gebhart/patrepeval huggingface dataset:
Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR) (2004)

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.
The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system (1999)

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.
Energy Landscape of Aptamer/Protein Complexes Studied by Single‐Molecule Force Spectroscopy (2007)

Aptamers are single-stranded nucleic acid molecules selected in vitro to bind to a variety of target molecules. Aptamers bound to proteins are emerging as a new class of molecules that rival commonly used antibodies in both therapeutic and diagnostic applications. With the increasing application of aptamers as molecular probes for protein recognition, it is important to understand the molecular mechanism of aptamer-protein interaction. Recently, we developed a method of using atomic force microscopy (AFM) to study the single-molecule rupture force of aptamer/protein complexes. In this work, we investigate further the unbinding dynamics of aptamer/protein complexes and their dissociation-energy landscape by AFM. The dependence of single-molecule force on the AFM loading rate was plotted for three aptamer/protein complexes and their dissociation rate constants, and other parameters characterizing their dissociation pathways were obtained. Furthermore, the single-molecule force spectra of three aptamer/protein complexes were compared to those of the corresponding antibody/protein complexes in the same loading-rate range. The results revealed two activation barriers and one intermediate state in the unbinding process of aptamer/protein complexes, which is different from the energy landscape of antibody/protein complexes. The results provide new information for the study of aptamer-protein interaction at the molecular level.
Phenotype analysis of hematopoietic CD34+ cell populations derived from human umbilical cord blood using flow cytometry and cDNA-polymerase chain reaction (1994)

A strategy to phenotype rare populations of hematopoietic cells expressing the cell-surface marker CD34 was studied. The antigenic phenotype of umbilical core blood (CB) CD34+ cells was investigated using flow cytometry and compared with the mRNA-phenotype determined by cDNA-polymerase chain reaction (cDNA-PCR) analysis. The cDNA-PCR method allowed an mRNA evaluation of small numbers of cells. Monoclonal antibodies and oligonucleotide primers that recognize myeloid, lymphoid, erythroid and platelet/megakaryocytic cell membrane antigens or corresponding mRNA transcripts were used. Evaluation by flow cytometry showed that the vast majority of CD34+ CB cells coexpressed CD38, CD18, HLA-DR, and CD33. Rare subpopulations of CD34+CD38-, CD34+CD18-, CD34+HLA-DR-, and CD34+CD33- were also identified. A large proportion of CD34+ CB cells expressed CD13, CD45R, and to a lesser extent CD71. The CD36, CD51, and CD61 antigens were identified on a small number of CD34+ cells. The three-color flow cytometry analysis showed that CD34+ cells stained with antibodies to CD61 and CD36 or CD51 can be divided into subsets that may represent progenitor cells committed to the erythroid and/or megakaryocytic lineage. A variety of other lineage-specific cell-surface antigens including pre-T-cell marker CD7 and markers of early B cells, ie, CD10 and CD19, were not coexpressed with CD34+. Using the cDNA-PCR it was seen that the mRNA phenotype of a small number of sorted CD34+ cells (purity &gt; 98%) was negative for the markers CD2, CD14, CD16, CD20, CD21, CD22, CD41b, and glycophorin A that are expressed on differentiated cells but positive for CD34, CD7, CD19, CD36, and CD61. The results suggest that circulating CD34+CD7+ and CD34+CD19+ CB cells cannot be distinguished by flow cytometry but can be detected by cDNA-PCR. This indicates that CB either contains very low numbers of these progenitors or that the antigen density of CD7 and CD19 on CD34+ cells is below the detection limit of the flow cytometer. In contrast to flow cytometry, cDNA-PCR allows the phenotypic analysis of cells even if their number is small. Thus, the cDNA-PCR method can be useful in linking phenotype analyses, ie, markers of differentiation, to studies on gene expression within rare populations of hematopoietic stem cells.
Plasmin Desensitization of the PAR1 Thrombin Receptor:  Kinetics, Sites of Truncation, and Implications for Thrombolytic Therapy (1999)

It has been hypothesized that protease-activated receptors may be activated and attenuated by more than one protease. Here, we explore a desensitization mechanism of the PAR1 thrombin receptor by anticoagulant proteases and provide an explanation to the enigma of why plasmin/tissue plasminogen activator (t-PA) can both activate and deactivate platelets prior to thrombin treatment. By using a soluble N-terminal exodomain (TR78) as a model for the full-length receptor, we were able to unambiguously compare cleavage rates and specificities among the serum proteases. Thrombin cleaves TR78 at the R41-S42 peptide bond with a kcat of 120 s-1 and a KM of 16 microM to produce TR62 (residues 42-103). We found that, of the anticoagulant proteases, only plasmin can rapidly truncate the soluble exodomain at the R70/K76/K82 sites located on a linker region that tethers the ligand to the body of the receptor. Plasmin cleavage of the TR78 exodomain is nearly equivalent to that of thrombin cleavage at R41 with similar rates (kcat = 30 s-1) and affinity (KM = 18 microM). Specificity was demonstrated since there is no observed cleavage at the five other potential plasmin-cleavage sites. Plasmin also cleaves the TR78 exodomain at the R41 thrombin-cleavage site generating transiently activated exodomain. We directly demonstrated that plasmin cleaves these same sites in full-length membrane-embedded receptor expressed in yeast and COS7 fibroblasts. The rate of plasmin truncation is similar between the extensively glycosylated COS7-expressed receptor and the nonglycosylated yeast-produced receptor. Mutation of the R70/K76/K82 sites to A70/A76/A82 eliminates plasmin truncation and desensitization of thrombin-dependent Ca2+ signaling and converts PAR1 into a plasmin-activated receptor with full agonist activity for plasmin. Plasmin does not desensitize the Ca2+ response of platelets or COS7 cells to SFLLRN consistent with intermolecular ligand-binding sites being located to the C-terminal side of K82. Truncation of the wild-type receptor at the C-terminal plasmin-cleavage sites removes the N-terminal tethered ligand or preligand, thereby providing an effective pathway for PAR1 desensitization in vivo.
Association of Plasma Homocysteine and Macular Edema in Type 2 Diabetes Mellitus (2008)

Mild to moderate elevation of homocysteine may explain the role of vascular dysregulation and endothelial dysfunction in patients with DR. The present study suggests hyperhomocysteinemia may be one of the crucial risk factors for development of ME.
Stimulation of hexose transport by metformin in L6 muscle cells in culture (1992)

L6 muscle cells grown in culture to the stage of fused myotubes were incubated with the oral hypoglycemic drug metformin to test the effects of this drug on glucose transport. Metformin increased the initial rate of uptake of 2-deoxyglucose and 3-O-methylglucose. The effect was time dependent, with half-maximal stimulation at 5-6 h and maximal stimulation by about 16 h. The stimulation of hexose uptake was not prevented by cycloheximide. In 15 mM glucose medium, the basal rate of transport was lower than in 5 mM glucose medium. The stimulation of hexose uptake by metformin was comparable in absolute units in both media; hence, relative to basal uptake, stimulation was greater in the high glucose medium than in the low glucose medium. In 5 mM glucose medium, half-maximal stimulation was obtained with 800 microM metformin when tested for 24 h. The stimulation of hexose transport by metformin was only detectable in fused myotubes and not in perfusion myoblasts. No significant changes were observed in glucose transporter levels in total cell membranes from L6 myotubes (measured as D-glucose-protectable binding sites for cytochalasin-B) or in the total levels of the immunoreactive glucose transporter isoforms GLUT4 or GLUT1. It is concluded that metformin stimulates hexose transport into differentiated muscle cells by acting at a posttranslational level. We speculate that this might also constitute the basis for the ability of the drug to lower glycemia in diabetic individuals.
Magnesium status in healthy free-living elderly Norwegians. (1994)

This study suggests that a significant subclinical Mg deficit, not detected by serum Mg, was present in many of these healthy elderly subjects. Mg supplementation improved Mg status and renal function.
Synthesis of functionalized bis-amides of L-(+)-tartaric acid and application as copper (II) ligands (2004)

The preparation of aliphatic, aromatic or functionalized tartramides directly from tartaric acid and amines under microwaves activation is described. A preliminary study of the chelating properties of some functionalized tartramides towards Cu 2+ ions is reported. .
스마트 웰니스 기초 조사를 위한 웰니스 관광 활동 분류 (2018)

Purpose - The objective of this study was to explore how wellness activities can be categorized by categorical principal components analysis based on...
Recent Patents on Eggshell: Shell and Membrane Applications (2011)

The chicken eggshell and its membranes are an inexpensive and abundant waste material which exhibit interesting characteristics for many potential applications. The eggshell is formed mainly of calcium carbonate (CaCO3) and is used widely as an animal feed, lime (Ca(OH)2) substitute or a fertilizer. Moreover, the associated eggshell membranes have a high content of bioactive components, as well as properties of moisture retention and biodegradability which have potential use for clinical, cosmetic, nutraceutical and nanotechnology applications. The eggshell membranes have been also used for biosorption of heavy metals and dyes and as a template to synthesize metal nanoparticles. The combination of nanosized calcium phosphate (Ca3(PO4)2) biomaterials synthesized from eggshell and eggshell membrane show promise to develop drug delivery system and nanowires for electronic devices. In addition, a derived product, the soluble eggshell membrane protein (SEP) has applications in tissue engineering. This review discusses the patented applications of eggshell membrane waste: shell and membrane for the last 10 years as well as their future applications.
Solid phase micro extraction of biopolymers, exemplified with adsorption of basic proteins onto a fiber coated with polyacrylic acid (1996)

Fused silica fibers coated with polyacrylic acid were used to extract proteins. The amount of protein extracted is proportional to the concentration of the protein in the sample for very short extraction times (a few seconds) when the binding capacity of the coated fiber for proteins is low. Proportionality is also obtained when the extraction time is extended to several minutes, provided that the binding capacity exceeds the protein content of the sample. However, when the capacity is low these long extraction times favor the extraction of the more strongly adsorbed proteins. The mixture of extracted proteins was analyzed by micro-HPLC using columns based on a new continuous polymer bed technology. © 1996 John Wiley & Sons, Inc.
Long‐term efficacy of Humalogã in subjects with Type 1 diabetes mellitus (1999)

We conclude that Humalog insulin is effective in lowering postprandial glucose excursions even after up to 5.4 years of treatment.
Leptin receptor (OB‐R) oligomerizes with itself but not with its closely related cytokine signal transducer gp130 (1997)

Leptin (OB) exerts weight-reducing effects in mice. The structure of the receptor for this factor, OB-R, is considerably similar to those of gp130, the common signal transducing receptor component for the interleukin-6 (IL-6) family of cytokines, and leukemia inhibitory factor receptor (LIFR). Since the IL-6 family of cytokines signal through gp130 homodimer or gp130/LIFR heterodimer, we have examined in this study the possible involvement of gp130 and LIFR in leptin signaling through OB-R. Leptin stimulation induces tyrosine phosphorylation of neither gp130 nor LIFR, while LIF stimulation does both. As examined by using two differently epitope-tagged OB-R molecules, the spontaneous homo-oligomerization of OB-R has been elucidated. Ba/F3 cells, which do not express gp130, are non-responsive to leptin and exhibit increased DNA synthesis in response to leptin after transfection of OB-R cDNA alone. OB-R appears to transduce the signal via its homo-oligomerization without interaction with gp130 or LIFR.
Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tau (1992)

The Alzheimer‐like state of tau protein includes phosphorylation by a proline‐directed Ser/Thr kinase present in normal or pathological human brain. Extending earlier results on MAP kinase, we show here that the proline‐directed kinase, GSK3, can induce an Alzheimer‐like immune response involving several distinct and phoshorylatable epitopes at Ser—Pro motifs, as well as gel mobility shift, similar to MAP kinase. Both kinases behave like microtubule‐associated proteins in that they co‐purify through cycles of assembly and disassembly, and both kinases are directly associated with paired helical filaments.
Prospective study of the association between serum antibodies to lipopolysaccharide O antigen and the attack rate of shigellosis (1991)

A means for determining immune status against shigellosis would significantly improve the design and evaluation of interventional and other epidemiologic studies. Previous case-control studies have indicated the potential role of humoral antilipopolysaccharide antibodies. To test this proposition, 190 soldiers serving in a field unit were monitored prospectively for 2.5 months for shigellosis. Blood samples were taken at the beginning of the follow-up period and tested for serological evidence of prior exposure to Shigella sonnei and Shigella flexneri. The risk for acquiring S. sonnei shigellosis was 3.7 times higher for individuals lacking homologous antibodies (P less than 0.02). The risk for acquiring S. flexneri shigellosis was 2.4 times higher for individuals lacking antibodies, although a low attack rate for S. flexneri resulted in numbers too small to achieve statistical significance. While the importance of the serum antilipopolysaccharide antibodies in protection against the disease remains unclear, these findings demonstrate that they are strong markers of acquired immunity. Serological markers should be incorporated in epidemiologic studies of shigellosis and in the design and evaluation of future trials of potential anti-Shigella vaccines.
Monte-Carlo Planning in Large POMDPs (2010)

This paper introduces a Monte-Carlo algorithm for online planning in large POMDPs. The algorithm combines a Monte-Carlo update of the agent’s belief state with a Monte-Carlo tree search from the current belief state. The new algorithm, POMCP, has two important properties. First, Monte-Carlo sampling is used to break the curse of dimensionality both during belief state updates and during planning. Second, only a black box simulator of the POMDP is required, rather than explicit probability distributions. These properties enable POMCP to plan effectively in significantly larger POMDPs than has previously been possible. We demonstrate its effectiveness in three large POMDPs. We scale up a well-known benchmark problem, rocksample, by several orders of magnitude. We also introduce two challenging new POMDPs: 10 × 10 battleship and partially observable PacMan, with approximately 10 18 and 10 56 states respectively. Our Monte-Carlo planning algorithm achieved a high level of performance with no prior knowledge, and was also able to exploit simple domain knowledge to achieve better results with less search. POMCP is the first general purpose planner to achieve high performance in such large and unfactored POMDPs. 1
Erythrocytosis caused by an erythropoietin-producing hepatocellular carcinoma (2000)

A case of erythrocytosis caused by a hepatocellular carcinoma (HCC) that produced erythropoietin (Epo) is described. A 64-year-old man, with a huge HCC tumor in the right lobe of the liver, showed a high concentration of hemoglobin and increased levels of serum Epo, alpha-fetoprotein (AFP), and protein induced by vitamin K absence II (PIVKA-II). Right lobectomy of the liver was performed. Histological findings of the specimen showed a moderately differentiated HCC. The existence of Epo was confirmed immunohistochemically only in the tumor tissue and not in the normal liver tissue. Erythrocytosis disappeared and the serum levels of Epo, AFP, and PIVKA-II returned to the normal range after the operation. Within 2 months after the operation, recurrent tumors appeared in the remnant liver, and the patient died 13 months after the operation.
Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types (2016)

Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis.