gebhart/patrepeval huggingface dataset:
Cyclodextrins and ternary complexes: technology to improve solubility of poorly soluble drugs (2011)

Cyclodextrins (CDs) are cyclic oligosaccharides composed of D-glucopyranoside units linked by glycosidic bonds. Their main property is the ability to modify the physicochemical and biological characteristics of low-soluble drugs through the formation of drug:CD inclusion complexes. Inclusion complexation requires that host molecules fit completely or partially within the CD cavity. This adjustment is directly related to the physicochemical properties of the guest and host molecules, easy accommodation of guest molecules within the CD cavity, stoichiometry, therapeutic dose, and toxicity. However, dosage forms may achieve a high volume, depending on the amount of CD required. Thus, it is necessary to increase solubilization efficiency in order to use smaller amounts of CD. This can be achieved by adding small amounts of water-soluble polymers to the system. This review addresses aspects related to drug complexation with CDs using water-soluble polymers to optimize the amount of CD used in the formulation in order to increase drug solubility and reduce dosage form volume.
Signaling through CD44 Is Mediated by Tyrosine Kinases (1996)

Evidence from a large body of studies indicates that CD44 is involved in a number of important biological processes, including lymphocyte activation and homing, hematopoiesis, and tumor progression and metastasis. A proper understanding of the role of CD44 in these processes has been severely hampered by a lack of insight into the mode in which CD44 communicates with intracellular signal transduction pathways. In this report, we have addressed this aspect of CD44 functioning by studying CD44 signaling in T lymphocytes. We show that ligation of CD44 by monoclonal antibodies (mAbs) transduces signals to T cells which lead to tyrosine phosphorylation of ZAP-70 and other intracellular proteins. In vitro kinase assays demonstrate that cross-linking of CD44 induces an increase in the intrinsic activity of p56lck. Furthermore, immunoprecipitations show that CD44 is physically associated with p56lck. Our findings suggest that tyrosine kinases, particularly p56lck, play a central role in CD44 mediated signaling.
Modulation of angiogenesis in vitro (1992)

Angiogenesis plays a critical role in a number of physiological and pathological settings, including wound healing, diabetic retinopathy, and tumor growth [1]. Until recently however, angiogenesis could only be studied in animal models, with the attendant drawbacks of not being able to precisely define the molecular components of this process in vivo. In an attempt to better understand the regulatory mechanisms of angiogenesis, we set out to develop novel experimental systems, in which essential components of the neovascularization process can be recapitulated and subsequently modulated and analyzed under well-defined in vitro conditions. In order to approximate as closely as possible the in vivo situation, we have designed three-dimensional culture systems allowing the re-establishment of the normal interactions between microvascular endothelial cells and the surrounding extracellular matrix.
Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability (2013)

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~4400 μg DM1/m(2)) and 30 mg/kg (~ 6000 μg DM1/m(2)) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600 μg DM1/m(2)). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.
Synthetic peptides of Shiga toxin B subunit induce antibodies which neutralize its biological activity (1988)

Shiga toxin B chain, the binding subunit of Shiga toxin, was recently purified; and the amino acid sequence of this 7,716-dalton polypeptide was determined (N.G. Seidah, A. Donohue-Rolfe, C. Lazure, F. Auclair, G. T. Keusch, and M. Chretien, J. Biol. Chem. 261:13928-13931, 1986). In the present study, synthetic peptides corresponding to three overlapping sequences from the N-terminal region of this subunit were prepared. The peptides synthesized consisted of residues 5 to 18, 13 to 26, and 7 to 26. This region coincides with the major peak of hydrophilicity and surface area residues predicted from a computer analysis. For the purpose of immunization, the peptides either were conjugated with a protein or synthetic carrier or were polymerized with glutaraldehyde. Antisera against these peptide derivatives raised in rabbits reacted not only with the respective homologous peptide but also to a comparable extent with the intact Shiga toxin. The anti-peptide antisera effectively neutralized the various biological activities of the Shiga toxin, namely, cytotoxicity to HeLa cells, enterotoxic activity (the fluid secretion into ligated ileal loops in rats), and neurotoxicity in mice. Furthermore, active immunization with the peptide conjugates was found to protect mice against the lethal effect of Shiga toxin.
Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling (2007)

Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8(+) T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8(+) T cells in mice genetically deficient in all lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand-containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8(+) T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
Protein Folding Theory: From Lattice to All-Atom Models (2001)

This review focuses on recent advances in understanding protein folding kinetics in the context of nucleation theory. We present basic concepts such as nucleation, folding nucleus, and transition state ensemble and then discuss recent advances and challenges in theoretical understanding of several key aspects of protein folding kinetics. We cover recent topology-based approaches as well as evolutionary studies and molecular dynamics approaches to determine protein folding nucleus and analyze other aspects of folding kinetics. Finally, we briefly discuss successful all-atom Monte-Carlo simulations of protein folding and conclude with a brief outlook for the future.
Association of a Germ-Line Copy Number Variation at 2p24.3 and Risk for Aggressive Prostate Cancer (2009)

We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.
The genome sequence of the psychrophilic archaeon,Methanococcoides burtonii: the role of genome evolution in cold adaptation (2009)

Psychrophilic archaea are abundant and perform critical roles throughout the Earth's expansive cold biosphere. Here we report the first complete genome sequence for a psychrophilic methanogenic archaeon, Methanococcoides burtonii. The genome sequence was manually annotated including the use of a five-tiered evidence rating (ER) system that ranked annotations from ER1 (gene product experimentally characterized from the parent organism) to ER5 (hypothetical gene product) to provide a rapid means of assessing the certainty of gene function predictions. The genome is characterized by a higher level of aberrant sequence composition (51%) than any other archaeon. In comparison to hyper/thermophilic archaea, which are subject to selection of synonymous codon usage, M. burtonii has evolved cold adaptation through a genomic capacity to accommodate highly skewed amino-acid content, while retaining codon usage in common with its mesophilic Methanosarcina cousins. Polysaccharide biosynthesis genes comprise at least 3.3% of protein coding genes in the genome, and Cell wall, membrane, envelope biogenesis COG genes are overrepresented. Likewise, signal transduction (COG category T) genes are overrepresented and M. burtonii has a high 'IQ' (a measure of adaptive potential) compared to many methanogens. Numerous genes in these two overrepresented COG categories appear to have been acquired from epsilon- and delta-Proteobacteria, as do specific genes involved in central metabolism such as a novel B form of aconitase. Transposases also distinguish M. burtonii from other archaea, and their genomic characteristics indicate they have an important role in evolving the M. burtonii genome. Our study reveals a capacity for this model psychrophile to evolve through genome plasticity (including nucleotide skew, horizontal gene transfer and transposase activity) that enables adaptation to the cold, and to the biological and physical changes that have occurred over the last several thousand years as it adapted from a marine to an Antarctic lake environment.
Matrine‐Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species‐Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling (2017)

Matrine-type alkaloids exert endothelial protective effects against advanced glycation end products induced reactive oxygen species-mediated apoptosis by targeting MKK3/6 and enhancing their phosphorylation.
Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators (1997)

Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon-DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)-1(alpha,beta)-N7Gua at 59-213 micromol/mol DNA-phosphate whereas the level of stable adducts was 0.1 micromol/mol DNA-phosphate. In female Sprague-Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 micromol 4-OHE2-1(alpha, beta)-N7Gua/molDNA-phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87-440 micromol of 4-OHE1(E2)-1(alpha, beta)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 micromol of adduct/mol DNA-phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.
Internetworking with TCP/IP, Vol. 3: Client-Server Programming and Applications, Linux/Posix Sockets Version (2000)

From the Publisher:
FEATURES


Practical client-server design principles and techniques are presented with the strengths and weaknesses of each approach.
The most complete coverage of server technology shows how to select among server algorithms and build an advanced server appropriate for each application.
A wide range of server designs applicable to the WWW and other applications are discussed.
Chapters on streaming technology and the Real-Time Transport Protocol explain how to transfer audio and video over the Internet.
Each client-server design is illustrated with a detailed example implementation that has been tested under Linus; all code from the book is available on a Web site.
The book examines powerful techniques such as application gateways and tunneling.
It includes the clearest explanation of remote procedure call (RCP) and how it can be used to construct distributed programs.
Pharmacologic Aspects of Cigarette Smoking and Nicotine Addiction (1988)

NICOTINE has been consumed in the form of tobacco and other plants for many hundreds of years. The compulsive use of tobacco has been observed in nearly every culture into which tobacco has been introduced. Nearly 30 percent of adult Americans smoke despite, in most cases, a desire to quit and despite common knowledge of the health hazards.1 Their failure to quit smoking is attributable in large part to the addictive properties of nicotine. Recently, nicotine has become available as a pharmaceutical agent, marketed as a chewing gum to help people stop smoking. In addition to its direct effect on . . .
Targeting tumor necrosis factor-alpha as a potential therapy in inflammatory skin diseases. (2002)

Tumor necrosis factor-a (TNFalpha) plays an important role in the initiation and persistence of inflammation in a variety of skin disorders. The availability of selective TNFalpha blockers has provided new therapeutic opportunities. TNFa inhibitors have been employed with success in treating psoriasis in controlled trials, although further studies are warranted to better define which subgroup of patients can benefit most from this treatment and modalities of combination therapy. In addition, an increasing number of case reports indicates that anti-TNFalpha agents are of value in the treatment of other skin diseases, such as pyoderma gangrenosum and Behcet's syndrome, and in the treatment of graft-versus-host disease.
Target-Specific Cellular Uptake of PLGA Nanoparticles Coated with Poly(l-lysine)−Poly(ethylene glycol)−Folate Conjugate (2005)

Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles with anionic surface charge were surface coated with cationic di-block copolymer, poly(L-lysine)-poly(ethylene glycol)-folate (PLL-PEG-FOL) conjugate, for enhancing their site-specific intracellular delivery against folate receptor overexpressing cancer cells. The PLGA nanoparticles coated with the conjugate were characterized in terms of size, surface charge, and change in surface composition by XPS. By employing the flow cytometry method and confocal image analysis, the extent of cellular uptake was comparatively evaluated under various conditions. PLL-PEG-FOL coated PLGA nanoparticles demonstrated far greater extent of cellular uptake to KB cells, suggesting that they were mainly taken up by folate receptor-mediated endocytosis. The enhanced cellular uptake was also observed even in the presence of serum proteins, possibly due to the densely seeded PEG chains. The PLL-PEG-FOL coated PLGA nanoparticles could be potentially applied for cancer cell targeted delivery of various therapeutic agents.
Quantitative shape-function modeling of the forearm in medical imaging (2004)

We present a preliminary quantitative approach to analyzing how 3D shapes match in order to better evaluate how such a coupling impacts on a functional motion. Addressing long bone morphometry, we study the influence of the 3D shape of forearm bone structures on the limitation of rotational range during pronation-supination motion. On the basis of modeling at successive stages-shape, motion, and deformation-, simulation here confirms the assumption that shape parameters are naturally optimal within a given non-pathological forearm. In addition, as regards this particular bone-joint subsystem, the restriction to only bones is questioned while the need to focus on shaft portions is supported. Consequently, the suggestion to investigate on the interosseous ligament in particular is made.
Face pose discrimination using support vector machines (SVM) (2002)

This paper describes an approach for the problem of face pose discrimination using support vector machines (SVM). Face pose discrimination means that one can label the face image as one of several known poses. Face images are drawn from the standard FERET database. The training set consists of 150 images equally distributed among frontal, approximately 33.75/spl deg/ rotated left and right poses, respectively, and the test set consists of 450 images again equally distributed among the three different types of poses. SVM achieved perfect accuracy-100%-discriminating between the three possible face poses on unseen test data, using either polynomials of degree 3 or radial basis functions (RBF) as kernel approximation functions.
Development of Norwalk Virus-Specific Monoclonal Antibodies with Therapeutic Potential for the Treatment of Norwalk Virus Gastroenteritis (2013)

Passive immunoprophylaxis or immunotherapy with norovirus-neutralizing monoclonal antibodies (MAbs) could be a useful treatment for high-risk populations, including infants and young children, the elderly, and certain patients who are debilitated or immunocompromised. In order to obtain antinorovirus MAbs with therapeutic potential, we stimulated a strong adaptive immune response in chimpanzees to the prototype norovirus strain Norwalk virus (NV) (genogroup I.1). A combinatorial phage Fab display library derived from mRNA of the chimpanzees' bone marrow was prepared, and four distinct Fabs reactive with Norwalk recombinant virus-like particles (rVLPs) were recovered, with estimated binding affinities in the subnanomolar range. Mapping studies showed that the four Fabs recognized three different conformational epitopes in the protruding (P) domain of NV VP1, the major capsid protein. The epitope of one of the Fabs, G4, was further mapped to a specific site involving a key amino acid residue, Gly365. One additional specific Fab (F11) was recovered months later from immortalized memory B cells and partially characterized. The anti-NV Fabs were converted into full-length IgG (MAbs) with human γ1 heavy chain constant regions. The anti-NV MAbs were tested in the two available surrogate assays for Norwalk virus neutralization, which showed that the MAbs could block carbohydrate binding and inhibit hemagglutination by NV rVLP. By mixing a single MAb with live Norwalk virus prior to challenge, MAbs D8 and B7 neutralized the virus and prevented infection in a chimpanzee. Because chimpanzee immunoglobulins are virtually identical to human immunoglobulins, these chimpanzee anticapsid MAbs may have a clinical application.
Active and Passive LC Based Polarization Elements (2014)

Passive and active polarization elements were created by surface and bulk photo-alignment of LCs, reactive LCs, photo-sensitive LCP and photo-curable monomer/LC composites. The use of different photo­sensitive liquid crystalline materials for the development of highly anisotropic elements with high spatial resolution and stability or, alternatively, fast switch ability will be discussed. Photo-active and voltage tunable polarization and diffraction elements are presented. For active micro-optic application a photo-addressed patterned retarder was created. Electrically switchable diffraction gratings were generated by interference exposure of photo-curable LC composites at room temperature characterized by droplet free morphology. These polarization sensitive diffraction elements are characterized be excellent optical properties and low switching times.
Boronated Carbohydrate Derivatives as Potential Boron Neutron Capture Therapy Reagents (2013)

The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among the types of boron-containing molecules used as boron neutron capture therapy agents, boronated carbohydrate derivatives have received significant attention because of their preferential uptake by growing tumor cells. This review provides a summary of the recent developments in the chemistry of carborane-containing carbohydrates.
Vivid-red and highly efficient phosphors bearing diphenylquinoxaline units and their application to organic light-emitting devices (2006)

The characterization of the iridium compounds bearing 2,3-diphenylquinoxaline units is presented here to afford vivid-red emitting phosphors with exceedingly high quantum yields and enhanced radiative transition performance. The series of 2,3-diphenylquinoxalinato-iridium phosphors are proposed to realize an efficient, bright and vivid-red emission.