gebhart/patrepeval huggingface dataset:
Circulating Tumors Cells as Biomarkers (2011)

Personalized cancer medicine requires the development of tumor-specific biomarkers to optimize selection of targeted therapies and to better assess response to therapy. Current efforts in several tumor types have shown that patients in whom circulating tumor cells (CTCs) are detected have an inferior prognosis relative to those in whom CTCs are not detected and that the elimination or decrease of CTCs following treatment is associated with improved clinical outcomes. Technological advances in the detection, isolation, capture, and characterization of CTCs from phlebotomy samples obtained in a routine clinical practice setting have enabled the evaluation of different CTC biomarkers. Unmet needs in cancer diagnosis and treatment where CTC biomarkers have been studied include determining prognosis, assessing the effects of treatment, and as a source of tumor for the biologic identification and characterization of determinants to predict sensitivity to one form of treatment versus another and to understand mechanisms of treatment resistance.At present, there is no single definition of a CTC and no single CTC "biomarker." Rather, multiple assays (tests) are in development for CTC biomarkers. However, before the role of any biomarker in medical decision making can be determined, it is essential that the assays used to measure the biomarker are analytically validated in a sequence of trials to generate the evidence to support the biomarker's use in the given context of use. It is against this background that this review focuses on the process of developing CTC biomarker assays, with the objective of outlining the necessary steps to qualify specific CTC tests for medical decision making in clinical practice or drug development. The potential for point-of-care tests is clear.
New Chemical Approaches for Control of Biennial Bearing of Apples (1994)

The chemicals sulfcarbamide (monocarbamide dihydrogen sulfate), pelargonic acid [CH3CH2)7CooH] and endothallic acid [7,oxybicylo(2,2,2)heptane-2-3 dicarboxylic acid] are new, effective blossom thinning agents used to prevent alternate year cropping of apples. Early removal of potential fruit reduces competition for photosynthates and favors flower initiation for the next year's crop. Sulfcarbamide is nearing full registration for commercial use. Pelargonic acid and endothallic acid require further testing for commercial development. Early application of the post-bloom thinner carbaryl (1-naphthyl-n-methyl carbamate) at petal fall time is effective for reducing fruit set and provides an alternative approach to blossom thinning for preventing biennial bearing.
Notch Antibody Antagonists for Cancer Therapy (2007)

PL07-04 The Notch signaling pathway stands as a compelling target for new cancer therapeutics. Increased levels of Notch signaling have been implicated in the development or maintenance of a variety of malignancies, and angiogenesis requires Notch signaling for proper maturation of the tumor vasculature. As cell-surface proteins, Notch receptors and ligands represent attractive molecular targets for the development of therapeutic antibody antagonists, and we are exploiting phage display technology to generate such synthetic human antibodies. We have targeted Delta-like4 (Dll4), a ligand required for active vascularization, and Notch1, a receptor that has been implicated in this process as well as in the control of tumor cell viability. Whereas anti-Dll4 blocks binding to Notch receptors, anti-Notch1 antagonizes signaling by targeting a receptor “on-off switch”---the negative regulatory region (NRR). Both antibodies were selected for strong binding to the human and mouse targets and, thus, can be used not only as therapeutic candidates but also to assess the biological consequences of inhibiting Dll4- and Notch1- mediated signaling in mouse models. Consistent with a key role for Dll4 in active vascularization, anti-Dll4 disrupts tumor growth in several mouse models by altering endothelial cell fate specification or differentiation (Ridgway et al., Nature 2006). The effects of anti-Notch1 in mouse models will also be discussed.
Selective repression of transcriptional activators at a distance by the Drosophila Krüppel protein. (1993)

The Krüppel (Kr) protein, bound at kilobase distances from the start site of transcription, represses transcription by RNA polymerase II in mammalian cells. Repression is monotonically dependent on the dose of Kr protein and the presence of Kr binding site(s) on the DNA. These data suggest an inhibitory protein-protein interaction between the Kr protein and proximal transcription factors. Repression by Kr depends on the specific activator protein driving transcription. In particular, Kr protein selectively represses transcription mediated by the Sp1 glutamine-rich activation domain, tethered to the promoter by a GAL4 DNA-binding domain, but does not repress transcription stimulated by the acidic GAL4 activator. We believe this represents repression by a quenching interaction between DNA-bound Kr protein and the activation region of Sp1, rather than competition between Sp1 and Kr for a limiting transcriptional component. Selective, context-related repression affords an added layer of combinatorial control of gene expression by sequence-specific transcription factors.
Computational Molecular Biology (2000)

In one of the first major texts in the emerging field of computational molecular biology, Pavel Pevzner covers a broad range of algorithmic and combinatorial topics and shows how they are connected to molecular biology and to biotechnology. The book has a substantial "computational biology without formulas" component that presents the biological and computational ideas in a relatively simple manner. This makes the material accessible to computer scientists without biological training, as well as to biologists with limited background in computer science. Computational Molecular Biology series Computer science and mathematics are transforming molecular biology from an informational to a computational science. Drawing on computational, statistical, experimental, and technological methods, the new discipline of computational molecular biology is dramatically increasing the discovery of new technologies and tools for molecular biology. The new MIT Press Computational Molecular Biology series provides a unique venue for the rapid publication of monographs, textbooks, edited collections, reference works, and lecture notes of the highest quality. Bradford Books imprint
Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. (2003)

Our data suggest that aberrant methylation of HIC1 may play a role in the pathogenesis of specific pediatric tumors.
Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. (2000)

MKT-077, a cationic rhodacyanine dye analogue has been under preclinical cancer therapeutical trials because of its selective toxicity to cancer cells. Its cellular targets and mechanism of action remain poorly understood. Here we report that MKT-077 binds to an hsp70 family member, mortalin (mot-2), and abrogates its interactions with the tumor suppressor protein, p53. In cancer cells, but not in normal cells, MKT-077 induced release of wild-type p53 from cytoplasmically sequestered p53-mot-2 complexes and rescued its transcriptional activation function. Thus, MKT-077 may be particularly useful for therapy of cancers with wild-type p53.
Flexible Loop of β2-Glycoprotein I Domain V Specifically Interacts with Hydrophobic Ligands (2001)

Beta2-glycoprotein I (beta2-GPI), which consists of four complement control protein modules and a distinctly folded fifth C-terminal domain, is an essential cofactor for the binding to phospholipids of anti-cardiolipin antibodies, isolated from patients with anti-phospholipid antibody syndrome, and its fifth domain has attracted attention as a specific phospholipid-binding site. We focused on the fifth domain of beta2-GPI (Domain V) and examined the interaction of intact Domain V, Domains IV-V, and nicked Domain V with various hydrophobic ligands, as a model molecule of phospholipid. We found that electrostatic and hydrophobic interactions are important for Domain V binding to the ligand molecules. We also found that, while Domain IV has no significant effect on the interactions with ligands, the nicked Domain V with cleavage in the flexible loop decreases the affinity, indicating that the flexible loop region is the binding site of the hydrophobic ligands. The synthetic peptide corresponding to the loop region was disordered and interacted with bis-ANS, confirming the critical role of the loop region. To clarify the nature of the interaction between the loop region and hydrophobic compounds, we prepared the reduced and alkylated Domain V, which was denatured but was assumed to be a collapsed state. Alkylation by iodoacetic acid decreased the interaction of Domain V with bis-ANS, probably because the protein net charge was decreased by the six introduced carboxyl groups and consequently the electrostatic interactions were decreased. In contrast, Domain V alkylated by iodoacetamide, therefore retaining a high positive net charge, bound bis-ANS more strongly than the intact Domain V. These results suggested that the interaction of Domain V with hydrophobic compounds through the flexible loop is similar to the binding of hydrophobic compounds to the protein folding intermediate.
Molecular Description of Erosion Phenomena in Biodegradable Polymers (2005)

A new model for the erosion kinetics of semicrystalline surface-erodible homopolymers and copolymers is presented. The model is derived for a class of surface-erodible polyanhydride copolymers, with the goal of describing erosion in terms of fundamental, elementary processes. This model is based on an accurate description of copolymer microstructure and can thereby account for the heterogeneous erosion due to microphase separation and crystallinity. In addition to accurately predicting the overall erosion profile and the release of individual monomer species, several key phenomena that occur during erosion are described. These include precipitation of slightly soluble degradation products inside the pores of the erosion zone and pH changes during erosion due to dissolution of acidic monomers and the consequent changes in monomer solubility. This model also motivates future experiments to investigate predicted phenomena such as the effects due to local changes in pH and degradation rate constants for crystalline and amorphous moieties. The rational design of biomedical devices such as vehicles for drug delivery and scaffolds for tissue engineering will be aided by the application of this model and future extensions of it.
Association of heat shock protein 70 with enterovirus capsid precursor P1 in infected human cells (1992)

Members of the human heat shock (HSP) family of related proteins are involved in the intracellular folding, transport, and assembly of proteins and protein complexes. We have observed that human heat shock protein 70 (HSP70) is associated with the capsid precursor P1 of poliovirus and coxsackievirus B1 in infected HeLa cells. Antiserum generated against HSP70 coimmunoprecipitated the poliovirus protein P1, an intermediate in capsid assembly. Similarly, alpha-virion serum coimmunoprecipitated HSP70 from virus-infected cell extracts, but not from mock-infected cell extracts. The HSP70-P1 complex was stable in high-salt medium but was sensitive to incubation with 2 mM ATP, which is a characteristic of other known functional complexes between HSP70 and cellular proteins. The P1 in the complex was predominantly newly synthesized, and the half-life of complexed P1 was nearly twice as long as that of total P1. The HSP70-P1 complex was found to sediment at 3S to 6S, suggesting that it may be part of, or a precursor to, the "5S promoter particles" thought to be an assembly intermediate of picornaviruses. The finding that HSP70 was associated with the capsid precursors of at least two enteroviruses may suggest a functional role of these complexes in the viral life cycles.
Differential effects of brefeldin A on transport of secretory and lysosomal proteins. (1993)

Brefeldin A (BFA) rapidly blocks anterograde exocytotic transport through the Golgi complex. Sustained retrograde traffic induced by brefeldin A causes redistribution of constituents of the Golgi, but not the trans-Golgi network (TGN), to the endoplasmic reticulum (ER). In the present study on HepG2 cells, we have observed a differential effect of BFA on transport from the TGN of two soluble proteins: alpha 1-antitrypsin as a representative of secretory proteins and cathepsin D as a prototype of lysosomal enzymes. The Golgi complex of HepG2 cells is sensitive to BFA, as within minutes after its addition nearly all activity of three resident Golgi enzymes was recovered in the ER as monitored by cell fractionation on sucrose density gradients. In accordance with this, "high mannose"-glycosylated alpha 1-antitrypsin was retained in or transported back to the ER. "Complex"-glycosylated alpha 1-antitrypsin was neither secreted into the medium nor transported back to the ER. Most of it was retained in vesicles with the buoyant density of Golgi. These vesicles contained the fluid phase endocytotic marker horseradish peroxidase when this was added to the culture medium prior to the BFA, suggesting that the vesicles derived from the TGN. After BFA addition, the compartment became inaccessible to endocytosed horseradish peroxidase. In contrast to blocking transport of complex alpha 1-antitrypsin, BFA did not affect processing of newly synthesized complex-glycosylated procathepsin D (53 kDa) to the mature 31-kDa form. Neither did it interfere with processing of endocytosed procathepsin D. That the mature cathepsin D had indeed reached the lysosomes was verified by Percoll density gradient fractionation. In conclusion, in HepG2 cells, BFA induces two blocks in the secretory pathway: one at the level of the ER-Golgi juncture and the other in the TGN. In contrast, transport from the Golgi complex to the lysosomes and from the plasma membrane to the lysosomes continued.
Posttraumatic Stress Disorder in the National Comorbidity Survey (1995)

Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.
erbB-2 and Response to Doxorubicin in Patients With Axillary Lymph Node-Positive, Hormone Receptor- Negative Breast Cancer (1998)

These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.
Long-term delivery of ivermectin by use of poly(D,L-lactic-co-glycolic)acid microparticles in dogs (2004)

All formulations were 100% effective in preventing development of adult heartworms. Results indicate that PLGA microparticles are a promising drug delivery matrix for use with ivermectin for the prevention of heartworm disease for at least 6 months after treatment.
Detection of cell-free fetal DNA in maternal urine (2006)

Cell-free fetal DNA either was not present or did not amplify in maternal urine.
Role of the Individual Interferon Systems and Specific Immunity in Mice in Controlling Systemic Dissemination of Attenuated Pseudorabies Virus Infection (1999)

The importance of each of the two interferon (IFN) systems in impeding herpesvirus replication and in stimulating virus-specific lymphocytes to control an acute systemic infection is not completely understood. To further our knowledge, pseudorabies virus, attenuated by deletion of the glycoprotein E gene to impair its neurovirulence and by deletion of the thymidine kinase gene (gE-TK-PRV), was used to infect wild-type 129Sv/Ev and congenic mice with immune system-associated genetic deficiencies. Mice with mature B and T lymphocytes but lacking either one or both functional receptors for members of each of the two IFN families were infected with gE-TK-PRV. At 3 and 7 but not 14 days after infection, replicating gE-TK-PRV could be isolated only from livers or spleens of mice lacking the receptors for both IFN families, and these mice survived the infection. Therefore, functional IFN receptors were not required to induce a protective immune response against an acute infection with gE-TK-PRV. Furthermore, PRV-specific antibodies of all immunoglobulin G isotypes were produced in these mice. Mice without mature B and T lymphocytes and lacking either one or both functional receptors for members of each of the two IFN families were also infected with gE-TK-PRV. Three days after infection, replicating virus could be isolated only from mice lacking both mature B and T lymphocytes and functional IFN receptors, and these mice were not able to clear the virus. We present evidence that mice with an intact gamma IFN system but without mature B and T cells were able to prevent systemic dissemination of gE-TK-PRV.
BindingDB Entry 50032703: Synthesis and evaluation ofß-carboline derivatives as potential monoamine oxidase inhibitors. (2011)

Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their Ki values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a Ki against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a Ki value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a Ki value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.
Small interfering RNA production by enzymatic engineering of DNA (SPEED) (2004)

Small interfering RNAs (siRNAs) potently silence expression of target genes. In principle siRNA libraries can be used to perform effective genome-scale functional genetic screens in mammalian cells, but their development has been hampered by the need to chemically synthesize thousands of oligonucleotides and to incorporate them into expression vectors. We have developed a technology to efficiently convert a double-stranded cDNA library into a retroviral siRNA library in which 21-base siRNAs are produced in infected cells at high levels and efficiently block expression of their target genes. The key steps are the generation of random cDNA fragments that are fused to a hairpin linker, cleavage with the MmeI endonuclease that creates 20- to 21-bp cDNA fragments, conversion to a double-stranded DNA that contains two copies of the cDNA insert in a head-to-head palindrome, and insertion of the construct downstream of a polymerase III promoter. We constructed a siRNA library with 3 x 10(6) clones from a mouse embryo cDNA library; siRNAs were found against many different genes; and multiple siRNAs can be generated from a single mRNA. We further showed that specific siRNAs were efficiently produced in stably infected mammalian cells and resulted in significant and specific reduction of their target mRNAs. Because no prior knowledge about target transcripts is needed, a cDNA-derived siRNA library will generate siRNAs against unknown transcripts and genes. Finally, cDNA-derived siRNA libraries can be readily generated from any cell type or species, enabling genome-wide functional screens in many biological systems.
Prediction of homology and divergence in the secondary structure of polypeptides. (1985)

A quantitative procedure is described for the comparison of secondary structure of homologous proteins. Standard predictive methods are used to generate probability profiles from pairs of homologous amino acid sequences; correlation coefficients (R) are then computed between each pair of amino acids for alpha-helix (R alpha), extended structure (R beta), turn (R(t)), and coil (R(c)). R values are >0.2 for correctly aligned homologous sequences. Unrelated or incorrectly aligned sequences give R values near zero. Lack of correlation for a segment of otherwise well-correlated sequences is used to identify structural divergence, which is then evaluated graphically by using difference profiles. A combination of these techniques correctly predicts secondary structural differences between melittin or beta-endorphin and their respective synthetic analogs. The method is potentially useful to describe evolutionary changes in protein secondary structure as well as in the design of peptide analogs.
[A new wound healing model using tissue cultured corneal endothelium. 1. Quantitative study of healing process]. (1989)

A new in vitro model for evaluating endothelial wound healing has been developed. Rabbit and bovine corneal endothelial cells were cultured on coverslips in areas 8mm in diameter with hydroxyethyl methacrylate (HEMA) and monolayer sheets were obtained. Wounds were produced by scraping cells in the center of the cell sheets with a rotating silicone tip. The areas of these wounds were measured with computed planimetry. The average wound area was 3.00 +/- 0.21 mm2 in rabbit cell cultures 3.18 +/- 0.28 mm2 in bovine cell cultures. The healing process after making the wound was observed by inverse phase contrast microscope and wound healing rates were calculated. Wounded areas were covered by 60 hours in rabbit cultures, and by 84 hours in bovine cultures respectively. Wound healing rates during 6-12 and 12-24 hours were 92.5 +/- 11.9 microns 2/h, 62.4 +/- 3.4 microns 2/h in rabbits and 10.6 +/- 3.6 microns 2/h, 62.9 +/- 7.8 microns 2/h in bovine material respectively. The healing rates were higher in rabbit cultures than in bovine cultures. This model can be used for quantitative evaluation of the wound healing process of corneal endothelium.
Efficient Neutralization of Anthrax Toxin by Chimpanzee Monoclonal Antibodies against Protective Antigen (2006)

Four single-chain variable fragments (scFvs) against protective antigen (PA) and 2 scFvs against lethal factor (LF) of anthrax were isolated from a phage display library generated from immunized chimpanzees. Only 2 scFvs recognizing PA (W1 and W2) neutralized the cytotoxicity of lethal toxin in a macrophage lysis assay. Full-length immunoglobulin G (IgG) of W1 and W2 efficiently protected rats from anthrax toxin challenge. The epitope recognized by W1 and W2 was conformational and was formed by C-terminal amino acids 614-735 of PA. W1 and W2 each bound to PA with an equilibrium dissociation constant of 4x10-11 mol/L to 5x10(-11) mol/L, which is an affinity that is 20-100-fold higher than that for the interaction of the receptor and PA. W1 and W2 inhibited the binding of PA to the receptor, suggesting that this was the mechanism of protection. These data suggest that W1 and W2 chimpanzee monoclonal antibodies may serve as PA entry inhibitors for use in the emergency prophylaxis against and treatment of anthrax.