gebhart/patrepeval huggingface dataset:
Therapeutic Opportunities in Colon-Specific Drug-Delivery Systems (2007)

Oral colon-specific drug-delivery systems have recently gained importance for delivering a variety of therapeutic agents. The major obstacles to delivering drugs to the colon are the absorption and degradation pathways in the upper gastrointestinal tract. However, a successfully designed colon-targeted system can overcome these obstacles. Targeting drugs to the colon has proven quite valuable in a variety of disorders, and the colon has proven to be a potential site for local as well as systemic administration of drugs. Colon targeting has proven beneficial for local action in a variety of disease conditions, such as inflammatory bowel disease, irritable bowel syndrome, and colonic cancer. Aminosalicylates, corticosteroids, immunosuppressive agents, cationized antioxidant enzymes, genetically engineered bacteria to produce cytokines, nicotine, and other drugs have exhibited significantly enhanced efficacy when delivered to the colon. Targeting drugs to cancer cells through receptors and ligands have opened up new avenues in the treatment of colonic cancer. Colon targeting has also proven useful for systemic action of protein-peptide drugs such as insulin, calcitonin, and met-enkaphalin and even for other nonpeptide drugs such as cardiovascular and antiasthmatic agents. This review also presents various approaches for targeting orally administered dosage forms to the colon. The use of a prodrug approach, bioadhesive polymers, and coating with pH-sensitive and biodegradable polymers has been, to an extent, highly successful in delivering the targeted formulations to the site of action. Biodegrable hydrogels such as amylose, chondroitin sulphate, chitosan, inulin, guar gum, and pectin have also been successfully used to achieve oral colon-targeted delivery.
Oxidative functionalization of adamantanes (review) (2017)

The results of studies in the area of oxidative functionalization of hydrocarbons of the adamantane series over the last two decades have been summarized and oxidation, carbonylation, and carboxylation reactions involving oxidizing agents and catalysts of various types, possible reaction mechanisms, properties and promising directions of the use of the obtained products have been considered.
Design of (Gd‐DO3A)n‐polydiamidopropanoyl‐peptide nucleic acid‐D(Cys‐Ser‐Lys‐Cys) magnetic resonance contrast agents (2008)

We hypothesized that chelating Gd(III) to 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) on peptide nucleic acid (PNA) hybridization probes would provide a magnetic resonance genetic imaging agent capable of hybridization to a specific mRNA. Because of the low sensitivity of Gd(III) as an magnetic resonance imaging (MRI) contrast agent, a single Gd-DO3A complex per PNA hybridization agent could not provide enough contrast for detection of cancer gene mRNAs, even at thousands of mRNA copies per cell. To increase the Gd(III) shift intensity of MRI genetic imaging agents, we extended a novel DO3An-polydiamidopropanoyl (PDAPm) dendrimer, up to n = 16, from the N-terminus of KRAS PNA hybridization agents by solid phase synthesis. A C-terminal D(Cys-Ser-Lys-Cys) cyclized peptide analog of insulin-like growth factor 1 (IGF1) was included to enable receptor-mediated cellular uptake. Molecular dynamic simulation of the (Gd-DO3A-AEEA)16-PDAP4-AEEA2-KRAS PNA-AEEA-D(Cys-Ser-Lys-Cys) genetic imaging nanoparticles in explicit water yielded a pair correlation function similar to that of PAMAM dendrimers, and a predicted structure in which the PDAP dendron did not sequester the PNA. Thermal melting measurements indicated that the size of the PDAP dendron included in the (DO3A-AEEA)n-PDAPm-AEEA2-KRAS PNA-AEEA-D(Cys-Ser-Lys-Cys) probes (up to 16 Gd(III) cations per PNA) did not depress the melting temperatures (Tm) of the complementary PNA/RNA hybrid duplexes. The Gd(III) dendrimer PNA genetic imaging agents in phantom solutions displayed significantly greater T1 relaxivity per probe (r1 = 30.64 +/- 2.68 mM(-1) s(-1) for n = 2, r1 = 153.84 +/- 11.28 mM(-1) s(-1) for n = 8) than Gd-DTPA (r1 = 10.35 +/- 0.37 mM(-1) s(-1)), but less than that of (Gd-DO3A)32-PAMAM dendrimer (r1 = 771.84 +/- 20.48 mM(-1) s(-1)) (P < 0.05). Higher generations of PDAP dendrimers with 32 or more Gd-DO3A residues attached to PNA-D(Cys-Ser-Lys-Cys) genetic imaging agents might provide greater contrast for more sensitive detection.
Resolution of Staphylococcus aureus Biofilm Infection Using Vaccination and Antibiotic Treatment (2011)

Staphylococcus aureus infections, particularly those from methicillin-resistant strains (i.e., MRSA), are reaching epidemic proportions, with no effective vaccine available. The vast number and transient expression of virulence factors in the infectious course of this pathogen have made the discovery of protective antigens particularly difficult. In addition, the divergent planktonic and biofilm modes of growth with their accompanying proteomic changes also demonstrate significant hindrances to vaccine development. In this study, a multicomponent vaccine was evaluated for its ability to clear a staphylococcal biofilm infection. Antigens (glucosaminidase, an ABC transporter lipoprotein, a conserved hypothetical protein, and a conserved lipoprotein) were chosen since they were found in previous studies to have upregulated and sustained expression in a biofilm, both in vitro and in vivo. Antibodies against these antigens were first used in microscopy studies to localize their expression in in vitro biofilms. Each of the four antigens showed heterogeneous production in various locations within the complex biofilm community in the biofilm. Based upon these studies, the four antigens were delivered simultaneously as a quadrivalent vaccine in order to compensate for this varied production. In addition, antibiotic treatment was also administered to clear the remaining nonattached planktonic cells since the vaccine antigens may have been biofilm specific. The results demonstrated that when vaccination was coupled with vancomycin treatment in a biofilm model of chronic osteomyelitis in rabbits, clinical and radiographic signs of infection significantly reduced by 67 and 82%, respectively, compared to infected animals that were either treated with vancomycin or left untreated. In contrast, vaccination alone resulted in a modest, and nonsignificant, decrease in clinical (34% reduction) and radiographic signs (9% reduction) of infection, compared to nonvaccinated animal groups untreated or treated with vancomycin. Lastly, MRSA biofilm infections were significantly cleared in 87.5% of vaccinated and antibiotic-treated animals, while antibiotics or vaccine alone could not significantly clear infection compared to controls (55.6, 22.2, and 33.3% clearance rates, respectively). This approach to vaccine development may lead to the generation of vaccines against other pathogenic biofilm bacteria.
Nonvagal Modulation of Hypoglossal Neural Activity (1992)

Upper airway dilating muscle activity is characterized by an early-peaking pattern which serves to dilate or stiffen the upper airway at the time when the greatest negative intraluminal pressure is generated by contraction of chest wall muscles. This pattern has been attributed to phasic afferent inputs from pulmonary stretch receptors. The present study examines the hypothesis that nonvagal factors may also influence the discharge pattern and coordination of upper airway and chest wall muscle activities. Therefore, in anesthetized, paralyzed, vagotomized and artificially ventilated cats, we examined the effects of changes in respiratory drive produced by activation of cholinergic and GA-BAergic (gamma-aminobutyric acid) receptors at the ventrolateral aspects of the medulla oblongata on phasic intrabreath discharge patterns of hypoglossal and phrenic nerves. Cholinergic agents (acetylcholine, carbachol, methacholine, physostigmine) applied directly to chemoreceptive areas on the ventral medullary surface increased hypoglossal activity, and in addition converted inspiratory discharge from an augmenting to a decrementing pattern of activity. The reverse effect on the discharge pattern of hypoglossal activity was observed with a decrease in respiratory drive. While the amplitude of the phrenic nerve discharge was also affected by these interventions, the augmenting discharge pattern of phrenic nerve activity did not change. These results suggest that the early peaking pattern of hypoglossal nerve discharge in vagotomized cats also depends on the level of respiratory drive, and is not solely dependent on vagal afferent inputs. In addition, the data suggest that structures near the ventral surface of the medulla are influential in shaping the pattern of hypoglossal nerve activity and maintaining balanced activity of upper airway and chest wall muscles.
Bifurcation of osteoclasts and dendritic cells from common progenitors (2001)

Osteoclasts and dendritic cells are derived from monocyte/macrophage precursor cells; however, how their lineage commitment is regulated is unknown. This study investigated the differentiation pathways of osteoclasts and dendritic cells from common precursor cells at the single-cell level. Osteoclastogenesis induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) or tumor necrosis factor-alpha (TNF-alpha) is completely inhibited by addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 at early stages of differentiation. GM-CSF-treated cells express both c-Fms and RANK and also low levels of CD11c and DEC205, which are detected on dendritic cells. Addition of GM-CSF also reduces expression of both c-Fos and Fra-1, which is an important event for inhibition of osteoclastogenesis. Overexpression of c-Fos by retroviral infection or induction in transgenic mice can rescue a failure in osteoclast differentiation even in the presence of GM-CSF. By contrast, differentiation into dendritic cells is inhibited by M-CSF, indicating that M-CSF and GM-CSF reciprocally regulate the differentiation of both lineages. Dendritic cell maturation is also inhibited when c-Fos is expressed at an early stage of differentiation. Taken together, these findings suggest that c-Fos is a key mediator of the lineage commitment between osteoclasts and dendritic cells. The lineage determination of osteoclast progenitors seen following GM-CSF treatment functions through the regulation of c-Fos expression.
Bacterial adherence to human endothelial cells in vitro (1985)

Differences in the ability of bacteria to adhere to normal valvular endothelium may account for the predominance of particular species as pathogens in acute endocarditis. An in vitro adherence assay was developed to simulate the host surface encountered in acute bacterial endocarditis by using confluent monolayers of human endothelial cells. Adherence of 32 gram-positive and -negative blood culture isolates to this surface was compared. All five Staphylococcus aureus strains tested were highly adherent to endothelial cells, as was one gram-negative strain (Serratia marcescens). The remaining gram-positive and -negative isolates, including four viridans streptococci, were relatively nonadherent. Transmission electron microscopy demonstrated attachment of Staphylococcus aureus and invagination of the underlying endothelial cell membrane at 1 h followed by engulfment of large numbers of bacteria after 3 h. The intracellular bacteria appeared to be contained within vacuoles. Preferential attachment of some strains of bacteria, in particular Staphylococcus aureus, to human endothelial cells occurred in vitro, suggesting that adherence is an important determinant of bacterial pathogenicity in acute endocarditis. Active uptake of bacteria by endothelial cells may help account for the virulence of Staphylococcus aureus in endovascular infections and for the ability of this organism to establish multiple metastatic foci of infection.
An oxo-bacteriochlorin derivative for long-wavelength fluorescence ratiometric alcohol sensing (2010)

A fluorescent ratiometric optical chemical sensor (optode) for alcohol detection is presented. A lipophilized bacteriochlorin derivative possessing a trifluoroacetyl group at the 3-position was synthesized for alcohol detection. When embedded in a plasticized poly(vinyl chloride) (PVC) membrane, the fluororeceptor shows a significant signal change on exposure to aqueous ethanol solutions both in the absorbance and the fluorescence emission. This optode allows the determination of ethanol concentrations in aqueous sample solutions by ratiometric fluorometry. The fluorescent indicator responds with increasing fluorescence around 701 nm and decreasing fluorescence around 751 nm towards the presence of ethanol. The optode response was found to be fully reversible in a dynamic measurement range from 0.3% to at least 25% (v/v) ethanol. The limit of detection (LOD) and the limit of quantification (LOQ) of the sensor for ethanol were estimated to be 0.1% and 0.4% (v/v), respectively. These results indicate that the new optode can be employed as an ethanol-sensing device with high sensitivity for beverage and industrial analyses.
Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu. (1995)

MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.
Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model (2014)

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
Two rhombomeres are altered in Hoxa-1 mutant mice (1993)

This study provides a detailed description of the anatomical defects in the Hoxa-1-/- mutant mice previously generated in our laboratory (T. Lufkin, A. Dierich, M. LeMeur, M. Mark and P. Chambon, 1991; Cell 66, 1105-1119). Three-dimensional reconstructions of the Hoxa-1-/- rhombencephalon reveals that it bears only five rhombomeric structures (ie. morphological segments) instead of the normal seven. The first three of these rhombomeres appear normal as judged from the distribution pattern of CRABPI transcripts in the neurectoderm and from the histological analysis of the cranial nerve components derived from these structures. In contrast, the neural-crest-cell-free region normally located opposite rhombomere 5 is lacking in Hoxa-1-/- embryos, and motor neurons of the facial and abducens nerves, which normally differentiate within rhombomeres 4, 5 and 6, are missing in Hoxa-1-/- fetuses. These morphological data, combined with the determination of the molecular positional identities of the rhombomeres 4 and 5 (P. Dollé, T. Lufkin, R. Krumlauf, M. Mark, D. Duboule and P. Chambon, 1993; Proc. Natl. Acad. Sci. USA, in press), suggest that rhombomere 4 is markedly reduced, whereas rhombomere 5 is almost absent. Thus, the remnants of rhombomeres 4 and 5 appear to be fused caudally with rhombomere 6 to form a single fourth rhombomeric structure. Moreover, the migration of neural crest cells contributing to the glossopharyngeal and vagus nerves occurs in a more rostral position, resulting in abnormalities of these cranial nerves, which were visualized by whole-mount anti-neurofilament immunostaining. The mutual relationship along the rostrocaudal axis between the otic pit and the neuroepithelial site of int-2 protein secretion (a putative otogenic cue) is not significantly changed in Hoxa-1-/- embryos. However, the abnormal relationship between the rhombencephalon and the epithelial inner ear may account for the aplasia and faulty differentiation of the membranous labyrinth, the disruption of the cartilaginous otic capsule and the disorganisation of some middle ear structures. This phenotype is compared with that of the Hoxa-1-/- mutants generated by O. Chisaka, T. S. Musci and M. R. Capecchi, 1992 (Nature 335, 516-520) and with that of the mice homozygous for the kreisler mutation.
Identification and targeting of cancer stem cells (2009)

Cancer stem cells (CSC) represent malignant cell subsets in hierarchically organized tumors, which are selectively capable of tumor initiation and self-renewal and give rise to bulk populations of non-tumorigenic cancer cell progeny through differentiation. Robust evidence for the existence of prospectively identifiable CSC among cancer bulk populations has been generated using marker-specific genetic lineage tracking of molecularly defined cancer subpopulations in competitive tumor development models. Moreover, novel mechanisms and relationships have been discovered that link CSC to cancer therapeutic resistance and clinical tumor progression. Importantly, proof-of-principle for the potential therapeutic utility of the CSC concept has recently been provided by demonstrating that selective killing of CSC through a prospective molecular marker can inhibit tumor growth. Herein, we review these novel and translationally relevant research developments and discuss potential strategies for CSC-targeted therapy in the context of resistance mechanisms and molecular pathways preferentially operative in CSC.
The Law of Fiduciary Duty in New York, 1920-1980 (2000)

S the center of American, if not world capitalism, New York has specialized in the management and investment of money throughout the twentieth century.Two forms of legal institution-the corporation and the trust-are among the principal devices historically used by New York's money managers in pursuit of their trade.This article will focus on one particular body of doctrine in connection these two institutions'-the law of fiduciary duty-specifically, on the level of honesty and care which a manager of money, whether a trustee of a fund or a director or officer of a corporation, owes to its owner.No explicit changes in doctrine occurred over the course of the century in the black-letter law of fiduciary duty.But the ways in which doctrine was applied did change subtly in two respects.The article will analyze the two changes.First, the article will discuss a shift in emphasis from protecting investors in the third and fourth decades of the twentieth century to empowering entrepreneurs during later decades.During the earlier part of the century, the courts declared that fiduciaries were bound to the highest of standards of loyalty to their cestuis and were free to make only limited sorts of investments involving no conflicts of interest.Fiduciaries who breached the rules tended to be held strictly accountable.In the latter part of the century, in contrast, judges gave money managers increased freedom to use and invest funds as they saw fit, subject only to the requirement that they use due care in making investment choices.This shift
Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics (2008)

Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.
The Trail Smelter Dispute [Abridged] (2006)

The Trail Smelter Dispute covered a period of thirteen years from 1928 to 1941. It arose out of the operation by the Consolidated Mining and Smelting Company of Canada, Limited, of a smelter at Trail, British Columbia, on the Columbia River about eleven miles from the international boundary. In roasting sulphur-bearing ores, sulphur dioxide gas was wasted into the air. When the air drift was down the valley, the smoke cloud containing the sulphur dioxide crossed the boundary in sufficient strength to cause damage in the State of Washington. In 1925 and 1926, the output of the smelter was increased and more sulphur dioxide was wasted into the air. By reason of the conformation of the valley and the atmospheric conditions prevalent, it was carried across the boundary into the State of Washington. It was common ground that some damage was caused in the years 1926 to 1930.
A minor high-molecular-weight outer membrane protein of Haemophilus influenzae type b is a protective antigen (1985)

Cell surface-exposed antigenic determinants of several high-molecular-weight outer membrane proteins of Haemophilus influenzae type b (Hib) have been shown to be consistently immunogenic in human infants convalescing from Hib meningitis. A monoclonal antibody (mab), 6G12, directed against one of these cell surface-exposed outer membrane proteins that has an apparent molecular weight of 98,000 (98K) was identified by radioimmunoprecipitation analysis. Of 120 clinical isolates of Hib, 83 were found to possess antigenic determinants which reacted with mab 6G12 in a colony blot-radioimmunoassay procedure, indicating that the antigenic determinant recognized by mab 6G12 is present in the majority of Hib strains. A different radioimmunoassay, which uses whole Hib cells as antigen, confirmed that strains reactive with mab 6G12 in the colony blot-radioimmunoassay procedure possessed a cell surface-exposed and antibody-accessible antigenic determinant recognized by this mab. Hib strains which did not react with mab 6G12 were found to lack a 98K protein. Passive immunization with mab 6G12 reduced the level of bacteremia that developed in infant rats challenged with the homologous Hib strain against which this mab was raised. In contrast, no protection was observed when the challenge strain was one which lacks the antigenic determinant recognized by mab 6G12. Radioimmunoprecipitation analysis of sera from human infants convalescing from Hib meningitis detected an antibody response directed against the 98K protein. The protection against experimental Hib disease provided by antibody to the 98K protein, the immunogenicity of this protein in human infants, and its presence in a majority of Hib strains indicate that the 98K outer membrane protein may have potential for vaccine development.