gebhart/patrepeval huggingface dataset:
Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy. (2001)

The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.
Cerebral hemodynamic and metabolic effects of chronic alcoholism. (1989)

The nervous system is particularly susceptible to the harmful effects of alcohol. These include Wernicke-Korsakoff syndrome, which is related to thiamine deficiency secondary to chronic alcohol abuse. Other neurotoxic effects of alcohol with cognitive impairments include delirium tremens, alcoholic seizures or "rum fits," and alcoholic neuropathies. It has become recognized in recent years that alcohol and its metabolites directly damage the nervous system even in the absence of nutritional deficiencies. Cerebral blood flow (CBF) measurements provide a noninvasive indirect monitor of cerebral metabolic activity. It has been shown conclusively that CBF measured by the 133Xe inhalation method is decreased in chronic alcoholism, correlating well with the amount of alcohol consumed. With abstinence, CBF returns toward normal levels provided the neurotoxic effects of chronic alcoholism are of recent onset. Clinical and pathological studies show significant loss of brain volume with ventricular dilatation after alcohol abuse even among young "social" drinkers. This toxic effect of alcohol is accompanied by varying degrees of cognitive impairments ranging from slight memory loss to frank dementia. Both the decrease in brain volume and the cognitive impairments, which occur with or without nutritional deficiency, are to a large extent reversible with abstinence and nutritional supplementation. Alcohol appears to accelerate age-related declines in CBF while nutritional deficiencies enhance the neurotoxic effects of alcohol. Measurements of local CBF (LCBF) and partition coefficients (L lambda) in deep cerebral structures, including the hypothalamus, thalamus, forebrain nuclei, and limbic system, can be achieved utilizing three-dimensional methods after inhalation of stable xenon as a contrast medium combined with serial computed tomographic imaging of the brain. Among chronic alcoholics, there are significant and diffuse reductions in cortical and subcortical gray matter CBF that are especially remarkable in hypothalamus and substantia innominata, which includes the nucleus basalis of Meynert, a major source of cholinergic input to neocortex and hippocampus. Reductions in LCBF are measurable in cognitively impaired patients with and without Wernicke-Korsakoff syndrome. Reductions of CBF include white matter and are more severe in patients with Wernicke-Korsakoff syndrome. Both types of encephalopathy improve with treatment, but recovery is usually more rapid and complete if nutritional deficiency is absent. Alcohol also appears to be a risk factor for stroke, possibly by depleting neuronal reserves and unfavorably influencing cardiovascular risks.
Digital optical spectrometer-on-chip (2009)

A concept of digital optical spectrometer-on-chip is proposed and results of their fabrication and characterization are reported. The devices are based on computer-designed digital planar holograms which involves millions of lines specifically located and oriented in order to direct output light into designed focal points according to the wavelength. Spectrometers were fabricated on silicon dioxide and hafnium dioxide planar waveguides using electron beam lithography and dry etching. Optical performances of devices with up to 1000 channels for a central wavelength of 660 nm are reported.
Molecular evidence for two forms of Crohn disease. (1994)

Recent epidemiological evidence suggests that there are two forms of Crohn disease (CD): perforating and nonperforating. We hypothesized that, just as with tuberculoid and lepromatous leprosy, differences in the two forms of CD would be both identified and determined by differences in the host immune response. Resected intestinal tissue from control patients as well as perforating and nonperforating CD patients was evaluated for mRNA levels. We employed 32P PCR amplification with published or custom-designed primers of a housekeeping gene (beta-actin); a human T-cell marker (CD3-delta); and the cytokines tumor necrosis factor alpha, transforming growth factor beta, granulocyte/macrophage colony-stimulating factor, interleukin (IL) 1 beta, IL-1ra, and IL-6. Differences were identified with IL-1 beta (control = 162 +/- 57 vs. perforating = 464 +/- 154 vs. nonperforating = 12,582 +/- 4733; P < or = 0.02) and IL-1ra (control = 1337 +/- 622 vs. perforating = 2194 +/- 775 vs. nonperforating = 9715 +/- 2988; P < or = 0.02). These data corroborate the epidemiological observation that there are two forms of CD. Nonperforating CD, the more benign form, is associated with increased IL-1 beta and IL-1ra mRNA expression. We conclude that it is the host immune response that determines which form of CD becomes manifest in any given individual and discuss the investigative, diagnostic, and therapeutic implications of these observations.
Chymase: Its Pathophysiological Roles and Inhibitors (1998)

Chymase is a chymotrypsin-type serine protease mainly localized in mast cells (MCs). Human, primate, and dog chymase generate angiotensin II (Ang II) from Ang I, while mouse and rat chymases degrade Ang II. It is suggested that chymase generating Ang II might be an alternative Ang II-forming enzyme to angiotensin-converting enzyme (ACE) in the renin-angiotensin system in tissues, but not in blood, and cause hypertrophy and remodeling of cardiovascular tissues. Chymase also degrades extracellular matrix, and processes procollagenase, inflammatory cytokines and other bioactive peptides. As a result, chymase plays important roles in inflammatory tissues through its proteolytic activities to cause tissue remodeling, that is, a chymase inhibitor may have the ability to prevent diseases caused by the above inflammatory reactions. The investigation of chymase inhibitors by pharmaceutical companies has yielded peptide and peptide mimetic inhibitors. We also found potent non-peptide low molecular inhibitors. However, the in vivo functions of chymase have not been verified so far by applying a chymase inhibitor to in vivo pathological models. In this article, we overview the pathophysiological roles of chymase and chymase inhibitors proposed to date, and discuss the structure-activity relationships of substituted 3-phenylsulfonyl-1-phenylimidazolidine-2,4-dione derivatives.
Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody (2001)

Bispecific antibodies (bsAbs) can efficiently mediate tumor cell killing by redirecting preactivated or costimulated T cells to disseminated tumor cells, especially in a minimal residual disease situation. This study demonstrates that the trifunctional bsAb BiLu is able to kill tumor cells very efficiently without any additional costimulation of effector cells in vitro and in vivo. Remarkably, this bsAb also induces a long-lasting protective immunity against the targeted syngeneic mouse tumors (B16 melanoma and A20 B-cell lymphoma, respectively). A strong correlation was observed between the induction of a humoral immune response with tumor-reactive antibodies and the survival of mice. This humoral response was at least in part tumor specific as shown in the A20 model by the detection of induced anti-idiotype antibodies. Both the survival of mice and antitumor titers were significantly diminished when F(ab')(2) fragments of the same bsAb were applied, demonstrating the importance of the Fc region in this process. With the use of T-cell depletion, a contribution of a cellular antitumor response could be demonstrated. These results reveal the necessity of the Fc region of the bsAb with its potent immunoglobulin subclass combination mouse immunoglobulin G2a (IgG2a) and rat IgG2b. The antigen-presenting system seems to be crucial for achieving an efficient tumor cell killing and induction of long-lasting antitumor immunity. Hereby, the recruitment and activation of accessory cells by the intact bsAb is essential.
Statistical Techniques For Comparing Measurers And Methods Of Measurement: A Critical Review (2002)

1. Clinical and experimental pharmacologists and physiologists often wish to compare two methods of measurement, or two measurers. 2. Biostatisticians insist that what should be sought is not agreement between methods or measurers, but disagreement or bias. 3. If measurements have been made on a continuous scale, the main choice is between the Altman-Bland method of differences and least products regression analysis. It is argued that although the former is relatively simple to execute, it does not distinguish adequately between fixed and proportional bias. Least products regression analysis, although more difficult to execute, does achieve this goal. There is almost universal agreement among biostatisticians that the Pearson product-moment correlation coefficient (r) is valueless as a test for bias. 4. If measurements have been made on a categorical scale, unordered or ordered, the most popular method of analysis is to use the kappa statistic. If the categories are unordered, the unweighted kappa statistic (K) is appropriate. If the categories are ordered, as they are in most rating scales in clinical, psychological and epidemiological research, the weighted kappa statistic (K(w)) is preferable. But K(w) corresponds to the intraclass correlation coefficient, which, like r for continuous variables, is incapable of detecting bias. Simple techniques for detecting bias in the case of ordered categorical variables are described and commended to investigators.
A Mesoporous Silica Nanosphere-Based Carrier System with Chemically Removable CdS Nanoparticle Caps for Stimuli-Responsive Controlled Release of Neurotransmitters and Drug Molecules (2003)

An MCM-41 type mesoporous silica nanosphere-based (MSN) controlled-release delivery system has been synthesized and characterized using surface-derivatized cadmium sulfide (CdS) nanocrystals as chemically removable caps to encapsulate several pharmaceutical drug molecules and neurotransmitters inside the organically functionalized MSN mesoporous framework. We studied the stimuli-responsive release profiles of vancomycin- and adenosine triphosphate (ATP)-loaded MSN delivery systems by using disulfide bond-reducing molecules, such as dithiothreitol (DTT) and mercaptoethanol (ME), as release triggers. The biocompatibility and delivery efficiency of the MSN system with neuroglial cells (astrocytes) in vitro were demonstrated. In contrast to many current delivery systems, the molecules of interest were encapsulated inside the porous framework of the MSN not by adsorption or sol-gel types of entrapment but by capping the openings of the mesoporous channels with size-defined CdS nanoparticles to physically block the drugs/neurotransmitters of certain sizes from leaching out. We envision that this new MSN system could play a significant role in developing new generations of site-selective, controlled-release delivery nanodevices.
Three-Dimensional Tissue Assemblies: Novel Models for the Study ofSalmonella entericaSerovar Typhimurium Pathogenesis (2001)

The lack of readily available experimental systems has limited knowledge pertaining to the development of Salmonella-induced gastroenteritis and diarrheal disease in humans. We used a novel low-shear stress cell culture system developed at the National Aeronautics and Space Administration in conjunction with cultivation of three-dimensional (3-D) aggregates of human intestinal tissue to study the infectivity of Salmonella enterica serovar Typhimurium for human intestinal epithelium. Immunohistochemical characterization and microscopic analysis of 3-D aggregates of the human intestinal epithelial cell line Int-407 revealed that the 3-D cells more accurately modeled human in vivo differentiated tissues than did conventional monolayer cultures of the same cells. Results from infectivity studies showed that Salmonella established infection of the 3-D cells in a much different manner than that observed for monolayers. Following the same time course of infection with Salmonella, 3-D Int-407 cells displayed minimal loss of structural integrity compared to that of Int-407 monolayers. Furthermore, Salmonella exhibited significantly lower abilities to adhere to, invade, and induce apoptosis of 3-D Int-407 cells than it did for infected Int-407 monolayers. Analysis of cytokine expression profiles of 3-D Int-407 cells and monolayers following infection with Salmonella revealed significant differences in expression of interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-1Ra, and tumor necrosis factor alpha mRNAs between the two cultures. In addition, uninfected 3-D Int-407 cells constitutively expressed higher levels of transforming growth factor beta1 mRNA and prostaglandin E2 than did uninfected Int-407 monolayers. By more accurately modeling many aspects of human in vivo tissues, the 3-D intestinal cell model generated in this study offers a novel approach for studying microbial infectivity from the perspective of the host-pathogen interaction.
Caspase activation in etoposide‐treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion (2002)

Activation of the extracellular signal-regulated kinases (ERKs) 1 and 2 is correlated to cell survival, but in some cases ERKs can act in signal transduction pathways leading to apoptosis. Treatment of mouse fibroblasts with 20 microM etoposide elicited a sustained phosphorylation of ERK 1/2, that increased until 24 h from the treatment in parallel with caspase activity. The inhibitor of ERK activation PD98059 abolished caspase activation, but caspase inhibition did not reduce ERK 1/2 phosphorylation, suggesting that ERK activation is placed upstream of caspases. Both ERK and caspase activation were blocked in cells depleted of polyamines by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO). In etoposide-treated cells, DFMO also abolished phosphorylation of c-Jun NH(2)-terminal kinases triggered by the drug. Polyamine replenishment with exogenous putrescine restored the ability of the cells to undergo caspase activation and ERK 1/2 phosphorylation in response to etoposide. Ornithine decarboxylase activity decreased after etoposide, indicating that DFMO exerts its effect by depleting cellular polyamines before induction of apoptosis. These results reveal a role for polyamines in the transduction of the death signal triggered by etoposide.
CpG-DNA-Mediated Transient Lymphadenopathy Is Associated with a State of Th1 Predisposition to Antigen-Driven Responses (2000)

Infections can influence concurrent and subsequent Th1 vs Th2 immune responses to Ags. Through pattern recognition of foreign unmethylated CpG dinucleotides, the vertebrate innate immune system can sense infectious danger and typically replies with a Th1-polarized adaptive immune response. We examined whether CpG-DNA exposure would influence subsequent responses to infection and soluble Ags. CpG-DNA injection led to local lymphadenopathy characterized by maintenance of cellular composition with some biasing toward elevated dendritic cell composition. Sustained local production of IL-12 and IFN-gamma from dendritic cells and T cells was shown. Prior injection by up to 2 wk with CpG-DNA protected BALB/c mice from Th2 driven lethal leishmaniasis. CpG-DNA injection by up to 5 wk before soluble Ag challenge resulted in the generation of Ag-specific CTL, Th1 recall responses to Ag, and Th1-polarized Ag-specific Abs. Thus, CpG-DNA instigated a local predisposition for intense CTL responses and Th1-polarized immune responses to subsequent infections or Ag challenge. The induction by the innate immune system of a locally contained hypersensitivity could represent a capacitating immune reaction yielding rapid conditioned responses to secondary infections.
Microfluidic Enzyme Immunoassay Using Silicon Microchip with Immobilized Antibodies and Chemiluminescence Detection (2002)

Silicon microchips with immobilized antibodies were used to develop microfluidic enzyme immunoassays using chemiluminescence detection and horseradish peroxidase (HRP) as the enzyme label. Polyclonal anti-atrazine antibodies were coupled to the silicon microchip surface with an overall dimension of 13.1 × 3.2 mm, comprising 42 porous flow channels of 235-μm depth and 25-μm width. Different immobilization protocols based on covalent or noncovalent modification of the silica surface with 3-aminopropyltriethoxysilane (APTES) or 3-glycidoxypropyltrimethoxysilane (GOPS), linear polyethylenimine (LPEI, MW 750 000), or branched polyethylenimine (BPEI, MW 25 000), followed by adsorption or covalent attachment of the antibody, were evaluated to reach the best reusability, stability, and sensitivity of the microfluidic enzyme immunoassay (μFEIA). Adsorption of antibodies on a LPEI-modified silica surface and covalent attachment to physically adsorbed BPEI lead to unstable antibody coatings. Covalent coupling of antibodies via glutaraldehyde (GA) to three different functionalized silica surfaces (APTES−GA, LPEI−GA, and GOPS−BPEI−GA) resulted in antibody coatings that could be completely regenerated using 0.4 M glycine/HCl, pH 2.2. The buffer composition was shown to have a dramatic effect on the assay stability, where the commonly used phosphate buffer saline was proved to be the least suitable choice. The best long-term stability was obtained for the LPEI−GA surface with no loss of antibody activity during one month. The detection limits in the μFEIA for the three different immuno surfaces were 45, 3.8, and 0.80 ng/L (209, 17.7, and 3.7 pM) for APTES−GA, LPEI−GA, and GOPS−BPEI−GA, respectively.
Nucleotide-Specific Recognition of Iron-Responsive Elements by Iron Regulatory Protein 1 (2013)

IRP1 [iron regulatory protein (IRP) 1] is a bifunctional protein with mutually exclusive end-states. In one mode of operation, IRP1 binds iron-responsive element (IRE) stem-loops in messenger RNAs encoding proteins of iron metabolism to control their rate of translation. In its other mode, IRP1 serves as cytoplasmic aconitase to correlate iron availability with the energy and oxidative stress status of the cell. IRP1/IRE binding occurs through two separate interfaces, which together contribute about two-dozen hydrogen bonds. Five amino acids make base-specific contacts and are expected to contribute significantly to binding affinity and specificity of this protein:RNA interaction. In this mutagenesis study, each of the five base-specific amino acids was changed to alter binding at each site. Analysis of IRE binding affinity and translational repression activity of the resulting IRP1 mutants showed that four of the five contact points contribute uniquely to the overall binding affinity of the IRP1:IRE interaction, while one site was found to be unimportant. The stronger-than-expected effect on binding affinity of mutations at Lys379 and Ser681, residues that make contact with the conserved nucleotides G16 and C8, respectively, identified them as particularly critical for providing specificity and stability to IRP1:IRE complex formation. We also show that even though the base-specific RNA-binding residues are not part of the aconitase active site, their substitutions can affect the aconitase activity of holo-IRP1, positively or negatively.
Control of programmed cell death in normal and leukemic cells: new implications for therapy (1993)

Programmed cell death (apoptosis) is a normal process by which cells are eliminated during normal embryonic development and in adult life. Disruption of this normal process resulting in illegitimate cell survival can cause developmental abnormalities and facilitate cancer development. Normal cells require certain viability factors and undergo programmed cell death when these factors are withdrawn. The viability factors are required throughout the differentiation process from immature to mature cells. Although many viability factors are also growth factors, viability and growth are separately regulated. Viability factors can have clinical value in decreasing the loss of normal cells including the loss that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that cancer cells are immortal. Programmed cell death can be induced in leukemic cells by removal of viability factors, by cytotoxic therapeutic agents, or by the tumor-suppressor gene wild-type p53. All these forms of induction of programmed cell death in leukemic cells can be suppressed by the same viability factors that suppress programmed cell death in normal cells. A tumor-promoting phorbol ester can also suppress this death program. The induction of programmed cell death can be enhanced by deregulated expression of the gene c-myc and suppressed by the gene bcl-2. Mutant p53 and bcl-2 suppress the enhancing effect on cell death of deregulated c-myc, and thus allow induction of cell proliferation and inhibition of differentiation which are other functions of deregulated c-myc. The suppression of cell death by mutant p53 and bcl-2 increases the probability of developing cancer. The suppression of programmed cell death in cancer cells by viability factors suggests that decreasing the level of these factors may increase the effectiveness of cytotoxic cancer therapy. Treatments that downregulate the expression or activity of mutant p53 and bcl-2 in cancer cells should also be useful for therapy.
GLUT-1 mediation of rapid glucose transport in dolphin (Tursiops truncatus) red blood cells (1998)

D-Glucose entry into erythrocytes from adult dolphins (Tursiops truncatus) was rapid, showed saturation at high substrate concentrations, and demonstrated a marked stimulation by intracellular D-glucose. Kinetic parameters were estimated from the concentration dependence of initial rates of tracer entry at 6 degrees C: for zero-trans entry, Michaelis constant (K(m)) was 0.78 +/- 0.10 mM and maximal velocity (Vmax) was 300 +/- 9 mumol.l cell water-1.min-1; for equilibrium exchange entry, K(m) was 17.5 +/- 0.6 mM and Vmax was 8,675 +/- 96 mumol.l cell water-1.min-1. Glucose entry was inhibited by cytochalasin B, and mass law analysis of reversible, D-glucose-displaceable, cytochalasin B binding gave values of 0.37 +/- 0.03 nmol/mg membrane protein for maximal binding and 0.48 +/- 0.10 microM for the dissociation constant. Dolphin glucose transporter polypeptides were identified on sodium-dodecyl sulfate-polyacrylamide gel electrophoresis immunoblots [using antibodies that recognized human glucose transporter isoform (GLUT-1)] as two molecular species, apparent relative molecular weights of 53,000 and 47,000. Identity of these polypeptides was confirmed by D-glucose-sensitive photolabeling of membranes with [3H]cytochalasin B. Digestion of both dolphin and human red blood cell membranes with glycopeptidase F led to the generation of a sharp band of relative molecular weight 46,000 derived from GLUT-1. Trypsin treatment of human and dolphin erythrocyte membranes generated fragmentation patterns consistent with similar polypeptide structures for GLUT-1 in human and dolphin red blood cells.