gebhart/patrepeval huggingface dataset:
Development of difluoromethylornithine (DFMO) as a chemoprevention agent. (1999)

D,L-alpha-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzyme-activated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, would be effective as a chemotherapy for hyperproliferative diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at high doses. This side effect, along with its minimal therapeutic activity, contributed to the loss of interest by many clinicians in further developing DFMO as a cancer therapeutic agent. However, DFMO was subsequently shown to inhibit carcinogen-induced cancer development in a number of rodent models, and interest in developing this compound as a preventive agent has increased. The rationale for the inhibition of ornithine decarboxylase as a cancer chemopreventive agent has been strengthened in recent years because this enzyme has been shown to be transactivated by the c-myc oncogene in certain cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation designs, indicate that DFMO can be given over long periods of time at low doses that suppress polyamine contents in gastrointestinal and other epithelial tissues but cause no detectable hearing loss or other side effects. Current clinical chemoprevention trials are investigating the efficacy of DFMO to suppress surrogate end point biomarkers (e.g., colon polyp recurrence) of carcinogenesis in patient populations at elevated risk for the development of specific epithelial cancers, including colon, esophageal, breast, cutaneous, and prostate malignancies.
Electron microscopy of beaded agarose gels (1988)

Abstract Electron microscopy has been carried out on sections of beaded agarose with a wide range of thicknesses, and the results have been analyzed by means of stereological theory using computer graphics. The results agree with a randomly orientated system in which, for 4% gels, the mean molecular weight per unit length of the fiber system is 110 kg mol −1 nm −1 , and the number average interjunction length is 37 nm, with an asymmetrical distribution resembling a Maxwell‐Boltzmann distribution. The spatial distribution of the structure is not uniformly random and there seem to be mi microvoids.
A Collaborative Framework for Distributed Microscopy (1998)

This paper outlines the motivation, requirements, and architecture of a collaborative framework for distributed virtual microscopy. In this context, the requirements are specified in terms of (1) functionality, (2) scalability, (3) interactivity, and (4) safety and security. Functionality refers to what and how an instrument does something. Scalability refers to the number of instruments, vendor specific desktop workstations, analysis programs, and collaborators that can be accessed. Interactivity refers to how well the system can be steered either for static or dynamic experiments. Safety and security refers to safe operation of an instrument coupled with user authentication, privacy, and integrity of data communication. To meet these requirements, we introduce three types of services in the architecture: Instrument Services (IS), Exchange Services (ES), and Computational Services (CS). These services may reside on any host in the distributed system. The IS provide an abstraction for manipulating different types of microscopes; the ES provide common services that are required between different resources; and the CS provide analytical capabilities for data analysis and simulation. These services are brought together through CORBA and its enabling services, e.g., Event Services, Time Services, Naming Services, and Security Services. Two unique applications have been introduced into the CS for analyzing scientific images either for instrument control or recovery of a model for objects of interest. These include: insitu electron microscopy and recovery of 3D shape from holographic microscopy. The first application provides a near real-time processing of the video-stream for on-line quantitative analysis and the use of that information for closed-loop servo control. The second application reconstructs a 3D representation of an inclusion (a crystal structure in a matrix) from multiple views through holographic electron microscopy. These application require steering external stimuli or computational parameters for a particular result. In a sense, ``computational instruments'' (symmetric multiprocessors) interact closely with data generated from ``experimental instruments'' (unique microscopes) to conduct new experiments and bring new functionalities to these instruments. Both of these features exploit high-performance computing and low-latency networks to bring novel functionalities to unique scientific imaging instruments.
Bis(trichloromethyl) Carbonate in Organic Synthesis (1996)

Although more than a century old compound, only in the last decade has the versatility of bis(trichloromethyl) carbonate (BTC) been demonstrated by numerous examples of its application in the synthesis of some important classes of organic compounds: chlorocarbonyl derivatives, isocyanates, N,N'-disubstituted (poly)ureas, (poly)carbonates, alkyl and acyl chlorides, acid anhydrides, heterocyclic compounds. BTC is fast becoming a useful auxiliary to prepare intermediates for the synthesis of many specific organic compounds, since it reacts with many nucleophiles usually found in organic transformations. Reactions with BTC are normally carried out under mild conditions and oft afford good to excellent yields. Well-defined protocols and procedures, which allow efficient synthesis of a variety of described classes of organic compounds on a large scale, are now available, illustrating the synthetic and technological potential of BTC. Safe handling of solid BTC has been demonstrated, underlying the advantages over its gaseous cogener phosgene. The goal of this review is to present applications of BTC in order to promote the chemistry of this very interesting carbonic acid derivative. It is the authors' belief that the chemistry of BTC will continue to grow and be used extensively by organic chemists and engineers in both new developments and in improving old processes.
Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer (2007)

Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC(50) dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC(50) of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR.
Demonstration of an Extracellular ATP-Binding Site in NCAM:  Functional Implications of Nucleotide Binding (1997)

A minor fraction of the total ecto-type (E-type) ATPase activity of rat synaptosomes has been detected in immunoprecipitates of the neural cell adhesion molecule, NCAM, indicating that this either is an intrinsic enzymatic activity of NCAM or of an ATPase tightly associated to NCAM [Dzhandzhugazyan & Bock (1993) FEBS Lett. 336, 279-283]. We here demonstrate ATPase activity in preparations of the lipid-anchored as well as the transmembrane NCAM isoforms immunoisolated from transfected L-cells. A fraction of the E-type ATPase activity is spontaneously released from synaptosomes. Released material was fractionated by various chromatographic procedures and an extracellular fragment of NCAM was shown to co-elute with the major part of the enzymatic activity. Furthermore, it was shown that agarose-coupled NCAM-antibodies retained 85% of the ATPase activity released from synaptosomes after treatment with phosphatidylinositol-specific phospholipase C. These findings restricted the association or expression of the enzymatic activity to the extracellular part of NCAM. An affinity reagent, 5'-p-fluorosulfonylbenzoyl adenosine, FSBA, was shown to inhibit ATPase activity of immunoisolated NCAM, and incorporation of FSBA was detected in all three major NCAM isoforms (A, B, and C). An excess of ATP prevented both inactivation of the enzyme and affinity labeling of NCAM. Thus, NCAM contains an ATP-binding site, and this site is localized extracellularly and probably has the catalytic function. Binding of the substrate or FSBA protected a proteolytic cleavage site in NCAM localized close to the membrane presumably by induction of a local conformational change in NCAM, indicating a mechanism by which ATP may regulate NCAM adhesion and adhesion-triggered processes. A possible role of this mechanism in synaptic plasticity and memory consolidation is proposed.
Immunologic treatments for precancerous lesions and uterine cervical cancer (2014)

Development of HPV-associated cancers not only depends on efficient negative regulation of cell cycle control that supports the accumulation of genetic damage, but also relies on immune evasion that enable the virus to go undetected for long periods of time. In this way, HPV-related tumors usually present MHC class I down-regulation, impaired antigen-processing ability, avoidance of T-cell mediated killing, increased immunosuppression due to Treg infiltration and secrete immunosuppressive cytokines. Thus, these are the main obstacles that immunotherapy has to face in the treatment of HPV-related pathologies where a number of different strategies have been developed to overcome them including new adjuvants. Although antigen-specific immunotherapy induced by therapeutic HPV vaccines was proved extremely efficacious in pre-clinical models, its progression through clinical trials suffered poor responses in the initial trials. Later attempts seem to have been more promising, particularly against the well-defined precursors of cervical, anal or vulvar cancer, where the local immunosuppressive milieu is less active. This review focuses on the advances made in these fields, highlighting several new technologies (such as mRNA vaccine, plant-derived vaccine). The most promising immunotherapies used in clinical trials are also summarized, along with integrated strategies, particularly promising in controlling tumor metastasis and in eliminating cancer cells altogether.After the early promising clinical results, the development of therapeutic HPV vaccines need to be implemented and applied to the users in order to eradicate HPV-associated malignancies, eradicating existing perception (after the effectiveness of commercial preventive vaccines) that we have already solved the problem.
Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery (2012)

Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-β and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.
Hemodynamic variability and circadian rhythm in rats with heart failure: role of locomotor activity (1993)

Heart rate variability is known to be decreased by heart failure; however, the influences of concomitant diseases, changes in activity level, evolution through time, and abnormalities in the circadian rhythm are unknown. This study evaluated the influence of these factors by assessing hemodynamic variability in rats with heart failure (n = 8) and sham-operated controls (n = 8) through telemetric monitoring of heart rate, blood pressure, and locomotor activity for 8 wk. Hemodynamic variability was assessed by the standard deviation as well as hourly standard deviations and coefficients of variation of these variables over 48 h at 2, 4, and 8 wk after myocardial infarction. The circadian rhythm was investigated through power spectral analysis. Heart failure was associated with marked decreases in heart rate and mean arterial pressure variability and circadian rhythm without any differences in activity and no change through time. Heart failure in rats due to myocardial infarction in the absence of any confounding diseases is associated with marked abnormalities in hemodynamic variability and circadian rhythm independent of locomotor activity.
Modulation of in vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody. (1993)

Four human glioblastoma cell lines (U251, UWR1, UWR2, and UWR3) were tested for the expression of the cell surface receptor for urokinase-type plasminogen activator (uPA). To our knowledge there have been no previous reports about the uPA receptors (uPARs) in glioblastoma cell lines. All four glioblastoma cell lines we tested were found to bind recombinant Pro-uPA saturably and reversibly. Scatchard analysis of radioligand binding with acid-pretreated cells showed the presence of a single population of high-affinity uPARs on glioblastoma cells. Northern blot analysis confirmed that glioblastoma cells like other human cell lines express a 1.4-kilobase uPAR mRNA and 2.4-kilobase uPA mRNA. The significance of the uPAR in the invasive potential of the cells was examined by incubating uPAR antibody in an in vitro invasion assay. The anti-uPAR monoclonal antibody blocked the invasion effectively in a Matrigel assay, in which inhibition of invasion ranged between 20 and 57% for the cells studied. These data suggest that the uPARs contribute significantly to the invasive capacity of the cells, possibly by facilitating uPA activity.
Coordinate Upregulation of Interleukin-8 and Growth-Related Gene Product-α is Present in the Colonic Mucosa of Inflammatory Bowel Disease (2001)

A coordinate upregulation of IL-8 and GROalpha may be involved in the tissue injury in patients with IBD through their stimulatory effects on neutrophils.
Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes (1997)

o-Quinones are physiological oxidation products of catecholamines that contribute to redox cycling, toxicity and apoptosis, i.e. the neurodegenerative processes underlying Parkinson's disease and schizophrenia. The present study shows that the cyclized o-quinones aminochrome, dopachrome, adrenochrome and noradrenochrome, derived from dopamine, dopa, adrenaline and noradrenaline respectively, are efficiently conjugated with glutathione in the presence of human glutathione transferase (GST) M2-2. The oxidation product of adrenaline, adrenochrome, is less active as a substrate for GST M2-2, and more efficiently conjugated by GST M1-1. Evidence for expression of GST M2-2 in substantia nigra of human brain was obtained by identification of the corresponding PCR product in a cDNA library. Glutathione conjugation of these quinones is a detoxication reaction that prevents redox cycling, thus indicating that GSTs have a cytoprotective role involving elimination of reactive chemical species originating from the oxidative metabolism of catecholamines. In particular, GST M2-2 has the capacity to provide protection relevant to the prevention of neurodegenerative diseases.
Highly Variable Contents of Phenolics in St. John’s Wort Products Affect Their Transport in the Human Intestinal Caco-2 Cell Model: Pharmaceutical and Biopharmaceutical Rationale for Product Standardization (2010)

The purposes of this study were to determine content uniformity of phenolics in the St. John's wort (SJW) supplements and to demonstrate how variations in the product matrices affect their absorption and efflux. LC and LC-MS/MS methods were used to determine the phenolic contents of 12 different products purchased locally or from the Internet. Three representative extracts were further submitted to Caco-2 cell transport experiment, and transport of rutin, hyperoside, and isoquercitrin was evaluated. The results indicated that the 12 different products displayed 12 different HPLC fingerprints, but all products contained the following major compounds: rutin, hyperoside, isoquercitrin, quercitrin, quercetin, and amentoflavone. The content uniformity of these major compounds was poor across products, with the smallest difference in the amounts of amentoflavone (3.6-fold) and largest difference in that of isoquercitrin (28.8-fold). The Caco-2 experiments indicated transport of rutin in products was vectorial, with the permeabilities varied about 3.6-fold in both directions of transport. The vectorial permeabilities of hyperoside and isoquercitrin were similarly different. Use of efflux transporter inhibitor studies suggested that MRP2 was involved in isoquercitrin's efflux and the product matrix affected the extent of its efflux. In conclusion, different SJW supplements had highly variable contents of phenolics, and the variability in product matrix and phytochemical compositions affected the permeabilities of key phenolics across the Caco-2 monolayers, which may further affect their bioavailabilities. Therefore, standardization will be necessary to ensure safe and efficacious using of supplements such as SJW.
Room temperature operation of epitaxially grown Si/Si0.5Ge0.5/Si resonant interband tunneling diodes (1998)

Resonant interband tunneling diodes on silicon substrates are demonstrated using a Si/Si0.5Ge0.5/Si heterostructure grown by low temperature molecular beam epitaxy which utilized both a central intrinsic spacer and δ-doped injectors. A low substrate temperature of 370 °C was used during growth to ensure a high level of dopant incorporation. A B δ-doping spike lowered the barrier for holes to populate the quantum well at the valence band discontinuity, and an Sb δ-doping reduces the doping requirement of the n-type bulk Si by producing a deep n+ well. Samples studied from the as-grown wafers showed no evidence of negative differential resistance (NDR). The effect of postgrowth rapid thermal annealing temperature was studied on tunnel diode properties. Samples which underwent heat treatment at 700 and 800 °C for 1 min, in contrast, exhibited NDR behavior. The peak-to-valley current ratio (PVCR) and peak current density of the tunnel diodes were found to depend strongly on δ-doping placement and on the annealing conditions. PVCRs ranging up to 1.54 were measured at a peak current density of 3.2 kA/cm2.
High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study (2011)

We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
A Human Gene Encoding a Putative Basic Helix–Loop–Helix Phosphoprotein Whose mRNA Increases Rapidly in Cycloheximide-Treated Blood Mononuclear Cells (1994)

G0S8 is a member of a set of putative G0/G1 switch regulatory genes (G0S genes) selected by screening cDNA libraries prepared from blood mononuclear cells cultured for 2 hr with lectin and cycloheximide. Comparison of a full-length cDNA sequence with the corresponding genomic sequence reveals an open reading frame of 211 amino acids, distributed across 5 exons. The 24-kD protein has a basic domain preceding a potential helix-loop-helix domain which contains a QTK motif found about 60 amino acids from the carboxyl terminus in the loop region of several helix-loop-helix proteins. There are potential phosphorylation sites for protein kinase C, creatine kinase II, and protein tyrosine kinases and regions of sequence similarity to helix-loop-helix proteins, tyrosine phosphatases, and RNA and DNA polymerases. The genomic sequence contains a CpG island, suggesting expression in the germ line. Potential binding sites for transcription factors are present in the 5' flank and introns; these include Zif268/NGFI-A/EGR1/G0S30, NGFI-B, Ap1, and factors that react with retroviral long terminal repeats (LTRs). There are several potential interferon response elements and a serum response element in the 3' flank overlapping a region of similarity to a cytomegalovirus immediate-early gene enhancer. Many of these motifs are found in immediate-early G0/G1 switch genes; however, we were unable to demonstrate an increase in G0S8 mRNA in response to lectin alone. Sequence similarities are noted between G0S8 and a variety of genes involved in the immune system, in the regulation of retroviruses, and in the cell cycle.
Topic Modeling using Variational Auto-Encoders with Gumbel-Softmax and Logistic-Normal Mixture Distributions (2018)

Probabilistic Topic Models are widely applied in many NLP-related tasks due to their effective use of unlabeled data to capture variable dependencies. Analytical solutions for Bayesian inference of such models, however, are usually intractable, hindering the proposition of highly expressive text models. In this scenario, Variational Auto-Encoders (VAEs), where an inference network (the encoder) is used to approximate the posterior distribution, became a promising alternative for inferring latent topic distributions of text documents. These models, however, also pose new challenges such as the requirement of continuous and reparameterizable distributions which may not fit so well the true latent topic distributions. Moreover, inference networks are prone to component collapsing, impairing the collection of coherent topics. To overcome these problems, we propose two new text topic models based on the categorical distribution Gumbel-Softmax (GSDTM) and on mixtures of Logistic-Normal distributions (LMDTM). We also provide a study on the impact of different modeling choices on the generated topics, observing a trade-off between topic coherence and document reconstruction. Through experiments using two reference datasets, we show that GSDTM largely outperforms previous state-of-the-art baselines when considering three different evaluation metrics.