gebhart/patrepeval huggingface dataset:
Targeting β-catenin/CBP interaction in breast cancer. (2011)

10516 Background: Aberrant regulation of the Wnt pathway has been shown to be associated with breast cancer. We hypothesize that (1) increased co-activator interaction of CBP with nuclear β-catenin is associated with a breast cancer stem-cell phenotype, disease progression, drug resistance, relapse and metastasis, and (2) the usage of the co-activator p300 leads to forced differentiation of cancer stem cells rendering them sensitive to existing chemotherapeutics. Methods: We have developed ICG-001, a small molecule antagonist of the CBP/β-catenin interaction. Breast cancer cells (MDA-MB-231, MDA-MB-468, MCF-7) were treated with ICG-001 and investigated for changes in proliferation, invasiveness and drug resistance. RNA sequencing and qRT-PCR were used to evaluate gene-expression. CoIP and CHiP assays demonstrated CBP/β-catenin disruption and differential coactivator usage at specific gene promoters. Protein expression was assessed by FACS and Immunoblotting. Viability assays were done to determine drug-sensitization. Stem cell assays were used to study the effect of ICG-001 on cancer stem cell populations. Preliminary in vivo studies explored the effect of ICG-001 on tumor growth. Results: ICG-001 treatment down-regulated anti-apoptotic (survivin) and mesenchymal markers (S100A4, vimentin) and up-regulated epithelial cell markers (e-cadherin, CD24) in basal-like breast cancer cells. ICG-001 disrupted the CBP/β-catenin interaction, and also re-sensitizes the hormone receptor-negative cell lines (MDA-MB-231, MDA-MB-468) to tamoxifen. ICG-001 eradicates cancer stem cell-like populations and reverses stem cell phenotype based on side population, Aldefluor and tumorsphere assays. Re-expression of CD24 is dependent on the usage of p300 in MDA-MB-231 cells (CD44+/CD24-). In vitro invasion assay demonstrated the loss of invasive potential. Preliminary in vivo studies suggested that ICG-001 alone could decrease tumor growth in a NOD/SCID mouse model. Conclusions: Antagonizing CBP/β-catenin signaling using a small molecule inhibitor is an attractive target for the treatment of resistant aggressive breast cancer and the eradication of breast cancer stem cells.
Endocrine Therapy of Breast Cancer (2011)

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.
Replacing Personally-Identifying Information in Medical Records, the Scrub System (2018)

We define a new approach to locating and replacing personally-identifying information in medical records that extends beyond straight search-and-replace procedures, and we provide techniques for minimizing risk to patient confidentiality. The straightforward approach of global search and replace properly located no more than 30-60% of all personally-identifying information that appeared explicitly in our sample database. On the other hand, our Scrub system found 99-100% of these references. Scrub uses detection algorithms that employ templates and specialized knowledge of what constitutes a name, address, phone number and so forth.
Tumor Transport Physiology (2001)

Tumor Transport PhysiologyImplications for Imaging and Imaging-Guided TherapyBrian S. Kuszyk1, Frank M. Corl, F. Nicholas Franano, David A. Bluemke, Lawrence V. Hofmann, Brian J. Fortman and Elliot K. FishmanAudio Available | Share
A versatile method for the coupling of protein to DNA: synthesls of αγ Marcroglobulin-Dna conjugates (1983)

We describe a simple, general method to link proteins covalently to DNA. The method uses two reagents, N-acetyl-N'-(p-glyoxylylbenzoyl)cystamine and 2-iminothiolane. The former reacts specifically with nonpaired quanine residues and upon reduction generates a free sulfhydryl group. The latter reacts with a protein to provide another sulfhydryl group which is subsequently conjugated to DNA by an intermolecular disulfide interchange reaction. Using this method alpha 2-macroglobulin was conjugated to plasmid DNA encoding the Herpes simplex virus-1 thymidine kinase gene or a DNA fragment containing the E. coli chloramphenicol acetyltransferase gene. Up to 20% of the total DNA was conjugated to alpha 2-macroglobulin and the alpha 2-macroglobulin-DNA conjugate had a protein/DNA molar ratio of approximately two. The whole reaction takes place under very mild conditions in aqueous solution. The structure of DNA appears not to be significantly affected by the chemical modification. This method may prove useful in ligand directed gene transfer studies.
Machine Learning of User Profiles: Representational Issues (1997)

As more information becomes available electronically, tools for finding information of interest to users becomes increasingly important. The goal of the research described here is to build a system for generating comprehensible user profiles that accurately capture user interest with minimum user interaction. The research described here focuses on the importance of a suitable generalization hierarchy and representation for learning profiles which are predictively accurate and comprehensible. In our experiments we evaluated both traditional features based on weighted term vectors as well as subject features corresponding to categories which could be drawn from a thesaurus. Our experiments, conducted in the context of a content-based profiling system for on-line newspapers on the World Wide Web (the IDD News Browser), demonstrate the importance of a generalization hierarchy and the promise of combining natural language processing techniques with machine learning (ML) to address an information retrieval (IR) problem.
Adenine Nucleotide Translocase-1, a Component of the Permeability Transition Pore, Can Dominantly Induce Apoptosis (1999)

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apoptosis, such as phenotypic alterations, collapse of the mitochondrial membrane potential, cytochrome c release, caspase activation, and DNA degradation. Both point mutations that impair ANT-1 in its known activity to transport ADP and ATP as well as the NH(2)-terminal half of the protein could still induce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptosis induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unable to elicit a form of cell death in yeast. This and the observed repression of apoptosis by the ANT-1-interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein-protein interactions within the permeability transition pore.
Age and platelet count are IPSS‐independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival (2009)

Age and platelet count are IPSS-independent predictors of survival in young patients with PMF, and they complement the IPSS in identifying patients with very long or very short survival.
Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function (2007)

The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.
Metal complexes with macrocyclic ligands. Part XXV. One‐step synthesis of mono‐N‐substituted azamacrocycles with a carboxylic group in the side‐chain and their complexes with Cu2+ and Ni2+ (1986)

Abstract Mono‐ N ‐substituted azamacrocycles 2 – 7 , containing a carboxyalkyl or carboxyaryl side‐chain, are obtained by reacting a five‐fold excess of the macrocycle with 1 equiv. of a suitable halogenocarboxylic acid in alkaline aqueous EtOH. For halogenocarboxylic acids, which easily lactonize under alkaline conditions, a variant with the corresponding ester or nitrile as alkylating agent is also described. The salient point of this synthesis lies in the use of an excess of the macrocycle over the alkylating agent, thus reducing the amount of polyalkylation to a minimum, and in the easy separation of the excess of unreacted educt from the aminocarboxylic acid. These new ligands form Ni 2+ and Cu 2+ complexes, the spectral properties of which have been studied. In the case of the Cu 2+ complexes with ligand 2 , 3 , and 6 , a pH‐dependent color change is observed. This is explained with an equilibrium between a species, in which the carboxylate group is bound to the metal, and one, in which it is protonated and non‐coordinated. In the case of the Ni 2+ complexes with the same ligands, only the species with a coordinated carboxylate was observed. In the Cu 2+ and Ni 2+ complexes with ligands 4 and 5 , however, the carboxylate group does not coordinate at all, because of the length or the special structure of the chain.
Optimizing the Parameters of Vagus Nerve Stimulation by Uniform Design in Rats with Acute Myocardial Infarction (2012)

Vagus nerve stimulation (VNS) has been shown to improve left ventricular function and survival in rats with acute myocardial infarction (AMI), and this maneuver has also been adopted clinically for the treatment of patients with chronic heart failure (CHF). Recent in vitro and in vivo studies have suggested that VNS can modulate the level of pro-inflammatory factors. Despite the beneficial effects of VNS, the stimulation parameters for obtaining favorable outcomes appear highly variable. To optimize VNS parameters, we set up different stimulation protocols with different pulse width (1-2 ms), frequency (1-6 Hz), voltage (1-6 V) and duration (40-240 min) of VNS by uniform design (UD). Rats were divided into seven groups with (Group1-Group6) or without VNS (MI group). Our results demonstrate that (1) the parameter sets in Group1, Group2 and Group3 yield the best post-MI protection by VNS, while the protective role were not observed in Group4, Group5 and Group6; (2) baroreflex sensitivity and the α7 nicotinic acetylcholine receptor level were also increased in Group1, Group2 and Group3. (3) the parameter set in Group1 (G1:1 ms, 2 Hz, 3 V, 240 min) is judged the most optimal parameter in this study as rats in this group not only showed a reduced myocardial injury with better-preserved cardiac function compared with other groups, more important, but also exhibited minimal heart rate (HR) reduction. (4) the duration of VNS plays an important role in determining the protection effect of VNS. In conclusion, VNS displays a beneficial role in Group1, Group2 and Group3. Of note, the parameter set in Group1 provides the most optimal cardioprotective effect. These results may provide insight into development of novel treatment for ischemic heart diseases.
Thyroid dysfunction: managing the ocular complications of Graves' disease. (1992)

The pathophysiology of Graves' orbitopathy has yet to be illucidated, but much can be done to reverse the potentially blinding effects of this debilitating ocular disease. Although only 5 to 10% of patients suffer severe ocular complications, many have significant signs and symptoms requiring ophthalmic medical and surgical intervention. Numerous systemic and topical therapies exist for all aspects of the ocular effects of hyperthyroidism, but clear clinical indications or advantages are lacking. Surgical therapies for residual abnormalities have solidified under recent clinical guidelines.
Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors (2002)

Many painful inflammatory and ischemic conditions such as rheumatoid arthritis, cardiac ischemia, and exhausted skeletal muscles are accompanied by local tissue acidosis.In such acidotic states, extracellular protons provoke the pain by opening cation channels in nociceptors.It is generally believed that a vanilloid receptor subtype-1 (VR1) and an acid-sensing ion channel (ASIC) mediate the greater part of acid-induced nociception in mammals.Here we provide evidence for the involvement of both channels in acid-evoked pain in humans and show their relative contributions to the nociception.In our psychophysical experiments, direct infusion of acidic solutions (pH 6.0) into human skin caused localized pain, which was blocked by amiloride, an inhibitor of ASICs, but not by capsazepine, an inhibitor of VR1.Under more severe acidification (pH 5.0) amiloride was less effective in reducing acid-evoked pain.In addition, capsazepine had a partial blocking effect under these conditions.Amiloride itself neither blocked capsaicin-evoked localized pain in human skin nor inhibited proton-induced currents in VR1-expressing Xenopus oocytes.Our results suggest that ASICs are leading acid sensors in human nociceptors and that VR1 participates in the nociception mainly under extremely acidic conditions.
INFLUENCE OF SACRAL NEUROMODULATION ON ELECTROSENSATION OF THE LOWER URINARY TRACT (2000)

Neuromodulation on S3 influences the nervous system involved in electrosensation of the bladder but not the skin afferent innervation or the nerves involved in urethral electrosensation. These data support the hypothesis that S3 neurostimulation is effective mainly through the afferent nervous system in the pelvic nerves.
Limited Breadth of the Protective Immunity Elicited by Simian Immunodeficiency Virus SIVmne gp160 Vaccines in a Combination Immunization Regimen (1999)

We previously reported that immunization with recombinant simian immunodeficiency virus SIVmne envelope (gp160) vaccines protected macaques against an intravenous challenge by the cloned homologous virus, E11S. In this study, we confirmed this observation and found that the vaccines were effective not only against virus grown on human T-cell lines but also against virus grown on macaque peripheral blood mononuclear cells (PBMC). The breadth of protection, however, was limited. In three experiments, 3 of 10 animals challenged with the parental uncloned SIVmne were completely protected. Of the remaining animals, three were transiently virus positive and four were persistently positive after challenge, as were 10 nonimmunized control animals. Protection was not correlated with levels of serum-neutralizing antibodies against the homologous SIVmne or a related virus, SIVmac251. To gain further insight into the protective mechanism, we analyzed nucleotide sequences in the envelope region of the uncloned challenge virus and compared them with those present in the PBMC of infected animals. The majority (85%) of the uncloned challenge virus was homologous to the molecular clone from which the vaccines were made (E11S type). The remaining 15% contained conserved changes in the V1 region (variant types). Control animals infected with this uncloned virus had different proportions of the two genotypes, whereas three of four immunized but persistently infected animals had >99% of the variant types early after infection. These results indicate that the protective immunity elicited by recombinant gp160 vaccines is restricted primarily to the homologous virus and suggest the possibility that immune responses directed to the V1 region of the envelope protein play a role in protection.
Engineered cellular response to scaffold architecture in a rabbit trephine defect (2003)

Tight control of pore architecture in porous scaffolds for bone repair is critical for a fully elucidated tissue response. Solid freeform fabrication (SFF) enables construction of scaffolds with tightly controlled pore architecture. Four types of porous scaffolds were constructed using SFF and evaluated in an 8-mm rabbit trephine defect at 8 and 16 weeks (n = 6): a lactide/glycolide (50:50) copolymer scaffold with 20% w/w tri-calcium phosphate and random porous architecture (Group 1); another identical design made from poly(desaminotyrosyl-tyrosine ethyl ester carbonate) [poly(DTE carbonate)], a tyrosine-derived pseudo-polyamino acid (Group 2); and two poly(DTE carbonate) scaffolds containing 500 microm pores separated by 500-microm thick walls, one type with solid walls (Group 3), and one type with microporous walls (Group 4). A commercially available coralline scaffold (Interpore) with a 486-microm average pore size and empty defects were used as controls. There was no significant difference in the overall amount of bone ingrowth in any of the devices, as found by radiographic analysis, but patterns of bone formation matched the morphology of the scaffold. These results suggest that controlled scaffold architecture can be superimposed on biomaterial composition to design and construct scaffolds with improved fill time.
Development of a multienzyme reactor for dopamine synthesis: II. Reactor engineering and simulation (1992)

Aspects of reaction engineering associated with multienzyme reactions have been studied in a system where dopamine is produced from catechol, pyruvate and ammonium by sequential enzymatic reactions catalyzed by tyrosine phenol lyase (TPL) and tyrosine decarboxylase (TDC). Microbial cells containing TPL activity (Erwinia herbicola) and TDC activity (Streptococcus faecalis) were coimmobilized in glutaraldehyde cross-linked porcine gelatin beads with a mean diameter of 2.8 mm for use in the reactions. Measurement of the transport properties in the beads indicate that the gelatin matrix does not significantly increase the diffusion resistance and that dopamine partitions into the matrix (K = 2). A packed-bed reactor containing the coimmobilized cell beads successfully produced dopamine, although with a low conversion. Using computer simultaneous it is shown that separate, sequential TPL and TDC, rather than simultaneous, reactions, would require smaller reactors overall for the same conversion.
Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. (1994)

We have shown that human macrophages (m phi s) play an important role in the elaboration of chemotactic cytokines in rheumatoid arthritis (RA) (Koch, A. E., S. L. Kunkel, J. C. Burrows, H. L. Evanoff, G. K. Haines, R. M. Pope, and R. M. Strieter. 1991. J. Immunol. 147:2187; Koch, A. E., S. L. Kunkel, L. A. Harlow, B. Johnson, H. L. Evanoff, G. K. Haines, M. D. Burdick, R. M. Pope, and R. M. Strieter. 1992. J. Clin. Invest. 90:772; Koch, A. E., P. J. Polverini, S. L. Kunkel, L. A. Harlow, L. A. DiPietro, V. M. Elner, S. G. Elner, and R. M. Strieter. 1992. Science (Wash. DC). 258:1798). Recently, m phi inflammatory protein-1 (MIP-1 alpha), a cytokine with chemotactic activity for m phi s and neutrophils (PMNs), has been described. We have examined the production of MIP-1 alpha using sera, synovial fluid (SF), and synovial tissue (ST) from 63 arthritic patients. MIP-1 alpha was higher in RA SF (mean, 29 +/- 8 ng/ml [SE]) compared with other forms of arthritis (2.8 +/- 1.7), or osteoarthritis (0.7 +/- 0.4; P < 0.05). RA SF MIP-1 alpha was greater than that found in either RA or normal peripheral blood (PB) (P < 0.05). Anti-MIP-1 alpha neutralized 36 +/- 3% (mean +/- SE) of the chemotactic activity for m phi s, but not PMNs, found in RA SFs. RA SF and PB mononuclear cells produced antigenic MIP-1 alpha. Mononuclear cell MIP-1 alpha production was augmented with phytohemagglutinin or LPS. Isolated RA ST fibroblast production of antigenic MIP-1 alpha was augmented upon incubation of cells with LPS, and to a lesser extent with tumor necrosis factor-alpha. Isolated RA ST m phi s expressed constitutive MIP-1 alpha mRNA and antigenic MIP-1 alpha. Using ST immunohistochemistry, MIP-1 alpha+ cells from RA compared with normal were predominantly m phi s and lining cells (P < 0.05). These results suggest that MIP-1 alpha plays a role in the selective recruitment of m phi s in synovial inflammation associated with RA.
Identification of oxygen responsive elements in the 5'-flanking region of the human glutathione peroxidase gene. (1993)

The -1389 to +588 region of the human genomic glutathione peroxidase gene (hgpx1) was amplified using the polymerase chain reaction. This DNA fragment was cloned and sequenced, and various deletion constructs derived from the hgpx1 5'-flanking region were fused to the chloramphenicol acetyltransferase gene. These reporter genes were analyzed in transient transfection assays using primary cultured human ventricular cardiomyocytes obtained from patients with tetralogy of Fallot. Two distinct regions upstream from the transcription start site, which was determined using S1 nuclease analysis, were identified to be responsive to the oxygen tension in culture (pO2 values of 150 or 40 mm Hg). Methylation interference footprinting assays revealed proteins closely apposed to two sequences located at -1232 to -1213 and -282 to -275. We have designated these oxygen responsive elements ORE1 and ORE2, respectively. Gel mobility shift assays using double-stranded oligonucleotides corresponding to each site have demonstrated the formation of specific complexes using both cultured human cardiomyocyte and HeLa nuclear extracts. ORE1 and ORE2 bind disparate proteins with equal precision as bound complexes could be competed away with identical sequences but not with either the other ORE or an unrelated sequence. Insertion of these oxygen responsive elements into a reporter gene governed by a SV40 promoter similarly regulated chloramphenicol acetyltransferase activity according to the oxygen tension in culture.