chromatin immunoprecipitation assay revealed that TNF-α induced p65 binding to the cis-acting κB elements in rat RANTES promoter, whereas disruption of PPARγ·p65 by its agonist blocked p65 interaction with its cognate κB sites. Knockdown of PPARγ via siRNA strategy completely abolished TNF-α-mediated p65 binding to κB sites and negated RANTES induction, suggesting that unliganded PPARγ is obligatory for NF-κB signaling. Consistently, overexpression of PPARγ in the absence of its ligand sensitized mesangial cells to TNF-α stimulation. These results uncover a paradoxical action of the unliganded and ligand-activated PPARγ in regulating NF-κB signaling and demonstrate PPARγ ligand as a molecular switch that controls its ability to modulate inflammatory responses in opposite directions.
The Skeletal Muscle Chloride Channel in Dominant and Recessive Human Myotonia (1992)

Autosomal recessive generalized myotonia (Becker's disease) (GM) and autosomal dominant myotonia congenita (Thomsen's disease) (MC) are characterized by skeletal muscle stiffness that is a result of muscle membrane hyperexcitability. For both diseases, alterations in muscle chloride or sodium currents or both have been observed. A complementary DNA for a human skeletal muscle chloride channel (CLC-1) was cloned, physically localized on chromosome 7, and linked to the T cell receptor beta (TCRB) locus. Tight linkage of these two loci to GM and MC was found in German families. An unusual restriction site in the CLC-1 locus in two GM families identified a mutation associated with that disease, a phenylalanine-to-cysteine substitution in putative transmembrane domain D8. This suggests that different mutations in CLC-1 may cause dominant or recessive myotonia.
Wnt5a through Noncanonical Wnt/JNK or Wnt/PKC Signaling Contributes to the Differentiation of Mesenchymal Stem Cells into Type II Alveolar Epithelial Cells In Vitro (2014)

The differentiation of mesenchymal stem cells (MSCs) into type II alveolar epithelial (AT II) cells is critical for reepithelization and recovery in acute respiratory distress syndrome (ARDS), and Wnt signaling was considered to be the underlying mechanisms. In our previous study, we found that canonical Wnt pathway promoted the differentiation of MSCs into AT II cells, however the role of the noncanonical Wnt pathway in this process is unclear. It was disclosed in this study that noncanonical Wnt signaling in mouse bone marrow-derived MSCs (mMSCs) was activated during the differentiation of mMSCs into AT II cells in a modified co-culture system with murine lung epithelial-12 cells and small airway growth media. The levels of surfactant protein (SP) C, SPB and SPD, the specific markers of AT II cells, increased in mMSCs when Wnt5a was added to activate noncanonical Wnt signaling, while pretreatment with JNK or PKC inhibitors reversed the promotion of Wnt5a. The differentiation rate of mMSCs also depends on their abilities to accumulate and survive in inflammatory tissue. We found that the Wnt5a supplement promoted the vertical and horizontal migration of mMSCs, ameliorated the cell death and the reduction of Bcl-2/Bax induced by H2O2. The effect of Wnt5a on the migration of mMSCs and their survival after H2O2 exposure were partially inhibited with PKC or JNK blockers. In conclusion, Wnt5a through Wnt/JNK signaling alone or both Wnt/JNK and Wnt/PKC signaling promoted the differentiation of mMSCs into AT II cells and the migration of mMSCs; through Wnt/PKC signaling, Wnt5a increased the survival of mMSCs after H2O2 exposure in vitro.
Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma (2010)

When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).
Peyronie’s Disease: AUA Guideline (2015)

There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.
Structured light using pseudorandom codes (1998)

We solve the correspondence problem in active stereo vision using a novel pseudorandom coded structured light (SL). This coding scheme performs well in the presence of occlusion. In settings where color coding is feasible, 3D information can be obtained using a single image.
Single-Channel Characteristics of Wild-Type IKs Channels and Channels formed with Two MinK Mutants that Cause Long QT Syndrome (1998)

IKs channels are voltage dependent and K+ selective. They influence cardiac action potential duration through their contribution to myocyte repolarization. Assembled from minK and KvLQT1 subunits, IKs channels are notable for a heteromeric ion conduction pathway in which both subunit types contribute to pore formation. This study was undertaken to assess the effects of minK on pore function. We first characterized the properties of wild-type human IKs channels and channels formed only of KvLQT1 subunits. Channels were expressed in Xenopus laevis oocytes or Chinese hamster ovary cells and currents recorded in excised membrane patches or whole-cell mode. Unitary conductance estimates were dependent on bandwidth due to rapid channel "flicker." At 25 kHz in symmetrical 100-mM KCl, the single-channel conductance of IKs channels was approximately 16 pS (corresponding to approximately 0.8 pA at 50 mV) as judged by noise-variance analysis; this was fourfold greater than the estimated conductance of homomeric KvLQT1 channels. Mutant IKs channels formed with D76N and S74L minK subunits are associated with long QT syndrome. When compared with wild type, mutant channels showed lower unitary currents and diminished open probabilities with only minor changes in ion permeabilities. Apparently, the mutations altered single-channel currents at a site in the pore distinct from the ion selectivity apparatus. Patients carrying these mutant minK genes are expected to manifest decreased K+ flux through IKs channels due to lowered single-channel conductance and altered gating.
A direct real-time polymerase chain reaction assay for rapid high-throughput detection of highly pathogenic North American porcine reproductive and respiratory syndrome virus in China without RNA purification (2015)

Background:Porcine reproductive and respiratory syndrome virus（PRRSV）,and particularly its highly pathogenic genotype（HP-PRRSV）,have caused massive economic losses to the global swine industry.Results:To rapidly identify HP-PRRSV,we developed a direct real-time reverse transcription polymerase chain reaction method（dRT-PCR） that could detect the virus from serum specimen without the need of RNA purification.Our dRT-PCR assay can be completed in 1.5 h from when a sample is received to obtaining a result.Additionally,the sensitivity of dRT-PCR matched that of conventional reverse transcription PCR（cRT-PCR） that used purified RNA.The lowest detection limit of HP-PRRSV was 6.3 TCID50 using dRT-PCR.We applied dRT-PCR assay to 144 field samples and the results showed strong consistency with those obtained by cRT-PCR.Moreover,the dRT-PCR method was able to tolerate 5-20%（v/v） serum.Conclusions:Our dRT-PCR assay allows for easier,faster,more cost-effective and higher throughput detection of HP-PRRSV compared with cRT-PCR methods.To the best of our knowledge,this is the first report to describe a real-time RT-PCR assay capable of detecting PRRSV in crude serum samples without the requirement for purifying RNA.We believe our approach has a great potential for application to other RNA viruses.
Serum and glucocorticoid kinase 3 at 8q13.1 promotes cell proliferation and survival in hepatocellular carcinoma (2012)

Amplification of broad regions of 8q is one of the most frequent genetic alterations in hepatocellular carcinoma (HCC), suggesting the existence of oncogenes in addition to MYC at 8q24.21. In this report we examine the potential role of the candidate amplified oncogene serum and glucocorticoid kinase 3 (SGK3) at 8q13.1 in HCC pathogenesis. We found amplification and overexpression of SGK3 was frequently detected in clinical HCC specimens and that SGK3 genomic activation was significantly associated with poor outcome of patients (P = 0.028). Functionally, we found that overexpression of SGK3 in HCC cells increased cell cycle progression through G(1), cell survival, clonogenicity, anchorage-independent growth, and tumor formation in nude mice. In contrast, RNA interference (RNAi) silencing of SGK3 inhibited its oncogenic effects. We provide evidence that SGK3 promotes HCC growth and survival through inactivating glycogen synthase kinase 3 beta and Bcl-2-associated death promoter, respectively. We also found that expression of SGK3, which like AKT is activated by PI3K/PDK1 signaling, has more significance than overexpression of AKT in predicting poor outcome in HCC patients. Taken together, our findings in the present study suggests that the SGK3 pathway may function in parallel with the AKT pathway and undergoes an AKT-independent signaling pathway in the pathogenesis of HCC. Further characterization of SGK3 may provide a prognostic biomarker for HCC outcome prediction and a novel therapeutic target in HCC treatment.