gebhart/patrepeval huggingface dataset:
Phase I evaluation and clinical pharmacology of tricyclic nucleoside 5'-phosphate using a weekly intravenous regimen. (1986)

Tricyclic nucleoside phosphate (TCN-P) was selected for clinical trials because of its unusual chemical structure and activity against L1210 murine leukemia and MX-1 mammary xenograft. Inhibiting DNA synthesis, TCN-P was more toxic during S-phase of cell cycle. A phase I study was conducted in 24 patients with advanced solid cancers. The drug was given as a slow i.v. injection over 5 min on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 12 to 96 mg/m2 were studied with 3 to 12 patients treated at each level; a total of 106 doses was administered. The major hematological toxicity was thrombocytopenia, with a median nadir occurring at Day 34 of the cycle and first appearing at doses greater than 24 mg/m2. Anemia was seen at each dose level occurring between Days 8 and 34. Non-myelosuppressive toxic effects included stomatitis, anorexia, transient fever, nausea and vomiting, and dose-limiting hyperglycemia and diarrhea. The highest tolerated dose was 48 mg/m2. Plasma, pleural fluid, urine, and tissue samples were analyzed for TCN-P and tricyclic nucleoside (TCN) in selected patients by high-performance liquid chromatography. Plasma decay curves revealed extended retention of both TCN and TCN-P. Autopsy specimens obtained 61 days after therapy showed the highest residues of TCN-P in liver metastases and of TCN in gall bladder, bile, and pancreas. No drug was detected in urine samples of two patients. Prolonged retention and erratic plasma levels of the drug are probably due to extensive enterohepatic circulation, as well as repeated interconversion between TCN-P and TCN within cells. This weekly schedule produced unexpected clinical toxicity and should not be pursued.
Brain-Computer Interface Virtual Keyboard for Accessiblity (2012)

This paper describes our experiences in building a virtual keyboard implemented using a Brain-Computer Interface (BCI) that interacts with the eMotiv EPOC Neural Headset. The contribution of the work is an alternative input device for those who have a motor disability and are challenged by traditional input devices. The advantages of a virtual keyboard based on BCI are summarized and we describe its design and implementation. We also present the results of a preliminary study that has suggested several improvements for enhancing the effectiveness of the virtual keyboard.
The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. (2002)

Despite the effectiveness of the selective estrogen receptor (ER) modulators in preventing ER-positive breast cancer, chemopreventive agents still need to be developed for the prevention of ER-negative breast cancers. The naturally occurring retinoids are promising agents for the prevention of human cancers but are too toxic for long-term chronic use. We previously demonstrated that the chemopreventive effects of the retinoids could be separated from the toxicity by using an RXR-selective retinoid, LGD1069. The studies described here demonstrate that LGD1069 effectively suppresses ER-negative tumor development in mouse mammary tumor virus-erbB2 transgenic mice with minimal toxicity. These studies suggest that receptor-selective retinoids are promising agents for the prevention of breast cancer and that they may be particularly useful in preventing ER-negative breast cancer.
Synergistic Augmentation of Rapamycin-Induced Autophagy in Malignant Glioma Cells by Phosphatidylinositol 3-Kinase/Protein Kinase B Inhibitors (2005)

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and a central modulator of cell proliferation in malignant gliomas. Therefore, the targeting of mTOR signaling is considered a promising therapy for malignant gliomas. However, the mechanisms underlying the cytotoxic effects of a selective mTOR inhibitor, rapamycin, on malignant glioma cells are poorly understood. The purpose of this study was thus to elucidate how rapamycin exerts its cytotoxic effects on malignant glioma cells. We showed that rapamycin induced autophagy but not apoptosis in rapamycin-sensitive malignant glioma U87-MG and T98G cells by inhibiting the function of mTOR. In contrast, in rapamycin-resistant U373-MG cells, the inhibitory effect of rapamycin was minor, although the phosphorylation of p70S6 kinase, a molecule downstream of mTOR, was remarkably inhibited. Interestingly, a PI3K inhibitor, LY294002, and an Akt inhibitor, UCN-01 (7-hydroxystaurosporine), both synergistically sensitized U87-MG and T98G cells as well as U373-MG cells to rapamycin by stimulating the induction of autophagy. Enforced expression of active Akt in tumor cells suppressed the combined effects of LY294002 or UCN-01, whereas dominant-negative Akt expression was sufficient to increase the sensitivity of tumor cells to rapamycin. These results indicate that rapamycin exerts its antitumor effect on malignant glioma cells by inducing autophagy and suggest that in malignant glioma cells a disruption of the PI3K/Akt signaling pathway could greatly enhance the effectiveness of mTOR inhibitors.
The Differential Diagnosis of Multiple Sclerosis (2007)

Neurologists are most likely to misdiagnose multiple sclerosis in patients who have psychiatric problems or who have uncommon presentations of common diseases such as migraine, stroke, or neuropathies.
The Birefringent Filter (1949)

Optical birefringent filters, which depend for their action on the interference of polarized light, can be designed to transmit very sharp bands (down to a fraction of an angstrom in width). The elementary theory necessary for their design is given.Three forms of wide field filters designed by Lyot are described in detail. A more recently developed split element, wide field filter requires only half as many polarizers as the earlier types, which may be an advantage for some applications.Various methods of adjusting the transmission bands of a birefringent filter, including the use of elements of variable thickness, and phase shifters are discussed. For most purposes the electro-optical phase shifters are probably the most promising. For special purposes, such as spectrophotometry, phase shifters composed of rotating fractional wave plates may be more advantageous. Two such phase shifters and their application, in simple and split element filters are described.A few crystalline materials which have been used or might be used to advantage in birefringent filters are mentioned.Finally, the possibility of using polarizing interferometers in combination with birefringent elements for filters with extremely sharp transmission bands (in the range of hundredths or thousandths of an angstrom) is very briefly discussed.
Pyrimidine derivatives. 4. Synthesis and antihypertensive activity of 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives (1983)

A series of 30 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives was prepared and tested for their ability to reduce blood pressure in conscious, spontaneously hypertensive rates (SHR). A number of these compounds, notably 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazolines 3a (R1 = H; R2 = Ph), 3j (R1 = H; R2 = 4-EtOPh), and 5a (R1 = H; R2 = 2-furyl), showed activity at oral doses of 0.3-10 mg/kg. The effects of the 4-substituents of the piperazino group on activity are discussed. Compounds 3a, 3j, and 5a were effective in renal hypertensive rats at oral doses of 3 and 10 mg/kg and showed alpha-adrenoceptor blocking effects in isolated aortas of rats. A 5-day consecutive oral administration of 3a and 3j in SHR did not lead to development of tolerance.
Telomeric associations and loss of telomeric DNA repeats in renal tumors (1993)

In a series of cytogenetically analyzed renal tumors of different histological types (chromophobe carcinoma, clear-cell carcinoma, chromophilic carcinoma, and oncocytoma) and normal renal tissue, the length of the telomeric DNA repeats was assessed using a (TTAGGG)3 oligonucleotide probe. A strong correlation was noted between pronounced telomere shortening and the appearance of telomeric associations of chromosomes. These data suggest an etiologic role of the loss of telomeric DNA repeats in the formation of telomeric associations and a possible involvement of this mechanism in the pathogenesis of chromosome aberrations in human tumors.
Effect of Ammonia on the Glycosylation of Human Recombinant Erythropoietin in Culture (2000)

Recombinant human erythropoietin (EPO) was produced by a stable transfected CHO-K1 cell clone (EPO-81) grown in serum-free medium. Our previous work showed that there was a significant increase in the heterogeneity of the glycoforms of EPO and a reduction of the sialylation at 20 mM NH(4)Cl. In the work presented here, the effects of ammonia on EPO N-linked oligosaccharides were analyzed. EPO was purified from culture supernatants by immunoaffinity chromatography. The N-linked oligosaccharides were released enzymatically and analyzed by fluorophore-assisted carbohydrate electrophoresis (FACE) and HPLC. The FACE N-linked oligosaccharide profile showed that the sialylated glycans contain one prominent band at a position corresponding to eight glucose units. The density of the major band was greatly diminished and the width was significantly increased in cultures containing added ammonia. The proportion of tetraantennary structures was reduced by 60%, while the tri- and biantennary structures were increased proportionally in the presence of ammonia. Glycan analysis by HPLC using a weak anion exchange column showed that the most significant characteristic effect of ammonia was a reduction of the proportion of glycans with four sialic acids from 46% in control cultures to 29% in ammonia-treated cultures. Analysis of the desialylated glycans by normal phase chromatography indicated a distribution of tetra-, tri-, and biantennary structures similar to that shown by FACE. The N-linked glycan sequence was determined by sequential exoglycosidase digestion followed by FACE. The results indicated a typical N-linked complex oligosaccharide structure. Glycans from ammonia-containing cultures showed the same sequence pattern. In conclusion, we showed that ammonia in the culture medium affected EPO glycosylation, which was observed as a reduction of the tetraantennary and tetrasialylated oligosaccharide structures. However, the presence of ammonia in the cultures did not change the oligosaccharide sequence.
Regulation of ubiquitin‐dependent processes by deubiquitinating enzymes (1997)

An astounding number of important regulatory and structural proteins are subject to modification by the attachment of ubiquitin or ubiquitin-like proteins. This modification acts as a targeting signal, delivering the modified protein to different locations in the cell and modifying its activity, macromolecular interactions, or half-life. Deubiquitination, or the removal of this modification, is being recognized as an important regulatory strategy. This reaction is catalyzed by processing proteases known as deubiquitinating enzymes (DUBs). More than 60 DUBs are already known, although little is known about their biological roles. This review concentrates on recent findings and new insights into this fascinating class of enzymes.
Treadmill protocols for determination of maximum oxygen uptake in runners. (1988)

Four testing protocols were completed by each of 10 runners using a common speed for protocols 1 and 2 (P1 and P2), each runner's training pace for protocol 3 (P3) and a speed selected manually by the runner for protocol 4 (P4). Stages were increased by 2.5% grade every 2 min for each protocol except for P1, which had 1 min stages. There were no significant differences in maximum oxygen uptake (VO2 max) between protocols (P1, 65.0 +/- 5.6 ml.kg-1 min-1; P2, 64.5 +/- 5.3 ml.kg-1 min-1; P3, 66.2 +/- 3.9 ml.kg-1 min-1; P4, 64.7 +/- 5.8 ml.kg-1 min-1). Treadmill time was significantly less for P1 than for the other protocols. The rate of perceived exertion obtained at maximal exercise during P1 was less than that obtained during the other three protocols. Heart rate was significantly lower (P less than 0.05) at any level of submaximal VO2 during P3 than during the other protocols. We recommend a testing protocol using speeds approximating the runner's training pace and 1 min stages. This may result in lower perception of difficulty and HR throughout the test and shorter testing times.
Evidence for Human Immunodeficiency Virus Type 1 Replication In Vivo in CD14 + Monocytes and Its Potential Role as a Source of Virus in Patients on Highly Active Antiretroviral Therapy (2002)

In vitro studies show that human immunodeficiency virus type 1 (HIV-1) does not replicate in freshly isolated monocytes unless monocytes differentiate to monocyte-derived macrophages. Similarly, HIV-1 may replicate in macrophages in vivo, whereas it is unclear whether blood monocytes are permissive to productive infection with HIV-1. We investigated HIV-1 replication in CD14(+) monocytes and resting and activated CD4(+) T cells by measuring the levels of cell-associated viral DNA and mRNA and the genetic evolution of HIV-1 in seven acutely infected patients whose plasma viremia had been <100 copies/ml for 803 to 1,544 days during highly active antiretroviral therapy (HAART). HIV-1 DNA was detected in CD14(+) monocytes as well as in activated and resting CD4(+) T cells throughout the course of study. While significant variation in the decay slopes of HIV-1 DNA was seen among individual patients, viral decay in CD14(+) monocytes was on average slower than that in activated and resting CD4(+) T cells. Measurements of HIV-1 sequence evolution and the concentrations of unspliced and multiply spliced mRNA provided evidence of ongoing HIV-1 replication, more pronounced in CD14(+) monocytes than in resting CD4(+) T cells. Phylogenetic analyses of HIV-1 sequences indicated that after prolonged HAART, viral populations related or identical to those found only in CD14(+) monocytes were seen in plasma from three of the seven patients. In the other four patients, HIV-1 sequences in plasma and the three cell populations were identical. CD14(+) monocytes appear to be one of the potential in vivo sources of HIV-1 in patients receiving HAART.
State‐of‐the‐Art Design and Rapid‐Mixing Production Techniques of Lipid Nanoparticles for Nucleic Acid Delivery (2018)

Abstract Lipid nanoparticles (LNPs) are currently the most clinically advanced nonviral carriers for the delivery of small interfering RNA (siRNA). Free siRNA molecules suffer from unfavorable physicochemical characteristics and rapid clearance mechanisms, hampering the ability to reach the cytoplasm of target cells when administered intravenously. As a result, the therapeutic use of siRNA is crucially dependent on delivery strategies. LNPs can encapsulate siRNA to protect it from degradative endonucleases in the circulation, prevent kidney clearance, and provide a vehicle to deliver siRNA in the cell and induce its subsequent release into the cytoplasm. Here, the structure and composition of LNP–siRNA are described including how these affect their pharmacokinetic parameters and gene‐silencing activity. In addition, the evolution of LNP–siRNA production methods is discussed, as the development of rapid‐mixing platforms for the reproducible and scalable manufacturing has facilitated entry of LNP–siRNA into the clinic over the last decade. Finally, the potential of LNPs in delivering other nucleic acids, such as messenger RNA and CRISPR/Cas9 components, is highlighted alongside how a design‐of‐experiment approach may be used to improve the efficacy of LNP formulations.
Cost-effective broad-band electrical impedance spectroscopy measurement circuit and signal analysis for piezo-materials and ultrasound transducers. (2008)

This paper explains the circuitry and signal processing to perform electrical impedance spectroscopy on piezoelectric materials and ultrasound transducers. Here, we measure and compare the impedance spectra of 2-5 MHz piezoelectrics, but the methodology applies for 700 kHz-20 MHz ultrasonic devices as well. Using a 12 ns wide 5 volt pulsing circuit as an impulse, we determine the electrical impedance curves experimentally using Ohm's law and fast Fourier transform (FFT), and compare results with mathematical models. The method allows for rapid impedance measurement for a range of frequencies using a narrow input pulse, digital oscilloscope and FFT techniques. The technique compares well to current methodologies such as network and impedance analyzers while providing additional versatility in the electrical impedance measurement. The technique is theoretically simple, easy to implement and completed with ordinary laboratory instrumentation for minimal cost.
TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase (2003)

Interactions of polymorphonuclear neutrophils (PMNs) with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. We explored a novel function of PMN NADPH oxidase in the mechanism of Toll-like receptor-2 (TLR2) upregulation induced by LPS-TLR4 signaling in endothelial cells. We showed that LPS induced TLR2 up-regulation through TLR4- and MyD88-dependent signaling. In neutropenic mice, the LPS-induced NF-kB activation and TLR2 expression were significantly reduced, and both responses were restored upon repletion by PMN obtained from WT mice but not by PMNs from NADPH oxidase gp91pho(-/-) mice. These findings were recapitulated in mouse lung vascular endothelial cells cocultured with PMNs, indicating that the augmented NF-kB activation and the resultant TLR2 upregulation in endothelial cells were secondary to oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in endothelial cells was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and peptidoglycan. Thus, PMN NADPH oxidase-derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.
A Nonlinear Variational Problem for Image Matching (1994)

Minimizing a nonlinear functional is presented as a way of obtaining a planar mapping that matches two similar images. A smoothing term is added to the nonlinear functional to penalize discontinuous and irregular solutions. One option for the smoothing term is a quadratic form generated by a linear differential operator. The functional is then minimized using the Fourier representation of the planar mapping. With this representation the quadratic form is diagonalized. Another option is a quadratic form generated via a basis of compactly supported wavelets. In both cases, a natural approximation scheme is described. Both quadratic forms are shown to impose the same smoothing. However, in terms of the finite dimensional approximations, it is easier to accommodate local deformations using the wavelet basis.
Nucleotide sequence of the human polyomavirus AS virus, an antigenic variant of BK virus (1989)

The complete DNA sequence of the human polyomavirus AS virus (ASV) is presented. Although ASV can be differentiated antigenically from the other human polyomaviruses (BK and JC viruses), it shares 94.9% homology at the nucleotide level with the Dunlop strain of BK virus. Differences found in ASV relative to BK virus include the absence of tandem repeats in its regulatory region, the deletion of 32 nucleotides in the late mRNA leader region (altering the initiation codon for the agnoprotein), the presence of a cluster of base pair substitutions within the coding region of the major capsid protein, VP1, and the absence of 4 amino acids in the carboxy-terminal region of the early protein, T antigen. The 43 nucleotides deleted in the Dunlop strain of BK virus relative to the Gardner prototype strain of BK virus are present in ASV. Possible reasons for the distinct antigenicity of the ASV capsid, given the high degree of nucleotide homology with BK virus, are discussed. To reflect the high degree of sequence homology between ASV and BK virus, we suggest ASV be renamed BKV(AS).
Neural Activity When People Solve Verbal Problems with Insight (2004)

People sometimes solve problems with a unique process called insight, accompanied by an "Aha!" experience. It has long been unclear whether different cognitive and neural processes lead to insight versus noninsight solutions, or if solutions differ only in subsequent subjective feeling. Recent behavioral studies indicate distinct patterns of performance and suggest differential hemispheric involvement for insight and noninsight solutions. Subjects solved verbal problems, and after each correct solution indicated whether they solved with or without insight. We observed two objective neural correlates of insight. Functional magnetic resonance imaging (Experiment 1) revealed increased activity in the right hemisphere anterior superior temporal gyrus for insight relative to noninsight solutions. The same region was active during initial solving efforts. Scalp electroencephalogram recordings (Experiment 2) revealed a sudden burst of high-frequency (gamma-band) neural activity in the same area beginning 0.3 s prior to insight solutions. This right anterior temporal area is associated with making connections across distantly related information during comprehension. Although all problem solving relies on a largely shared cortical network, the sudden flash of insight occurs when solvers engage distinct neural and cognitive processes that allow them to see connections that previously eluded them.
The mechanism of action of erythropoietin (1986)

The proliferation and differentiation of committed erythroid progenitor cells is regulated by the glycoprotein hormone erythropoietin. Erythropoietin increases the number of developing erythroid precursors and accelerates the release of reticulocytes from the marrow without markedly altering the cell cycle length or number of mitotic divisions involved in the differentiation process. Although the hormone has been purified, molecularly cloned and sequenced, its secondary and tertiary structure and active site have not been defined. Erythropoietin has both mitogenic and differentiation functions, and whether an erythroid progenitor cell responds to the hormone by proliferating or differentiating appears to depend on its level of maturation. Erythroid progenitor cells are responsive to a variety of growth and developmental agents but only erythropoietin appears obligatory in vivo for terminal differentiation. Erythropoietin interacts with its target cells through specific high-affinity receptors and Ca2+ may be involved in the receptor-ligand interaction. Ca2+ may also be involved in the induction of differentiation by erythropoietin. An increase in RNA synthesis due to activation of transcription is one of the earliest recognized effects of the hormone and appears not to require protein or DNA synthesis but the initial sequence of biochemical events triggered by erythropoietin is still undefined.