gebhart/patrepeval huggingface dataset:
Mechanisms of resistance to immune checkpoint inhibitors (2018)

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors ('targeted therapies') largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
Improving compiler-runtime separation with XIR (2010)

Intense research on virtual machines has highlighted the need for flexible software architectures that allow quick evaluation of new design and implementation techniques. The interface between the compiler and runtime system is a principal factor in the flexibility of both components and is critical to enabling rapid pursuit of new optimizations and features. Although many virtual machines have demonstrated modularity for many components, significant dependencies often remain between the compiler and the runtime system components such as the object model and memory management system. This paper addresses this challenge with a carefully designed strict compiler-runtime interface and the XIR language. Instead of the compiler backend lowering object operations to machine operations using hard-wired runtime-specific logic, XIR allows the runtime system to implement this logic, simultaneously simplifying and separating the backend from runtime-system details. In this paper we describe the design and implementation of this compiler-runtime interface and the XIR language in the C1X dynamic compiler, a port of the HotSpotTM Client compiler. Our results show a significant reduction in backend complexity with XIR and an overall reduction in the compiler-runtime interface complexity while still generating comparable quality code with only minor impact on compilation time.
(4-Hydroxy-3-nitro)benzylated Polystyrene. An Improved Polymeric Nitrophenol Derivative for Peptide Synthesis (1974)

Insoluble (4-hydroxy-3-nitro)benzylated polystyrene (PHNB) was prepared by reacting 4-hydroxy-3-nitrobenzyl chloride with copolystyrene-2%-divinylbenzene in the presence of aluminium trichloride. PHNB-active esters of many N-blocked amino acids were prepared using dicyclohexylcarbodiimide as a coupling agent, and used for the preparation of di, tri and tetra-peptides. The synthesis of the tetra-peptide Boc-l-Leu-l-Leu-l-Val-OBzl-l-Tyr-OBzl, was effected by means of the polymeric active esters of Boc-l-Val and Boc-l-Leu. The synthesis was initiated by reacting O-benzyl-l-tyrosine benzyl ester with Boc-Val-PHNB in dichloromethane to yield N-tert-butyloxycarbonyl-l-valyl-O-benzyl-l- tyrosine benzyl ester. Removal of the tert-butyloxycarbonyl group yielded a dipeptide ester which was coupled with the corresponding polymeric active ester to yield an N-blocked tripeptide ester. Repetition of this set of reactions led to the formation of the pure blocked tetrapeptide in 82% over-all yield.
Chemical Action of Halogenated Agents in Fire Extinguishing (1955)

From Summary: "The action of halogenated agents in preventing flame propagation in fuel-air mixtures in laboratory tests is discussed in terms of a possible chemical mechanism. The mechanism chosen is that of chain-breaking reactions between agent and active particles (hydrogen and oxygen atoms and hydroxyl radicsls). Data from the literature on the flammability peaks of n-heptane agent-air mixtures are treated. Ratings of agent effectiveness in terms of the fuel equivalent of the agent, based on both fuel and agent concentrations at the peak, are proposed as preferable to ratings in terms of agent concentration alone."
Clinical Efficacy of BG-12 (Dimethyl Fumarate) in Relapsing–Remitting Multiple Sclerosis (RRMS): An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies (P07.097) (2013)

OBJECTIVE: To report a pre-specified integrated analysis of clinical efficacy data from DEFINE and CONFIRM, which was conducted to obtain more precise estimates of the treatment effect of BG-12 (dimethyl fumarate) versus placebo.
Synthesis of nitrogen-substituted cycloparaphenylenes (2014)

Bottom-up synthesis is increasingly becoming the method of choice for assembling and studying novel nanomaterials. Whereas more traditional top-down methods may lead to mixtures of products and suffer from reproducibility issues, bottom-up approaches offer atomistic control over the material's structure. Bottom-up synthesis can also produce materials that would otherwise be unobtainable with top-down methodologies. Finite substructures of carbon nanotubes (CNTs) are one such example. The work encompassed in this thesis details the study of two related classes of CNT substructures: the cycloparaphenylenes (CPPs) and [5.7]ncyclacenes. &#13;\n&#13;\nCycloparaphenylenes are a class of graphitic material with many unique properties that make them intriguing candidates for study in a variety of electronic applications. Chapter 1 describes the current state of CPP research, from preliminary synthesis to fundamental understanding of their properties. To optimize device performance, carbon materials are often doped with heteroatoms. Towards this end, the synthesis of a series of nitrogen-doped [8]CPPs (N-[8]CPPs) are detailed in Chapter 2. Nitrogen is incorporated into the CPP structure by way of the reductive aromatization strategy used for the all carbon CPPs, replacing 1,4-dibromobenzene with 2,5-dibromopyridine. The synthesis utilizes oxidatively masked benzenes to assemble less strained, macrocyclic precursors. Through the divergent nature of the synthesis, macrocycles containing up to three nitrogen atoms at precise locations are prepared. Macrocycles are aromatized via a single electron reduction to reveal the final N-CPP structures. Chapter 3 details the full characterization of the properties of the novel N-[8]CPPs. The differences between the N-[8]CPPs and [8]CPP are rationalized in the context of DFT studies. Finally, the study of 1N-[8]CPP and [8]CPP as novel electrode materials in supercapacitor cells is presented. Preliminary results show that the CPP electrodes are more conductive than the activated carbon control group, but the specific capacitances are found to be low. &#13;\n&#13;\nFinally, Chapter 4 describes the computational study of a novel family of macrocycle: [5.7]ncyclacenes. [5.7]ncyclacenes are isomers of the sought after [n]cyclacenes. Unlike their isomeric cousins, DFT studies show that [5.7]ncyclacenes have stable, closed-shell singlet ground states with relatively low strain energies. NICS values also show the molecules to be non-aromatic. These results suggest that with proper synthetic design, the [5.7]ncyclacenes should be accessible synthetically.
Neuropeptides activate human mast cell degranulation and chemokine production (2007)

During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcepsilonRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34(+) progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-gamma (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte-macrophage colony-stimulating factor, but not IL-4, interferon-gamma or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.
PECAM-1, Apoptosis and CD34<sup>+</sup> Precursors (2004)

Apoptosis is a physiological process that controls tissue homeostasis, in combination with survival signals delivered by distinct receptors that bind hormones, growth factors or extracellular matrix components. The extrinsic pathway of apoptosis is due to the triggering of death receptors and the activation of the caspase cascade; the intrinsic pathway is due to withdrawal of growth factors and mainly related to mitochondrial metabolism. The choice between survival or apoptosis, which is the result of such different integrated environmental signals, is crucial for the maintainance of bone marrow reservoir of hematopoietic precursors (HPC). CD34+ HPC can receive multiple survival signals during homing and maturation, due to different interactions with adhesion molecules expressed on endothelial and bone marrow stromal cells, proteins of the extracellular matrix and chemokines or growth factors. Among them, the signal delivered via platelet endothelial cell adhesion molecule-1 (PECAM-1) seems to contribute to the resistance of this cell population to starvation, and it is related to the maintainance of mitochondrial metabolism. Indeed, this molecule, originally described as an adhesion receptor belonging to the immunoglobulin superfamily, capable of homophilic and heterophilic interactions, turned out to be a signalling molecule, containing an immunoreceptor tyrosine-based inhibitory motifs (ITIM) within its cytoplasmic domain. In particular, it has been shown that PECAM-1 binds to different kinases and phosphatases, including the phosphatidylinositide-3-kinase that phosphorylates Akt, which, in turn can upregulate transcription and function of antiapoptotic proteins, such as Bcl-2 and Bcl-x or A1, responsible for the rescue from mitochondrial apoptosis. The possible role of PECAM-1 engagement in the prevention of starvation-induced apoptosis of HPC precursors and in the maintainance of their survival is discussed.
MRI of the basement membrane using charged nanoparticles as contrast agents (2008)

The integrity of the basement membrane is essential for tissue cellular growth and is often altered in disease. In this work a method for noninvasively detecting the structural integrity of the basement membrane, based on the delivery of cationic iron-oxide nanoparticles, was developed. Cationic particles accumulate due to the highly negative charge of proteoglycans in the basement membrane. The kidney was used to test this technique because of its highly fenestrated endothelia and well-established disease models to manipulate the basement membrane charge barrier. After systemic injection of cationic or native ferritin (CF or NF) in rats, ex vivo and in vivo MRI showed selective accumulation of CF, but not NF, causing a 60% reduction in signal intensity in cortex at the location of individual glomeruli. Immunofluorescence and electron microscopy demonstrated that this CF accumulation was localized to the glomerular basement membrane (GBM). In a model of GBM breakdown during focal and segmental glomerulosclerosis, MRI showed reduced single glomerular accumulation of CF, but a diffuse accumulation of CF in the kidney tubules caused by leakage of CF through the glomerulus. Cationic contrast agents can be used to target the basement membrane and detect the breakdown of the basement membrane in disease.
Transformations of steroidal neopentyl systems. Part IV. Stereochemistry of products of reaction of methyl-lithium with Δ<sup>5</sup>-19-aldehydes (1968)

The reaction of methyl-lithium with 3β,17β-diacetoxyandrost-5-en-19-al and certain transformations of the derived products have been studied. Only the 19R-alcohol was formed by this reaction and its stereochemistry was proved through transformation into 17β-acetoxy-3α-methoxy-19-methyl-5α-androstane 3,19-oxide (9d). A reduction–oxidation reaction involving a 1,5-hydride ion transfer was observed during ethylene dioxide formation.
Increased Ubiquitin Expression Suppresses the Cell Cycle Defect Associated with the Yeast Ubiquitin Conjugating Enzyme, CDC34 (UBC3) (1995)

The yeast ubiquitin (Ub) conjugating enzyme CDC34 plays a crucial role in the progression of the cell cycle from the G1 to S phase. In an effort to identify proteins that interact with CDC34 we undertook a genetic screen to isolate genes whose increased expression suppressed the cell cycle defect associated with the cdc34-2 temperature-sensitive allele. From this screen, the poly-Ub gene UBI4 was identified as a moderately strong suppressor. The fact that the overexpression of a gene encoding a single Ub protein could also suppress the cdc34-2 allele indicated that suppression was related to the increased abundance of Ub. Ub overexpression was found to suppress two other structurally unrelated cdc34 mutations, in addition to the cdc34-2 allele. In all three cases, suppression depended on the expression of Ub with an intact carboxyl terminus. Only the cdc34-2 allele, however, could be suppressed by Ub with an amino acid substitution at lysine 48 which is known to be involved in multi-Ub chain assembly. Genetic results showing allele specific suppression of cdc34 mutations by various Ub derivatives suggested a specific noncovalent interaction between Ub and CDC34. Consistent with this prediction, we have shown by chemical cross-linking the existence of a specific noncovalent Ub binding site on CDC34. Together, these genetic and biochemical experiments indicate that Ub suppression of these cdc34 mutations results from the combined contributions of Ub-CDC34 thiol ester formation and a noncovalent interaction between Ub and CDC34 and therefore suggest that the correct positioning of Ub on a surface of the ubiquitin conjugating enzyme is a requirement of enzyme function.
Involvement of the M7/M8 Extracellular Loop of the Sodium Pump α Subunit in Ion Transport (1997)

Mutations were introduced in the motif 884DDRW887 from an extracellular peptide of the sodium pump alpha subunit localized between M7 and M8 membrane spans to investigate a possible role of this structure in ion recognition. A homologous sequence 399QDCW402 that occurs in the P-loops of Na+ channels was shown earlier to be important for ion gating. Mutant sodium pumps were expressed in yeast and subsequently investigated for their behavior toward ouabain, Na+, K+, and ATP. Native enzyme and D884A, D884R, D885A, D885E, or D885R mutants all bind ouabain in the presence of phosphate and Mg2+. The KD values determined from Scatchard analysis are in the range 5-8 nM for the native enzyme and the D884A, D885E, or D885A mutants, and 15.7 +/- 2.04 and 30.1 +/- 4.32 nM for mutants D884R and D885R, respectively. This ouabain binding is reduced in the presence of K+ in a similar way for both native or mutant sodium pumps with relative affinities (K0.5) for K+ ranging from 1.4 to 3.7 mM. Ouabain binding in the presence of 100 microM ATP is promoted by Na+ with K0.5 = 1.64 +/- 0.01 mM for the native enzyme and K0.5 = 8. 6 +/- 1.35 mM for the D884R mutant. The K0.5 values of the two enzymes for ATP are 0.66 +/- 0.16 microM and 1.1 +/- 0.12 microM, respectively. Ouabain binding as a function of Na+ concentration, on the other hand, is very low for the D885R mutant, even at an ATP concentration of 2 mM. Phosphate or eosin, however, are recognized by this mutant enzyme, so that a major conformational change within the ATP-binding site appears unlikely. The inability of the D885R mutant to bind ouabain in the presence of Na+ and ATP could be explained by assuming that the M7/M8 connecting extracellular loop, which also contains the mutated amino acids, is invaginated within the plane of the plasma membrane and possibly involved in acceptance and/or release of Na+ ions coming from cytosolic areas of the protein. In this case, the placement of an additional positive charge might repel Na+ ions and interrupt their flow, thus not allowing the enzyme to assume the proper conformational state for ouabain binding. Such invaginated hydrophilic protein structures, such as the P-loops of Na+ and K+ channels, are already known and have been shown to participate in ion conduction.
New macromodels and measurements for the analysis of EMI effects in 741 op-amp circuits (1991)

Presents the design of two macromodels for the 741 op-amp that prove trustworthy in simulating the consequences of high-frequency, large-amplitude sinusoidal voltages that represent EMI (electromagnetic interference) effects and are applied to the input of inverting and noninverting amplifiers. One of the macromodels accounts for power supply voltage change, reproduces correct voltage waveforms at the main nodes of the full circuit, and gives rise to computer time saving factors of 5 or more in comparison with full device-level simulations. The other comprises the minimum number of components necessary to estimate the DC output voltage only and reduces the simulation time by a further factor of about 5. Extensive experimental results were obtained from laboratory measurements and are compared with the numerical simulations.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Discerning structure from freeform handwritten notes (2004)

This paper presents an integrated approach to parsing textual structure in freeform handwritten notes. Text-graphics classification and text layout analysis are classical problems in printed document analysis, but the irregularity in handwriting and content in freeform notes reveals limitations in existing approaches. We advocate an integrated technique that solves the layout analysis and classification problems simultaneously: the problems are so tightly coupled that it is not possible to solve one without the other for real user notes. We tune and evaluate our approach on a large corpus of unscripted user files and reflect on the difficult recognition scenarios that we have encountered in practice.
A study of locking objects with bimodal fields (1999)

Object locking can be efficiently implemented by bimodal use of a field reserved in an object. The field is used as a lightweight lock in one mode, while it holds a reference to a heavyweight lock in the other mode. A bimodal locking algorithm recently proposed for Java achieves the highest performance in the absence of contention, and is still fast enough when contention occurs.
Surface-Tethered DNA Complexes for Enhanced Gene Delivery (2002)

Overcoming the barriers to efficient gene transfer is a fundamental goal of biotechnology. A versatile approach to enhance the delivery of nonviral DNA involves complexation with cationic polymers, which can be designed to overcome the barriers to effective gene transfer. More recently, DNA release from a polymer substrate or scaffold has been shown to enhance gene transfer, likely by increasing DNA concentrations in the cell microenvironment. We propose a novel approach that combines these two strategies in which cationic polymer/DNA complexes are tethered to a substrate that supports cell adhesion. The cationic polymers package the DNA for efficient internalization and the surface tethering functions to maintain elevated concentrations in the cell microenvironment for cells adhered to the substrate. The cationic polymer polylysine (degree of polymerization equal to 19 or 150) was modified with biotin groups, which was confirmed by mass spectrometry and biochemical analysis. Complex formation of DNA with biotinylated-polylysine, or mixtures of biotinylated and nonbiotinylated polylysines, was confirmed by gel electrophoresis. Plasmid DNA encoding for the reporter gene beta-galactosidase was complexed with different mixtures of biotinylated and nonbiotinylated polylysine and incubated on neutravidin (nonglycosylated avidin)-coated surfaces. DNA surface densities ranging from 0.1 to 4.3 microg/cm2 were observed and found to be a function of the number of biotin groups, the molecular weight of the polylysine, and the amount of DNA. HEK293T or NIH/3T3 cells were then seeded onto the DNA-modified surfaces, and transfection was quantified at 48 and 96 h. Transfection by the DNA surfaces was observed with both cell lines, and expression levels up to 100 fold greater than bulk delivery of the complexes was obtained. Transfection was found to be a function of the surface DNA quantities and the number of tethers on the complex. Transfected cells were observed only in the region in which DNA complexes were tethered, suggesting that the location of transfected cells can be specifically controlled. Surface tethering of DNA represents a promising approach to enhancing gene transfer and spatially controlling gene delivery, which may have applications to a multitude of fields ranging from tissue engineering to functional genomics.
Integrated solution to purification challenges in the manufacture of a soluble recombinant protein in <i>E. coli</i> (2009)

Apolipoprotein A 1 Milano (ApoA-1M), the protein component of a high-density lipoprotein (HDL) mimic with promising potential for reduction of atherosclerotic plaque, is produced at large scale by expression in E. coli. Significant difficulty with clearance of host cell proteins (HCPs) was experienced in the original manufacturing process despite a lengthy downstream purification train. Analysis of purified protein solutions and intermediate process samples led to identification of several major HCPs co-purifying with the product and a bacterial protease potentially causing a specific truncation of ApoA-1M found in the final product. Deletion of these genes from the original host strain succeeded in substantially reducing the levels of HCPs and the truncated species without adversely affecting the overall fermentation productivity, contributing to a much more efficient and robust new manufacturing process.