gebhart/patrepeval huggingface dataset:
External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing (2004)

Local radiation is an established therapy for human tumors. Radiation also has been shown to alter the phenotype of target tissue, including gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. We demonstrate a biological synergy between local radiation of tumor and active vaccine therapy. The model used consisted of mice transgenic for human carcinoembryonic antigen (CEA) and a murine carcinoma cell line transfected with CEA. The vaccine regimen consisted of a prime and boost strategy using vaccinia and avipox recombinants expressing CEA and three T-cell costimulatory molecules. One dose of 8-Gy radiation to tumor induced up-regulation of the death receptor Fas in situ for up to 11 days. However, neither radiation at this dose nor vaccine therapy was capable of inhibiting growth of 8-day established tumor. When vaccine therapy and local radiation of tumor were used in combination, dramatic and significant cures were achieved. This was mediated by the engagement of the Fas/Fas ligand pathway because Ag-bearing tumor cells expressing dominant-negative Fas were not susceptible to this combination therapy. Following the combination of vaccine and local radiation, tumors demonstrated a massive infiltration of T cells not seen with either modality alone. Mice cured of tumors demonstrated CD4(+) and CD8(+) T-cell responses specific for CEA but also revealed the induction of high levels of T-cell responses to two other antigens (gp70 and p53) overexpressed in tumor, indicating the presence of a consequential antigen cascade. Thus, these studies demonstrate a new paradigm for the use of local tumor irradiation in combination with active specific vaccine therapy to elicit durable antitumor responses of established tumors.
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist (2012)

MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.
Phase and Morphology Changes in Lipid Monolayers Induced by SP-B Protein and Its Amino-Terminal Peptide (1996)

Both human lung surfactant protein, SP-B, and its amino-terminal peptide, SP-B1-25, inhibit the formation of condensed phases in monolayers of palmitic acid, resulting in a new fluid phase. This fluid phase forms a network, separating condensed-phase domains at coexistence. The network persists to high surface pressures, altering the nucleation, growth, and morphology of monolayer collapse structures, leading to lower surface tensions on compression and more reversible respreading on expansion. The network is stabilized by the low line tension between the fluid phase and the condensed phase as confirmed by the formation of "stripe" phases.
The in vitro influences of epidermal growth factor and heregulin-β1 on the efficacy of trastuzumab used in Her-2 positive breast adenocarcinoma (2013)

Cell type specific interactions of endogenous ligands appear to be dependent on absolute Her-receptor expression and cross activation of signaling pathways. This supports the notion that receptor density of Her-family members and multiplicity of growth ligands are of mutual importance in breast cancer cell proliferation and therefore also in resistance associated with trastuzumab.
Molecular Structures and Interactions of Pulmonary Surfactant Components (1997)

The dominating functional property of pulmonary surfactant is to reduce the surface tension at the alveolar air/liquid interface, and thereby prevent the lungs from collapsing at the end of expiration. In addition, the system exhibits host-defense properties. Insufficient amounts of pulmonary surfactant in premature infants causes respiratory distress syndrome, a serious threat which nowadays can be effectively treated by airway instillation of surfactant preparations. Surfactant is a mixture of many molecular species, mainly phospholipids and specific proteins, surfactant protein A (SP-A), SP-B, SP-C and SP-D. SP-A and SP-D are water-soluble and belong to the collectins, a family of large multimeric proteins which structurally exhibit collagenous/lectin hybrid properties and functionally are Ca2+-dependent carbohydrate binding proteins involved in innate host-defence functions. SP-A and SP-D also bind lipids and SP-A is involved in organization of alveolar surfactant phospholipids. SP-B belongs to another family of proteins, which includes also lipid-interacting polypeptides with antibacterial and lytic properties. SP-B is a 17.4-kDa homodimer and each subunit contains three intrachain disulphides and has been proposed to contain four amphipathic helices oriented pairwise in an antiparallel fashion. SP-A, SP-B and SP-D all have been detected also in the gastrointestinal tract. SP-C, in contrast, appears to be a unique protein with extreme structural and stability properties and to exist exclusively in the lungs. SP-C is a lipopeptide containing covalently linked palmitoyl chains and is folded into a 3.7-nm alpha-helix with a central 2.3-nm all-aliphatic part, making it perfectly suited to interact in a transmembranous way with a fluid bilayer composed of dipalmitoylglycerophosphocholine, the main component of surfactant. Homozygous genetic deficiency of proSP-B causes lethal respiratory distress soon after birth and is associated with aberrant processing of the precursor of SP-C. This review focuses on the chemical composition, structures and interactions of the pulmonary surfactant, in particular the associated proteins.
Molecular Approaches to Receptors as Targets for Drug Discovery (1997)

The cloning of a great number of receptors and channels has revealed that many of these targets for drug discovery can be grouped into superfamilies based on sequence and structural similarities. This review presents an overview of how molecular biological approaches have revealed a plethora of receptor subtypes, led to new definitions of subtypes and isoforms, and played a role in the development of high selective drugs. Moreover, the diversity of subtypes has molded current views of the structure and function of receptor families. Practical difficulties and limitations inherent in the characterization of the ligand binding and signaling properties of expressed recombinant receptors are discussed. The importance of evaluating drug-receptor interactions that differ with temporally transient and distinct receptor conformational states is emphasized. Structural motifs and signal transduction features are presented for the following major receptor superfamilies: ligand-gated ion channel, voltage-dependent ion channel, G-protein coupled, receptor tyrosine-kinase, receptor protein tyrosine-phosphatase, cytokine and nuclear hormone. In addition, a prototypic receptor is analyzed to illustrate functional properties of a given family. The review concludes with a discussion of future directions in receptor research that will impact drug discovery, with a specific focus on orphan receptors as targets for drug discovery. Methods for classifying orphan receptors based upon homologies with members of existing superfamilies are presented together with molecular approaches to the greater challenge of defining their physiological roles. Besides revealing new orphan receptors, the human genome sequencing project will result in the identification of an abundance of novel receptors that will be molecular targets for the development of highly selective drugs. These findings will spur the discovery and development of an exciting new generation of receptor-subtype specific drugs with enhanced therapeutic specificity.
Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma (2015)

Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.
The synthesis and antiallergy activity of 1-(aryloxy)-4-(4-arylpiperazinyl)-2-butanol derivatives (1990)

A series of 1-(aryloxy)-4-(4-arylpiperazinyl)-2-butanol derivatives were prepared and evaluated for antiallergy activity in the passive foot anaphylaxis (PFA) assay in rats. Twenty-seven derivatives had activity equal to or greater than the parent, alpha-(phenoxymethyl)-4-phenyl-1-piperazinepropanol. Six derivatives that possessed greater activity in the PFA than the parent compound were then tested in the guinea pig anaphylaxis (GPA) assay. Five of the derivatives were more potent than the parent (PD50 = 40 mg/kg) in the GPA with alpha-[(4-fluorophenoxy)methyl]-4-(4-fluorophenyl)-1-piperazinepropan ol (PD50 = 3 mg/kg) having the greatest potency.
When Defense Pathways Collide. The Response of Arabidopsis to a Combination of Drought (2004)

Ludmila Rizhsky, Hongjian Liang, Joel Shuman, Vladimir Shulaev, Sholpan Davletova,and Ron Mittler*Department of Biology, Technion, Israel Institute of Technology, Technion City, Haifa 32000, Israel (L.R.);Department of Botany, Plant Sciences Institute, Iowa StateUniversity,Ames,Iowa50011(H.L.);VirginiaBioinformatics Institute, Blacksburg, Virginia 24061 (J.S., V.S.); Department of Biochemistry, Universityof Nevada, Reno, Nevada 89557 (S.D., R.M.)
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations (2021)

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M<sup>pro</sup>) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC<sub>50</sub> values in a kinetic assay. Free-energy perturbation (FEP) calculations for M<sup>pro</sup>-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M<sup>pro</sup>. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.
Treatment with Succinic Anhydride Improves the Immunogenicity ofShigella flexneriType 2a O-Specific Polysaccharide–Protein Conjugates in Mice (1999)

Seroepidemiological data and a clinical trial with a Shigella sonnei O-specific polysaccharide (O-SP)-Pseudomonas aeruginosa recombinant exoprotein A (rEPA) conjugate provide evidence that a critical level of immunoglobulin G (IgG) lipopolysaccharide (LPS) antibodies in serum confers protection against shigellosis. We evaluated the immunogenicity of conjugates whose carrier proteins and O-SPs were treated with succinic anhydride (SA), which reacts with amino groups at neutral pH to form amide-linked carboxyls (succinylation). Conjugates were synthesized with either of two genetically inactivated medically useful toxins, the diphtheria protein CRM9 or rEPA, bound to the O-SP of Shigella flexneri type 2a. Conjugates composed of the succinylated protein, succinylated O-SP, or both succinylated components were administered to mice by a clinically relevant scheme, and their levels of serum IgG anti-LPS and anti-proteins were assayed 7 days after the second and third injections. CRM9 served as a more immunogenic carrier than rEPA. Conjugates composed of succinylated components were more immunogenic than the conjugates composed of the native components. SA treatment of both the carrier protein and the O-SP did not confer an advantage over the succinylated protein alone. Conjugates prepared with native proteins, in general, elicited slightly higher levels of IgG protein antibodies than conjugates composed of the SA-treated proteins.
Cold Atmospheric Plasma Modified Electrospun Scaffolds with Embedded Microspheres for Improved Cartilage Regeneration (2015)

Articular cartilage is prone to degeneration and possesses extremely poor self-healing capacity due to inherent low cell density and the absence of a vasculature network. Tissue engineered cartilage scaffolds show promise for cartilage repair. However, there still remains a lack of ideal biomimetic tissue scaffolds which effectively stimulate cartilage regeneration with appropriate functional properties. Therefore, the objective of this study is to develop a novel biomimetic and bioactive electrospun cartilage substitute by integrating cold atmospheric plasma (CAP) treatment with sustained growth factor delivery microspheres. Specifically, CAP was applied to a poly(ε-caprolactone) electrospun scaffold with homogeneously distributed bioactive factors (transforming growth factor-β1 and bovine serum albumin) loaded poly(lactic-co-glycolic) acid microspheres. We have shown that CAP treatment renders electrospun scaffolds more hydrophilic thus facilitating vitronectin adsorption. More importantly, our results demonstrate, for the first time, CAP and microspheres can synergistically enhance stem cell growth as well as improve chondrogenic differentiation of human marrow-derived mesenchymal stem cells (such as increased glycosaminoglycan, type II collagen, and total collagen production). Furthermore, CAP can substantially enhance 3D cell infiltration (over two-fold increase in infiltration depth after 1 day of culture) in the scaffolds. By integrating CAP, sustained bioactive factor loaded microspheres, and electrospinning, we have fabricated a promising bioactive scaffold for cartilage regeneration.
Term Structure Movements and Pricing Interest Rate Contingent Claims (1986)

ABSTRACT This paper derives an arbitrage‐free interest rate movements model (AR model). This model takes the complete term structure as given and derives the subsequent stochastic movement of the term structure such that the movement is arbitrage free. We then show that the AR model can be used to price interest rate contingent claims relative to the observed complete term structure of interest rates. This paper also studies the behavior and the economics of the model. Our approach can be used to price a broad range of interest rate contingent claims, including bond options and callable bonds.
A time domain based classifier for ECG pattern recognition (2011)

Pattern recognition, and in particular dynamic time warping has been applied to the ECG for many different purposes over the last decade. Significant research on creating adaptive, feature based, and more complex forms of the algorithm in order to increase its ability to classify an ECG signal accurately has been performed. Despite this increase in complexity and in the number of variations of the dynamic time warping algorithm there has been less focus on actually using the results of dynamic time warping to relate the reference and test signals to each other as accurately as possible. The majority of dynamic time warping algorithms published in the literature, even the most complex of them, classify the most accurate match to a reference signal based only on resulting Euclidean distance or slope difference between samples of the known reference and unknown query signal. This article demonstrates how a combination of measurements including heart-rate, amplitude and required warping time alignment can be used to reduce the resulting error in the classification of a query signal after the query and reference signals have been warped together. Its benefits are verified with significant testing.
Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia (2013)

These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.
Behavioral effects mediated by the modulatory glycine site of the NMDA receptor in the anterodorsal striatum and nucleus accumbens (1996)

The striatum and the nucleus accumbens are the main input structures of the basal ganglia (BG). They contribute differently to motor behavior controlled by the BG in rats, e.g., stereo-typed behavior, catalepsy, and locomotion. Whereas the striatum is predominantly involved in the control of sniffing behavior and catalepsy, the nucleus accumbens contributes to control of locomotion. To test whether the allosteric glycine site of the NMDA receptor complex modulates these behavioral variables, we injected the glycine-site antagonist 7-chlorokynurenate and the glycine-site agonist D-serine into the anterodorsal striatum and the nucleus accumbens and studied their influence on stereotypical snout contacts and locomotion. Additionally, the effects of intrastriatal injections of 7-chlorokynurenate on haloperidol- and SCH 23390-induced catalepsy were investigated. 7-Chlorokynurenate enhanced stereotypical snout contacts in the anterodorsal striatum and in the nucleus accumbens but did not change spontaneous locomotion in either of these structures. Haloperidol- but not SCH 23390-induced catalepsy was attenuated by intrastriatally administered 7-chlorokynurenate. The glycine-site agonist D-serine had no effect on stereotypical snout contacts and locomotion. The results suggest that motor behavior mediated by the striatopallidal output pathway is modulated by the glycine site, whereas motor behavior mediated by the accumbopallidal and striatonigral output pathway is not.
Specificity of bone morphogenetic protein-related factors: cell fate and gene expression changes in Drosophila embryos induced by decapentaplegic but not 60A. (1994)

Reported assays of the bone morphogenetic proteins (BMPs) have not in general revealed specific functions for the different proteins, belying the specificity implied by the evolutionary conservation and distinct expression patterns of the genes encoding BMPs. We have used assays of developmental function to show that the two Drosophila homologues of the BMPs, decapentaplegic (dpp) and 60A, that both induce ectopic bone formation in mammalian assay systems, have distinct effects in Drosophila development. A binary expression system using the yeast transcriptional activator GAL4 directed identical patterns of tissue and temporally specific dpp and 60A expression. When dpp enhancer elements drove GAL4 expression, GAL4-responsive dpp transgenes rescued dpp mutant phenotypes, but GAL4-responsive 60A transgenes did not. Ectopic ectodermal expression of dpp during gastrulation respecified the dorsal/ventral pattern of the embryo. In contrast, ectopic 60A expression had no detectable effects on embryonic development but led to defects in adult structures or lethality during metamorphosis. Expression of 60A in cells expressing dpp did not interfere with dpp functions, indicating that dysfunctional heterodimers did not form at sufficient levels to inhibit dpp. These specific developmental responses in Drosophila indicate that in vivo functions of BMP-like factors can be more specific than indicated by the ectopic bone formation assays and that the Drosophila embryo provides an assay system sensitive to the structural differences that contribute to BMP specificity in vivo.
Cell-based tissue engineering for lung regeneration (2006)

Emphysema is a chronic lung disease characterized by alveolar enlargement and tissue loss. Tissue engineering represents an attractive potential for regeneration of several organ systems. The complex three-dimensional architectural structure of lung parenchyma requiring connections of alveolar units to airways and the pulmonary circulation makes this strategy less optimistic. In the present study, we used Gelfoam sponge as a scaffold material, supplemented with fetal rat lung cells as progenitors, to explore the potential application of cell-based tissue engineering for lung regeneration in adult rats. After injection into lung parenchyma, the sponge showed porous structures similar to alveolar units. It did not induce severe local inflammatory response. Fetal lung cells in the sponge were able to survive in the adult lung for at least 35 days, determined by CMTMR [5-(and-6)-{[(4-chloromethyl)benzoyl]amino}tetramethylrhodamine] labeling. Proliferation of cells within the sponge was demonstrated in vivo by bromodeoxyuridine (BrdU) labeling. Cells formed "alveolar-like structures" at the border between the sponge and the surrounding lung tissue with positive immunohistochemical staining for epithelial and endothelial cells. Neovascularization of the sponge was demonstrated with India ink perfusion. The sponge degraded after several months. This study suggests that cell-based tissue engineering possesses the potential to regenerate alveolar-like structures, an important step towards our ultimate goal of lung regeneration.
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway (2001)

HMG-CoA reductase inhibitors (statins) have been developed as lipid-lowering drugs and are well established to reduce morbidity and mortality from coronary artery disease. Here we demonstrate that statins potently augment endothelial progenitor cell differentiation in mononuclear cells and CD34-positive hematopoietic stem cells isolated from peripheral blood. Moreover, treatment of mice with statins increased c-kit+/Sca-1+–positive hematopoietic stem cells in the bone marrow and further elevated the number of differentiated endothelial progenitor cells (EPCs). Statins induce EPC differentiation via the PI 3-kinase/Akt (PI3K/Akt) pathway as demonstrated by the inhibitory effect of pharmacological PI3K blockers or overexpression of a dominant negative Akt construct. Similarly, the potent angiogenic growth factor VEGF requires Akt to augment EPC numbers, suggesting an essential role for Akt in regulating hematopoietic progenitor cell differentiation. Given that statins are at least as potent as VEGF in increasing EPC differentiation, augmentation of circulating EPC might importantly contribute to the well-established beneficial effects of statins in patients with coronary artery disease.