gebhart/patrepeval huggingface dataset:
Combining DNA damaging therapeutics with immunotherapy: more haste, less speed (2017)

The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.
Evaluation of the Virulence of a Streptococcus pneumoniae Neuraminidase-Deficient Mutant in Nasopharyngeal Colonization and Development of Otitis Media in the Chinchilla Model (2000)

Considerable evidence has implicated Streptococcus pneumoniae neuraminidase in the pathogenesis of otitis media (OM); however, its exact role has not been conclusively established. Recently, an S. pneumoniae neuraminidase-deficient mutant, DeltaNA1, has been constructed by insertion-duplication mutagenesis of the nanA gene of S. pneumoniae strain D39. The relative ability of DeltaNA1 and the D39 parent strain to colonize the nasopharynx and to induce OM subsequent to intranasal inoculation and to survive in the middle ear cleft after direct challenge of the middle ear were evaluated in the chinchilla model. Nasopharyngeal colonization data indicate a significant difference in the ability of the DeltaNA1 mutant to colonize as well as to persist in the nasopharynx. The neuraminidase-deficient mutant was eliminated from the nasopharynx 2 weeks earlier than the D39 parent strain. Both the parent and the mutant exhibited similar virulence levels and kinetics during the first week after direct inoculation of the middle ear. The DeltaNA1 neuraminidase-deficient mutant, however, was then completely eliminated from the middle ear by day 10 postchallenge, 11 days before the D39 parent strain. Data from this study indicate that products of the nanA gene have an impact on the ability of S. pneumoniae to colonize and persist in the nasopharynx as well as the middle ear.
Diabetic dyslipidaemia: past, present and future (2004)

Abstract Prevention of cardiovascular disease (CVD) in diabetes remains a major challenge for both physicians and patients. Diabetic dyslipidaemia is a major risk factor for CVD and is open to therapeutic intervention. Information now available from randomised, controlled, clinical trials (principally with statins) confirms highly significant benefits in terms of CVD reduction for diabetic patients with and without symptomatic CVD. This evidence base has moved treatment of dyslipidaemia to centre stage in CVD prevention. Important European and American guidelines point to the high CVD risk in type 2 diabetes and type 1 diabetes with albuminuria and advocate aggressive lipid management for primary as well as secondary CVD prevention. Currently there is evidence of sub‐optimal uptake of appropriate lipid‐lowering therapy and guidelines need to be fully implemented in clinical practice for the benefit of individual patients. In the future it is likely that more combination therapy will be used to treat diabetic dyslipidaemia in order to achieve better overall lipid control. Copyright © 2004 John Wiley &amp; Sons, Ltd.
SINGULARITY THEORY APPROACH TO SWEPT VOLUMES (2000)

An approach to the study of the topology and geometry of swept volumes is developed based on the theory of singularities of sweep mappings. It is shown how the computation of the critical point and bifurcation sets of a certain (sweep) mapping yields important information about both the local and global structure of swept volumes. For example, it is proved under mild restrictions that a swept volume can be arbitrary closely approximated by a product manifold. A computer program – incorporating singularity calculations – for the approximate analysis and representation of swept volumes is developed and applied to several examples in order to demonstrate its usefulness.
Green fluorescent protein as an indicator to monitor membrane protein overexpression in Escherichia coli (2001)

Escherichia coli is one of the most widely used vehicles to overexpress membrane proteins (MPs). Currently, it is not possible to predict if an overexpressed MP will end up in the cytoplasmic membrane or in inclusion bodies. Overexpression of MPs in the cytoplasmic membrane is strongly favoured to overexpression in inclusion bodies, since it is relatively easy to isolate MPs from membranes and usually impossible to isolate them from inclusion bodies. Here we show that green fluorescent protein (GFP), when fused to an overexpressed MP, can be used as an indicator to monitor membrane insertion versus inclusion body formation of overexpressed MPs in E. coli. Furthermore, we show that an overexpressed MP can be recovered from a MP-GFP fusion using a site specific protease. This makes GFP an excellent tool for large-scale MP target selection in structural genomics projects.
Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition (2018)

PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.
Microarray expression analysis and identification of serum biomarkers for Niemann–Pick disease, type C1 (2012)

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.
Identification of high affinity receptors for human monocyte chemoattractant protein-1 on human monocytes. (1990)

The binding of human monocyte chemoattractant protein-1 (MCP-1) to human monocytes was studied. MCP-1 was radioiodinated with Iodo-beads (Pierce Chemical Co., Rockford, IL) without significant loss of biologic activity. 125I-MCP-1 binding to PBMC occurred within 5 min at 0 degrees C and the binding was inhibited by unlabeled MCP-1 dose dependently but not by neutrophil attractant/activation protein-1 or FMLP. 125I-MCP-1 bound to monocytes; no significant binding to either neutrophils or lymphocytes was observed. Scatchard plot analysis indicated that monocytes had a minimum of 1700 +/- 600 binding sites per cell with a Kd of 1.9 +/- 0.2 x 10(-9) M. For analysis of binding by flow cytometry, MCP-1 was biotinylated. In contrast to radioiodination, biotinylation resulted in loss of activity; potency was 10-fold less, but the efficacy was retained. Detection by flow cytometry of bound biotinylated MCP-1 with avidin-FITC confirmed results obtained with 125I-MCP-1. Biotinylated MCP-1 bound to monocytes but not to lymphocytes; and the binding was inhibited by a 100-fold excess of unlabeled MCP-1.
Comparison of the Immunopharmacological Activities of Triple and Single-Helical Schizophyllan in Mice. (1995)

(1-->3)-beta-D-Glucans exhibit a variety of biological and immunopharmacological activities, and the significance of these activities is dependent on the structure of the glucans such as molecular weight, degree of branching, and conformation. Based on the generally accepted evidence that the conformation of clinically used Sonifilan (SPG) is a triple helix, we prepared alkaline treated SPG (SPG-OH) as a single helix conformer. In this report, we examined (A) the antitumor effect on a solid form tumor in vivo, (B) hematopoietic response on cyclophosphamide induced leukopenia, (C) antagonistic effect for zymosan mediated-hydrogen peroxide synthesis on peritoneal macrophage (PM), (D) priming effect of lipopolysaccharide (LPS) triggered tumor necrosis factor (TNF) synthesis, (E) nitric oxide synthesis of PM in vivo, and (F) hydrogen peroxide synthesis of PM in vivo. Both SPG and SPG-OH showed a significant effect on (A) and (B). The activity on (C) was stronger in SPG than SPG-OH. The activities of (D), (E), and (F) were stronger in SPG-OH. These facts strongly suggested that the glucan-mediated immunopharmacological activities were dependent on the helical conformation, and the conformation dependency varied dependent on the assays used.
Comparison of Anatomic and Neurophysiological Methods for Subthalamic Nucleus Targeting (2000)

Although all anatomic targeting methods provide accurate STN localization, a combination of the three methods offers the best correlation with the final physiological target. In our experience, direct magnetic resonance targeting was the least accurate method.
An Integrated Model of Top-Down and Bottom-Up Attention for Optimizing Detection Speed (2006)

Integration of goal-driven, top-down attention and image-driven, bottom-up attention is crucial for visual search. Yet, previous research has mostly focused on models that are purely top-down or bottom-up. Here, we propose a new model that combines both. The bottom-up component computes the visual salience of scene locations in different feature maps extracted at multiple spatial scales. The topdown component uses accumulated statistical knowledge of the visual features of the desired search target and background clutter, to optimally tune the bottom-up maps such that target detection speed is maximized. Testing on 750 artificial and natural scenes shows that the model’s predictions are consistent with a large body of available literature on human psychophysics of visual search. These results suggest that our model may provide good approximation of how humans combine bottom-up and top-down cues such as to optimize target detection speed.
WNT signalling events near the cell membrane and their pharmacological targeting for the treatment of cancer (2017)

This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
Properties and active center of the thermostable branching enzyme from Bacillus stearothermophilus (1994)

Although the branching enzyme (EC 2.4.1.18) is a member of the alpha-amylase family, the characteristics are not understood. The thermostable branching enzyme gene from Bacillus stearothermophilus TRBE14 was cloned and expressed in Escherichia coli. The branching enzyme was purified to homogeneity, and various enzymatic properties were analyzed by our improved assay method. About 80% of activity was retained when the enzyme was heated at 60 degrees C for 30 min, and the optimum temperature for activity was around 50 degrees C. The enzyme was stable in the range of pH 7.5 to 9.5, and the optimum pH was 7.5. The nucleotide sequence of the gene was determined, and the active center of the enzyme was analyzed by means of site-directed mutagenesis. The catalytic residues were tentatively identified as two Asp residues and a Glu residue by comparison of the amino acid sequences of various branching enzymes from different sources and enzymes of the alpha-amylase family. When the Asp residues and Glu were replaced by Asn and Gln, respectively, the branching enzyme activities disappeared. The results suggested that these three residues are the catalytic residues and that the catalytic mechanism of the branching enzyme is basically identical to that of alpha-amylase. On the basis of these results, four conserved regions including catalytic residues and most of the substrate-binding residues of various branching enzymes are proposed.
The adaptive bases algorithm for intensity-based nonrigid image registration (2003)

Nonrigid registration of medical images is important for a number of applications such as the creation of population averages, atlas-based segmentation, or geometric correction of functional magnetic resonance imaging (fMRI) images to name a few. In recent years, a number of methods have been proposed to solve this problem, one class of which involves maximizing a mutual information (MI)-based objective function over a regular grid of splines. This approach has produced good results but its computational complexity is proportional to the compliance of the transformation required to register the smallest structures in the image. Here, we propose a method that permits the spatial adaptation of the transformation's compliance. This spatial adaptation allows us to reduce the number of degrees of freedom in the overall transformation, thus speeding up the process and improving its convergence properties. To develop this method, we introduce several novelties: 1) we rely on radially symmetric basis functions rather than B-splines traditionally used to model the deformation field; 2) we propose a metric to identify regions that are poorly registered and over which the transformation needs to be improved; 3) we partition the global registration problem into several smaller ones; and 4) we introduce a new constraint scheme that allows us to produce transformations that are topologically correct. We compare the approach we propose to more traditional ones and show that our new algorithm compares favorably to those in current use.
Postsynthetic DNA Modification through the Copper‐Catalyzed Azide–Alkyne Cycloaddition Reaction (2008)

The attachment of labels onto DNA is of utmost importance in many areas of biomedical research and is valuable in the construction of DNA-based functional nanomaterials. The copper(I)-catalyzed Huisgen cycloaddition of azides and alkynes (CuAAC) has recently been added to the repertoire of DNA labeling methods, thus allowing the virtually unlimited functionalization of both small synthetic oligonucleotides and large gene fragments with unprecedented efficiency. The CuAAC reaction yields the labeled polynucleotides in very high purity after a simple precipitation step. The reviewed technology is currently changing the way in which functionalized DNA strands are generated cost-efficiently in high quality for their application in molecular diagnostics systems and nanotechnological research.
The Normal Apex Cardiogram (1964)

The configuration of the apex cardiogram and its temporal relationship to the electrocardiogram, phonocardiogram, carotid pulse, and jugular venous pulse were analyzed in 25 normal subjects. In two patients with rheumatic valvular disease simultaneous electrocardiograms, phonocardiograms, left intraventricular pressure and apex cardiograms were obtained. In all cases the apex cardiogram showed a characteristic and reproducible contour in both its systolic and diastolic components. The curves of the apex cardiogram display all consecutive phases of the cardiac cyle; contraction-and-emptying and relaxation-and-filling. It bears a constant relationship to the phonocardiogram and is more useful as a reference tracing for acoustic events than the electrocardiogram, carotid pulse, or jugular venous pulse. The onset of the systolic wave of the apex cardiogram precedes the rise of left intraventricular pressure and mitral valve closure. The maximal systolic peak of the apex cardiogram occurs simultaneously with the onset of left ventricular ejection and the rise of the carotid pulse pressure. Small deflections are frequently inscribed on the apex cardiogram at the time of mitral, tricuspid, and aortic valve closure. The wave form of the apex cardiogram is caused primarily by movements of the left ventricle against the chest wall. It is thus a translation of the sequence of hemodynamic events occurring in the underlying left ventricle. The inaccuracy of the jugular venous pulse for timing right- and left-sided cardiac events is emphasized.
Large vocabulary continuous speech recognition using HTK (2002)

HTK is a portable software toolkit for building speech recognition systems using continuous density hidden Markov models developed by the Cambridge University Speech Group. One particularly successful type of system uses mixture density tied-state triphones. We have used this technique for the 5 k/20 k word ARPA Wall Street Journal (WSJ) task. We have extended our approach from using word-internal gender independent modelling to use decision tree based state clustering, cross-word triphones and gender dependent models. Our current systems can be run with either bigram or trigram language models using a single pass dynamic network decoder. Systems based on these techniques were included in the November 1993 ARPA WSJ evaluation, and gave the lowest error rate reported on the 5 k word bigram, 5 k word trigram and 20 k word bigram "hub" tests and the second lowest error rate on the 20 k word trigram "hub" test.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Magnesium Methyl Carbonate-Activated Alkylation of Methyl Ketones with an ω-Halo Nitrile, Esters, and Amides (1997)

Terminally substituted, extended-chain derivatives of the 2-dibenzofuranyl methyl ketone 6 and its phenylethyl analogue 12 were readily obtained by converting the ketones to magnesium chelates of their β-carboxylated enolates with magnesium methyl carbonate (MMC, methyl methoxymagnesium carbonate, Stiles's reagent), followed by alkylation in situ with ω-halo compounds, X(CH2)nY where X = Br and Y = CO2Me, CN, CONMe2, CON(i-Pr)2, CON(CH2)4, or CON(CH2)5 for n = 1; X = Br or I, and Y = CO2Me for n = 2; and X = Br and Y = CO2Me for n = 3. Dimethylcarbamoyl chloride (n = 0) gave products derived from MMC and the solvent, N,N-dimethylformamide. The order of reactivity of the halides was α > β > γ and β-I > β-Br. β-Bromo amides were found to be unsuitable reactants. Lower reaction temperatures favored alkylation over competing elimination of HX from methyl β-halopropionate. No self-condensation products of the ketones were observed; however, bis-alkylation and monomethylation products were formed when reaction times were prolonged. In contrast to the unsubstituted β-keto acid 13, all intermediate α-alkyl β-keto acids decarboxylated during the reaction or the workup.
Interleukin-1 alpha differentially synchronizes estrogen-dependent and estrogen-independent human breast cancer cells in the G0/G1 phase of the cell cycle. (1991)

Direct in vitro effects of IL-1 alpha on cell cycle progression of the estrogen-responsive, MCF-7, and estrogen-unresponsive, MDA-231, human breast cancer cells were investigated by flow cytometry. IL-1 alpha, at nanomolar concentrations, caused the synchronization of MCF-7, but not MDA-231, cells in the G0/G1 phase of the cell cycle. The S phase of IL-1 treated MCF-7 cells was correspondingly decreased. The IL-1 induced synchronization of MCF-7 cells was observed in the dose range of 10(-11) M to 10(-7) M and was seen as early as 6 h after the start of treatment. Furthermore, these effects were shown to be sensitive to the weak estrogen, phenol red, since the IL-1-induced shifts in G0/G1 and S phases were markedly blunted in its presence. In cell proliferation experiments, the IL-1-induced synchronization of MCF-7 cells increased the cytotoxic efficacy of the chemotherapeutic drug, 5-fluorodeoxyuracil. These data demonstrate that IL-1 by arresting the estrogen-responsive human breast cancer cells, MCF-7, in the G0/G1-phase of the cell cycle can not only directly inhibit the growth of MCF-7 cells, but also increase the efficacy of FUDR.
Proteosome-Lipopeptide Vaccines: Enhancement of Immunogenicity for Malaria CS Peptides (1988)

Proteosomes are hydrophobic, membranous, multimolecular preparations of meningococcal outer membrane proteins that are also B cell mitogens. These characteristics suggested that proteosomes may serve as carrier proteins and adjuvants to enhance peptide immunogenicity. Although high titers of malaria circumsporozoite (CS) antibodies protect against malaria, vaccines thus far tested in humans have been insufficiently immunogenic to be clinically useful. Here it is shown that synthetic CS peptides hydrophobically complexed to proteosomes by way of lauroyl-cysteine become highly immunogenic in mice without other adjuvants. The high titers of antibodies produced and the safety of proteosomes in humans suggest that this novel system is widely applicable for the development of peptide vaccines to protect against many diseases.