gebhart/patrepeval huggingface dataset:
In lymph node‐negative invasive breast carcinomas, specific chromosomal aberrations are strongly associated with high mitotic activity and predict outcome more accurately than grade, tumour diameter, and oestrogen receptor (2003)

The objectives of this study were to analyse whether specific chromosomal gains and losses in lymph node-negative breast cancer correlate with other features and to evaluate their prognostic value. Seventy-six lymph node-negative breast carcinomas (median follow-up 46 months; range 9-105 months) were used. Histological grade, tumour type, maximal tumour diameter, oestrogen/progesterone receptor (ER/PR), mitotic activity index (MAI), and mean nuclear area (MNA) were assessed. Whole genome DNA analysis was performed by comparative genomic hybridization (CGH). Chromosomal aberrations were compared with classical and other prognostic features. Kaplan-Meier curves and multivariate survival analysis (Cox model) were used to assess the prognostic value of the CGH and other data. Fifteen (21.4%) out of 70 patients (six cases were lost to follow-up) developed locoregional (n=3) or distant metastases (n=12). The following criteria were prognostic for (any) recurrence (in decreasing significance): 3q gain, simultaneous gain at 1q and 8q, MAI < versus > or =10, MNA < versus > or =63 microm. Loss of 1p occurred significantly more often in the large group of ductal breast carcinomas with a MAI > or =10 (n=38) than in cancers with a MAI<10. Moreover, 8/15 (53%) patients with recurrences had a gain at 3q, as opposed to three (5.5%) of the 55 recurrence-free patients. This association was even stronger in ductal carcinomas (hazard ratio=10.9, p<0.0001). Cox regression revealed that the 3q gain was the strongest prognostic factor; other features did not have additional prognostic value. In conclusion, loss of 1p is associated with a high MAI. A gain of 3q is a stronger predictor of recurrence than grade, MAI, and other features in invasive breast cancers.
Fully 2‘-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability Compared to Unmodified Small Interfering RNA (2005)

We have identified a small interfering RNA (siRNA) motif, consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides, that displays enhanced plasma stability and increased in vitro potency. At one site, this motif showed remarkable >500-fold improvement in potency over the unmodified siRNA. This marks the first report of such a potent fully modified motif, which may represent a useful design for therapeutic oligonucleotides.
Priority inheritance protocols: an approach to real-time synchronization (1990)

An investigation is conducted of two protocols belonging to the priority inheritance protocols class; the two are called the basic priority inheritance protocol and the priority ceiling protocol. Both protocols solve the uncontrolled priority inversion problem. The priority ceiling protocol solves this uncontrolled priority inversion problem particularly well; it reduces the worst-case task-blocking time to at most the duration of execution of a single critical section of a lower-priority task. This protocol also prevents the formation of deadlocks. Sufficient conditions under which a set of periodic tasks using this protocol may be scheduled is derived.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
1848–1849 IN HUNGARY (2001)

There can be no doubt that the Hungarian Revolution of 1848 and the subse- quent war of independence belong to the events that significantly contributed to the development of modern Hungarian historical consciousness. Decisive alter- natives emerged during this critical period: national sovereignty versus develop- ment under foreign power, or the cultivation of friendly compromises reached through negotiations versus violent confrontations. The patterns of thinking asso- ciated with these choices also imposed their influence on the interpretations of other recent historic turning points such as the events of 1956.
Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014)

The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting "classically activated," to anti-inflammatory or "alternatively activated" macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.
Studies on the effect of serine protease inhibitors on activated contact factors (1987)

Amidolytic assays have been developed to determine factor XIIa, factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic p-nitroanilide substrates Pro-Phe-Arg-NH-Np (S2302 or chromozym PK), Glp-Pro-Arg-NH-Np (S2366), Ile-Glu-(piperidyl)-Gly-Arg-NH-Np (S2337), and Ile-Glu-Gly-Arg-NH-Np (S2222) were tested for their suitability as substrates in these assays. The kinetic parameters for the conversion of S2302, S2222, S2337 and S2366 by beta factor XIIa, factor XIa and plasma kallikrein indicate that each active enzyme exhibits considerable activity towards a number of these substrates. This precludes direct quantification of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors have been tested for their ability to inhibit those contact factors selectively that may interfere with the factor tested for. Soybean trypsin inhibitor very efficiently inhibited kallikrein, inhibited factor XIa at moderate concentrations, but did not affect the amidolytic activity of factor XIIa. Therefore, this inhibitor can be used to abolish a kallikrein and factor XIa contribution in a factor XIIa assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethyl ketones. D-Phe-Pro-Arg-CH2Cl was moderately active against contact factors (k = 2.2 X 10(3) M-1 s-1 at pH 8.3) but showed no differences in specifity. D-Phe-Phe-Arg-CH2Cl was a very efficient inhibitor of plasma kallikrein (k = 1.2 X 10(5) M-1 s-1 at pH 8.3) whereas it slowly inhibited factor XIIa (k = 1.4 X 10(3) M-1 s-1) and factor XIa (k = 0.11 X 10(3) M-1 s-1). Also Dns-Glu-Gly-Arg-CH2Cl was more reactive towards kallikrein (k = 1.6 X 10(4) M-1 s-1) than towards factor XIIa (k = 4.6 X 10(2) M-1 s-1) and factor XIa (k = 0.6 X 10(2) M-1 s-1). Since Phe-Phe-Arg-CH2Cl is highly specific for plasma kallikrein it can be used in a factor XIa assay selectively to inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for factor XIIa, factor XIa and kallikrein in mixtures of contact activation factors.
Dynamical thermal behavior and thermal self-stability of microcavities (2004)

As stability and continuous operation are important for almost any use of a microcavity, we demonstrate here experimentally and theoretically a self-stable equilibrium solution for a pump-microcavity system. In this stable equilibrium, intensity- and wavelength-perturbations cause a small thermal resonant-drift that is enough to compensate for the perturbation (noises); consequently the cavity stays warm and loaded as perturbations are self compensated. We also compare here, our theoretical prediction for the thermal line broadening (and for the wavelength hysteretic response) to experimental results.
A gridless multi-layer router for standard cell circuits using CTM cells (1997)

We present a gridless multi-layer router suitable for standard cell circuits using central terminal model (CTM) cells. A CTM cell has pins in the middle which split the over-the-cell routing region into top and bottom parts. Our router routes nets in both the channel (if needed) and over-the-cell. The router uses a combined constraint graph and tile expansion algorithm. It achieves channelless solutions for the Primary1 circuit by routing over the cell in three layers. For classical channel routing examples, it achieves solutions at density for Deutsch's difficult example in two, three, four and five metal layers. It also generates equal or better results compared to the best of the previous channel routers for all the examples we have tried.
A Comparison of Long-Term Functional Outcome After 2 Middle Cerebral Artery Occlusion Models in Rats (2001)

Based on the range of functions affected and stability of observed deficits, the pMCAO model appears to be preferable to the dMCAO/tCCAO model for use in assessing therapeutic agents for stroke.
The Central Nervous Depressive Effect of Khellin (1951)

SummaryKhellin has been shown to be effective in suppressing excitement in rats induced by caffeine. At slightly depressive levels, it is more effective against metrazol than against electrically induced convulsions. The central nervous depression produced by Khellin is mild but of long duration; with increasing dosage this is followed in mice by excitement.
Proteases as catalysts for enzymic syntheses of opioid peptides. (1980)

Two alternative pathways leading to protease-mediated syntheses of Leu- and Met-enkephalin are described. Each peptide bond of the opiate peptides was formed by either papain, or alpha-chymotrypsin catalysis. N alpha-t-Butyloxycarbonyl amino acids and peptides or their esters served as carboxyl components, whereas amino acid and peptide phenylhydrazides were used as acceptor nucleophiles. After removal of the protecting groups, the free pentapeptides were purified to homogeneity. They exhibited naloxone-reversible opiate like activity in guinea pig ileum and mouse vas deferens assays. The present study indicates that enzymic synthesis is a useful tool for rapid preparation of homogeneous peptides with highest obtainable optical purity.
Stimulation of Slow Skeletal Muscle Fiber Gene Expression by Calcineurin in Vivo (2000)

Adult skeletal muscle fibers can be categorized into fast and slow twitch subtypes based on specialized contractile and metabolic properties and on distinctive patterns of muscle gene expression. Muscle fiber-type characteristics are dependent on the frequency of motor nerve stimulation and are thought to be controlled by calcium-dependent signaling. The calcium, calmodulin-dependent protein phosphatase, calcineurin, stimulates slow fiber-specific gene promoters in cultured skeletal muscle cells, and the calcineurin inhibitor, cyclosporin A, inhibits slow fiber gene expression in vivo, suggesting a key role of calcineurin in activation of the slow muscle fiber phenotype. Calcineurin has also been shown to induce hypertrophy of cardiac muscle and to mediate the hypertrophic effects of insulin-like growth factor-1 on skeletal myocytes in vitro. To determine whether activated calcineurin was sufficient to induce slow fiber gene expression and hypertrophy in adult skeletal muscle in vivo, we created transgenic mice that expressed activated calcineurin under control of the muscle creatine kinase enhancer. These mice exhibited an increase in slow muscle fibers, but no evidence for skeletal muscle hypertrophy. These results demonstrate that calcineurin activation is sufficient to induce the slow fiber gene regulatory program in vivo and suggest that additional signals are required for skeletal muscle hypertrophy.
Isolation and characterization of the subunits of human plasma carboxypeptidase N (kininase i). (1982)

Carboxypeptidase N (kininase I, arginine carboxypeptidase; EC 3.4.17.3) cleaves COOH-terminal basic amino acids of kinins, anaphylatoxins, and other peptides. The tetrameric enzyme of Mr 280,000 was purified from human plasma by ion-exchange and arginine-Sepharose affinity chromatography. Treatment with 3 M guanidine dissociated the enzyme into subunits of 83,000 and 48,000 molecular weight, which were separated and purified by gel filtration or affinity chromatography. When tested with hippurylarginine, hippurylargininic acid, benzoylalanyllysine, or bradykinin, the Mr 48,000 subunit was as active as the intact enzyme and was easily distinguished from human pancreatic carboxypeptidase B (EC 3.4.17.2). However, the Mr 48,000 subunit was less stable at acid pH or at 37 degrees C than the intact enzyme was. The carbohydrate-containing Mr 83,000 subunit was enzymatically inactive but stabilized the Mr 48,000 subunit at 37 degrees C. Trypsin, plasmin, and plasma or urinary kallikrein cleaved carboxypeptidase N into lower molecular weight active fragments, which were unstable at 37 degrees C. Cleavage of the Mr 48,000 subunit with the same enzymes increased activity and yielded fragments of Mr 29,000 or less. Antibodies to the Mr 83,000 of Mr 48,000 subunits crossreacted with the intact enzyme, and antibody to carboxypeptidase N also recognized both subunits. However, antibody to the Mr 83,000 subunit did not recognize Mr 48,000 subunit and antibody to the Mr 48,000 subunit did not crossreact with the Mr 83,000 subunit. Thus, this study indicates that carboxypeptidase N is composed of two immunologically distinct subunits, a Mr 48,000 subunit that is responsible for the enzymatic activity and a Mr 83,000 subunit that may stabilize the enzyme in blood.
A new approach for local intravascular drug delivery. Iontophoretic balloon. (1994)

(1) High local concentrations of hirudin in the arterial wall may be achieved with the iontophoretic balloon catheter. (2) The drug is distributed throughout the entire vessel wall without significant damage. (3) The retention of hirudin in the arterial wall is time dependent. (4) This technique might be useful to deliver therapeutic agents before or after percutaneous vascular interventions.
Flow cytometry with gold nanoparticles and their clusters as scattering contrast agents: FDTD simulation of light–cell interaction (2009)

The formulation of the finite-difference time-domain (FDTD) approach is presented in the framework of its potential applications to in-vivo flow cytometry based on light scattering. The consideration is focused on comparison of light scattering by a single biological cell alone in controlled refractive-index matching conditions and by cells labeled by gold nanoparticles. The optical schematics including phase contrast (OPCM) microscopy as a prospective modality for in-vivo flow cytometry is also analyzed. The validation of the FDTD approach for the simulation of flow cytometry may open up a new avenue in the development of advanced cytometric techniques based on scattering effects from nanoscale targets.
Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis (2013)

Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix (ECM) in the metastatic process may lead to the development of improved therapies to treat patients with cancer. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, hypoxia-inducible factor 1 (HIF-1) activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the ECM. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We show that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs.
About the Phase Transitions in Aqueous Solutions of Thermoresponsive Copolymers and Hydrogels Based on 2-(2-methoxyethoxy)ethyl Methacrylate and Oligo(ethylene glycol) Methacrylate (2007)

The phase transitions in water of well-defined copolymers of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA, Mn = 475 g mol-1) were studied by means of 1H NMR, dynamic light scattering (DLS) and turbidimetry. These copolymers were synthesized by atom transfer radical polymerization (ATRP) in order to obtain macromolecules with a homogeneous chain-to-chain comonomer composition and therefore with a narrow phase transition. As previously reported, copolymers containing 10 mol % of OEGMA per chain (Mn = 20 100 g mol-1 ; Mw/Mn = 1.35) exhibited a sharp LCST in water around 40 °C, whereas copolymers having 20 mol % of OEGMA per chain (Mn = 19 500 g mol-1; Mw/Mn = 1.32) precipitated slightly above 50 °C. DLS indicated that these phase transitions are most likely due to a reversible coil-to-globule transition. Moreover covalently cross-linked networks of MEO2MA and OEGMA were synthesized by ATRP in the presence of the cross-linker ethylene glycol dimethacrylate. These hydrogels were thermoresponsive and exhibited LCST values comparable to those measured for their single-chains analogues (e.g., hydrogels containing 20 mol % of OEGMA within the network underwent phase transitions at approximately 51−53 °C).
Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model. (2000)

One of the leading causes of death for women is metastatic breast cancer. Because most animal tumors do not accurately model clinical metastatic disease, the development of effective therapies has progressed slowly. In this study, we establish the poorly immunogenic mouse 4T1 mammary carcinoma as a postsurgical animal model. 4T1 growth characteristics parallel highly invasive human metastatic mammary carcinoma and, at the time of surgery, the extent of disease is comparable with human stage IV breast cancer. Progress in understanding the immune response has led to innovative immune-based anticancer therapies. Here, we test in this postsurgical model, a novel cell-based vaccine, combining MHC class II, CD80(B7.1), and SEB superantigen. Effective treatment of tumor-bearing mice with this immunotherapy requires expression of all three molecules. Mean survival time is extended from 5-7.5 weeks for control-treated mice to 6-10.5 weeks for therapy-treated mice. Increased survival is accompanied by a maximum of 100-fold decrease in clonogenic lung metastases. These therapeutic effects are particularly noteworthy because: (a) the postoperative model demonstrates that early metastases responsible for morbidity are established by 2 weeks after tumor inoculation with 7 x 10(3) parental 4T1 cells into the mammary gland; (b) the immunotherapy is started 4 weeks after tumor inoculation when the mice contain extensive, pre-established, disseminated metastases; and (c) CD4+ and CD8+ T cells are required for the effect.
Comparison of in vitro Inhibitory and Bactericidal Activities of Daptomycin (LY 146032) and Four Reference Antibiotics, Singly and in Combination, against Gentamicin-Susceptible and High-Level-Gentamicin-Resistant Enterococci (1993)

The in vitro inhibitory and bactericidal activities of daptomycin and reference antibiotics were determined by serial macrobroth dilution for 23 gentamicin-susceptible (MIC: < 2,000 mg/l) and 21 high-level-gentamicin-resistant (HLGR) Enterococcus faecalis, Enterococcus faecium, and Enterococcus avium isolates. The activities of daptomycin, vancomycin, and teicoplanin were independent of the gentamicin susceptibility profile and species tested. For all the isolates, the inhibitory activity of daptomycin (MIC90: 2 mg/l) was comparable to vancomycin (MIC90: 2 mg/l), but less than that of teicoplanin (MIC90: 0.5 mg/l). Daptomycin demonstrated excellent bactericidal activity against all enterococci tested (MBC90: 8 mg/l). In contrast, all microorganisms were tolerant to vancomycin and teicoplanin. Ampicillin and ciprofloxacin MICs and MBCs were dependent on enterococcal gentamicin resistance profile and species, with MICs and MBCs that ranged between 1 and > 64 mg/l. By time-kill curves, the combination of daptomycin plus ampicillin demonstrated synergistic bactericidal activity against gentamicin-susceptible and HLGR E. faecalis. Daptomycin, singly and in combination, may be useful in treating enterococcal infections, including those caused by HLGR microorganisms.
Mutations in the MHC class II binding domains of staphylococcal enterotoxin A differentially affect T cell receptor Vbeta specificity (1996)

C-terminal residues of staphylococcal enterotoxin A (SEA), including H187, D225, and D227, are involved in moderate affinity binding to MHC class II beta-chain, whereas N-terminal residues, including F47, are involved in low affinity binding to MHC class II alpha-chain. The effect of alanine substitutions at residues D227 or F47 on induction of T cell proliferation and the expansion of specific TCR Vbeta families was determined. SEA wild type specifically activated T cells expressing Vbeta1, Vbeta5.2, Vbeta6, Vbeta7, Vbeta9, Vbeta18, and Vbeta22. Although SEA-D227A exhibited substantially reduced mitogenicity compared with SEA wild type, it expanded the same Vbeta-bearing T cells, except those expressing Vbeta1. By contrast, SEA-F47A, which was slightly less mitogenic than SEA wild type, induced expansion only of T cells expressing Vbeta6, Vbeta7, and to a lesser extent Vbeta22. Therefore, specific mutations affecting either MHC class II alpha or beta binding sites differentially affect the Vbeta specificity of this superantigen. The lack of expansion in four of seven Vbeta families by SEA-F47A suggests that the class II alpha binding site may position SEA on the MHC class II molecules in an appropriate conformation for interaction with certain Vbeta elements.