gebhart/patrepeval huggingface dataset:
Signal Transduction Cross-talk During Colorectal Tumorigenesis (2006)

Colorectal carcinoma (CRC) is the second leading cause of cancer-related death in the United States in the general population (men and women combined). Epidemiologic data obtained over the last several decades shows convincing evidence for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of risk of CRC through the inhibition of cycloxygenase (COX). Recent research has also demonstrated that prostaglandin E2 (PGE2), a predominant product of COX, plays a critical role in tumorigenesis of CRCs through its guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), EP2, and EP4. Molecular analysis of CRC and its precursor lesions have shown that mutation of Adenomatous Polyposis Coli (APC), a gene involved in the wingless type signaling pathway, is an early event during the neoplastic progression in the majority of sporadic CRCs. The fundamental questions are: why is wild type APC so important in adult colorectal tissues in preventing this tumorigenesis, and what are the mechanisms by which NSAIDs prevent colorectal tumorigenesis? We reviewed the recent literature concerning the PGE2-GPCR signaling pathway and the APC-beta-catenin (wingless type) pathway in CRC cells and propose a unifying schema regarding the tumorigenesis of CRC. Colorectal epithelia are continuously exposed to various extracellular agonists (including low levels of PGE2). The binding of these agonists to their corresponding GPCRs leads to formation of activated Galphas, which in turn activates beta-catenin. In normal colorectal epithelia, wild type APC blocks the Galphas-induced activation of beta-catenin, and therefore maintains homeostasis and prevents tumorigenesis. In contrast, in the absence of functional APC, continuous formation of activated Galphas by the binding of various extracellular agonists to their receptors leads to the activation and nuclear accumulation of beta-catenin. This elevated nuclear beta-catenin in turn increases transcription of many genes (COX-2, C-myc, Cyclin D1, vascular endothelial growth factor, T cell factor, etc.) involved in tumorigenesis. Increased transcription of COX-2 also leads to excessive production of PGE2 that in turn forms a stimulatory loop with many biologic functions (proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis), which may result in the development of CRC. Because NSAIDs inhibit COX and decrease the production of PGE2, interruption of the cycle helps prevent colorectal tumorigenesis.
A Software-Managed Approach to Die-Stacked DRAM (2015)

Advances in die-stacking (3D) technology have enabled the tight integration of significant quantities of DRAM with high-performance computation logic. How to integrate this technology into the overall architecture of a computing system is an open question. While much recent effort has focused on hardware-based techniques for using die-stacked memory (e.g., caching), in this paper we explore what it takes for a software-driven approach to be effective. First we consider exposing die-stacked DRAM directly to applications, relying on the static partitioning of allocations between fast on-chip and slow off-chip DRAM. We see only marginal benefits from this approach (9% speedup). Next, we explore OS-based page caches that dynamically partition application memory, but we find such approaches to be worse than not having stacked DRAM at all! We analyze the performance bottlenecks in OS page caches, and propose two simple techniques that make the OS approach viable. The first is a hardware-assisted TLB shoot-down, which is a more general mechanism that is valuable beyond stacked DRAM, and enables OS-managed page caches to achieve a 27% speedup, the second is a software-implemented prefetcher that extends classic hardware prefetching algorithms to the page level, leading to 39% speedup. With these simple and lightweight components, the OS page cache can provide 70% of the performance benefit that would be achievable with an ideal and unrealistic system where all of main memory is die-stacked. However, we also found that applications with poor locality (e.g., graph analyses) are not amenable to any page-caching schemes -- whether hardware or software -- and therefore we recommend that the system still provides APIs to the application layers to explicitly control die-stacked DRAM allocations.
Lifetime Risk for Development of Atrial Fibrillation (2004)

Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.
Synergistic Effect between Ultrasmall Cu(II) Oxide and CuCr2O4 Spinel Nanoparticles in Selective Hydroxylation of Benzene to Phenol with Air as Oxidant (2015)

Phenol is an important commodity chemical, and the catalytic conversion of benzene to phenol by molecular oxygen with minimum waste production is of high significance from an academic as well as industrial point of view. We have developed a facile synthesis method for the preparation of 2–8 nm Cu(II) oxide nanoparticles supported on CuCr2O4 spinel nanoparticles (with size ∼55 nm). Detailed characterization of the material was carried out by XRD, SEM, TEM, XPS, FTIR, TGA, TPR, BET surface area, XANES, and ICP-AES methods. XRD and XPS analyses revealed that the main phase is CuCr2O4 spinel, where a small amount of CuO is dispersed on it. The catalyst was highly active for selective oxidation of benzene to phenol with air as oxidant. The influence of reaction parameters was investigated in detail. The high catalytic performance of the catalyst is due to the ultrasmall size of Cu(II) oxide nanoparticles and the strong synergy between ultrasmall Cu(II) oxide and CuCr2O4 spinel nanoparticles that plays a pivotal role in activating air to generate active oxygen species which accomplishes benzene to phenol conversion (36%) with very high selectivity (78%) in a continuous process.
Anticarcinoma activity of rhodamine 123 against a murine renal adenocarcinoma. (1988)

The mitochondria of carcinoma cells retain the permeant cationic compound rhodamine 123 longer than the mitochondria of normal epithelial cells. The possibility of exploiting this difference in the chemotherapy of a murine renal adenocarcinoma was investigated. Rhodamine 123 exhibited anticarcinoma activity in mice and this activity was potentiated by 2-deoxyglucose and methylglyoxal bis(guanylhydrazone), a chemotherapeutic agent that is toxic to mitochondria. Prolonged retention of rhodamine 123 by renal tumor cells compared with normal renal epithelial cells was demonstrated by flow cytometry, perhaps explaining its antitumor activity. A combination of both mitochondrial toxins, rhodamine 123 and methylglyoxal bis(guanylhydrazone) produced the longest survival and had the greatest antitumor effect.
Quantitative phase-gradient imaging at high resolution with asymmetric illumination-based differential phase contrast (2009)

We describe a full-field phase-gradient imaging method: asymmetric illumination-based differential phase contrast (AIDPC). Imaging properties of AIDPC are evaluated using the phase-gradient transfer-function approach and elucidated with experimental images of an optical fiber and a histochemical preparation of a skeletal muscle section. In comparison with full-field differential interference contrast, AIDPC does not require phase shifting for quantitative imaging of phase gradient, provides artifact-free images of birefringent specimens, requires shorter camera exposure, and has larger depth of focus. It is amenable to transfer-function engineering, simultaneous fluorescence imaging, and automated live cell imaging.
Nucleic Acid Transfer Using Cationic Lipids (2003)

The use of cationic lipids or cationic polymers to mediate the transfer of nucleic acids into mammalian cells has become a widely applied technology in recent years. The principal reasons for this have been the ease with which the methodology can be applied to a wide range of cell types; the relatively low cytotoxicity compared to other techniques; the high efficiency of nucleic acid transfer in comparison with methods such as calcium phosphate or diethylaminoethyl-dextran-mediated transfection; and the potential application of these systems to human gene therapy. The use of positively charged lipid-based macromolecules to deliver nucleic acids makes use of the fact that DNA, RNA, and oligonucleotides carry a negative charge caused by the phosphate groups that form the backbone of these molecules. The electrostatic interaction between the negatively charged nucleic acid and the positively charged macromolecule induces a range of structural changes that vary, depending on the macro-molecule used. In general, however, the process results in condensation or compaction of the nucleic acid and physical association of the nucleic acid with the lipid. The interaction generates a complex that is more amenable to cellular uptake, protects sufficient nucleic acid molecules to allow trafficking to the nucleus, and, in at least some cases, may also facilitate transfer into the nucleus.
Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expression. (1990)

We investigated the effects of glucocorticoids on group II phospholipase A2 (PLA2) expression in rat cultured smooth muscle cells. Both forskolin-induced and tumor necrosis factor (TNF)-induced PLA2 release responses were almost completely blocked by 10 and 100 nM dexamethasone, respectively, as assayed by protein blotting and PLA2 activity assays. Dexamethasone-mediated inhibition of PLA2 release appeared to be mediated by the glucocorticoid receptor. Dexamethasone at concentrations greater than 10 nM inhibited forskolin-induced elevation of the group II PLA2 mRNA level but not TNF-induced elevation. These data suggest that the mechanism mediating forskolin-induced mRNA accumulation is sensitive to glucocorticoids, but the mechanism mediating the TNF-induced accumulation is not. Inhibition of TNF-induced PLA2 release by glucocorticoids may be explained by the blocking of post-transcriptional synthesis of the group II PLA2.
Robust cellular reprogramming occurs spontaneously during liver regeneration (2013)

Cellular reprogramming-the ability to interconvert distinct cell types with defined factors-is transforming the field of regenerative medicine. However, this phenomenon has rarely been observed in vivo without exogenous factors. Here, we report that activation of Notch, a signaling pathway that mediates lineage segregation during liver development, is sufficient to reprogram hepatocytes into biliary epithelial cells (BECs). Moreover, using lineage tracing, we show that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following injuries that provoke a biliary response, a process requiring Notch. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under injury conditions.
Cell-based screening approach for antitumor drug leads which exploits sensitivity differences between normal and cancer cells: identification of two novel cell-cycle inhibitors. (2001)

A cell-based in vitro screening approach for identification of antitumor drug leads that exploits the differential sensitivity between normal and cancer cells was developed. It is a three-step, high-throughput screen for antiproliferative and/or cytotoxic activity measured by a 7 day MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromidel assay using small panels of proliferating primary human cells and established cancer cell lines. Proof-of-concept experiments successfully identified 11 known cancer drugs randomly mixed with 5000 test compounds. Application of this screening approach to a library of 110000 compounds allowed for the identification of several novel chemical classes of compounds active against an expanded panel of cancer cell lines in vitro. Two of the compounds representing novel mitotic inhibitors with in vivo potency against established breast cancer xenografts (MDA-MB-435) are reported here.
Human serum amyloid P component, a circulating lectin with specificity for the cyclic 4,6-pyruvate acetal of galactose. Interactions with various bacteria (1985)

Serum amyloid P component (SAP), a normal plasma glycoprotein, has recently been shown to have Ca2+-dependent binding specificity for methyl 4,6-O-(1-carboxyethylidene)-beta-D-galactopyranoside (MO beta DG) [Hind, Collins, Renn, Cook, Caspi, Baltz &amp; Pepys (1984) J. Exp. Med. 159, 1058-1069]. SAP was found to bind in vitro to Klebsiella rhinoscleromatis, the cell wall of which is known to contain this particular cyclic pyruvate acetal of galactose. SAP also bound in similar amounts (approx. 6000 molecules per organism) to group A Streptococcus pyogenes, but very much less was taken up on Xanthomonas campestris, which contains the 4,6-cyclic pyruvate acetal of mannose. No SAP bound to Escherichia coli, which contains the 4,6-cyclic pyruvate acetal of glucose, or to Streptococcus pneumoniae type 4, which contains the 2,3-cyclic pyruvate acetal of alpha- rather than beta-galactopyranoside, or to other organisms (Streptococcus agalactiae, Staphylococcus aureus and Staphylococcus epidermidis), the carbohydrate structures of which are less well characterized. Binding of SAP to those organisms which it did recognize was completely inhibited or reversed by millimolar concentrations of free MO beta DG. SAP, a human plasma protein, thus behaves as a lectin and may be a useful probe for its particular specific ligand in the cell walls of bacteria and other organisms.
Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. (1994)

Expression of the O6-methylguanine DNA methyltransferase (MGMT) gene in human glioma cell lines is strongly associated with resistance to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea. To examine the possibility that methylation of the body and promoter regions of the MGMT gene is associated with MGMT expression in a graded, rather than a completely on/off fashion, the present study analyzed the methylation status of the MGMT gene in human glioma cell lines exhibiting a wide range of MGMT expression. Methylation in the body of the gene was uniform within each cell line and correlated directly with MGMT expression. The level of MGMT promoter methylation was also graded across the cell lines, at 21 of 25 CpGs tested, but correlated inversely with MGMT expression. Two sites in the MGMT promoter were also much more accessible to restriction enzyme digestion, and thus in a more open chromatin conformation, in nuclei from high MGMT expressors relative to nuclei from cells with little or no MGMT expression. We conclude that the level of methylation, in both the body and promoter of the MGMT gene, is associated with MGMT expression in a graded fashion and may be important in setting the transcriptional state of the MGMT promoter through changes in chromatin structure.
Characterization of the Structure and Function of W → F WW Domain Variants:  Identification of a Natively Unfolded Protein That Folds upon Ligand Binding (1999)

The WW domain adopts a compact, three-stranded, antiparallel beta-sheet structure that mediates protein-protein interactions by binding to xPPxY-based protein ligands, such as the PY-ligand (EYPPYPPPPYPSG) derived from p53 binding protein-2. The conserved Trp residues, after which this domain was named, were replaced with Phe so their importance in structural integrity and for ligand binding could be evaluated. A biophysical approach was employed to compare the W17F, W39F, and W17F/W39F WW domains to the wild-type protein. The data demonstrate that replacement of Trp39 with Phe (W39F) does not disrupt the structure of the WW domain variant, but does abolish ligand binding. In contrast, the W17F WW domain variant is largely if not completely unfolded; however, this variant undergoes a PY-ligand induced disorder to order (folding) transition. The dissociation constant for the W17F WW domain-PY-ligand interaction is 15.1 +/- 1.2 microM, only slightly higher than that observed for the wild-type WW domain interaction (5.9 +/- 0.33 microM). The W17F WW domain is a natively unfolded protein which adopts a native conformation upon PY-ligand binding.
Cell Encapsulation in Biodegradable Hydrogels for Tissue Engineering Applications (2008)

Encapsulating cells in biodegradable hydrogels offers numerous attractive features for tissue engineering, including ease of handling, a highly hydrated tissue-like environment for cell and tissue growth, and the ability to form in vivo. Many properties important to the design of a hydrogel scaffold, such as swelling, mechanical properties, degradation, and diffusion, are closely linked to the crosslinked structure of the hydrogel, which is controlled through a variety of different processing conditions. Degradation may be tuned by incorporating hydrolytically or enzymatically labile segments into the hydrogel or by using natural biopolymers that are susceptible to enzymatic degradation. Because cells are present during the gelation process, the number of suitable chemistries and formulations are limited. In this review, we describe important considerations for designing biodegradable hydrogels for cell encapsulation and highlight recent advances in material design and their applications in tissue engineering.
Treatment of Inflammatory Diseases with a Monoclonal Antibody to Intercellular Adhesion Molecule 1 (2007)

A mouse monoclonal antibody to intercellular adhesion molecule 1 (ICAM-1) has been evaluated in multiple animal models of inflammation as well as in the clinic. Anti-ICAM-1 has been found to protect against allograft rejection and ischaemia/reperfusion injury in non-human primates and rabbits. In open-label phase I-II studies, anti-ICAM-1 appears to have prolonged kidney allograft survival when used as induction therapy in conjunction with traditional triple immunosuppressive therapy. Anti-ICAM-1 has shown beneficial effects in the treatment of rheumatoid arthritis when given for five days. Most patients receiving anti-ICAM-1 made antibodies to the mouse immunoglobulin.
Linkage of polynucleotides through phosphodiester bonds by an enzyme from Escherichia coli. (1967)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Transgene Expression Is Associated with Copy Number and Cytomegalovirus Promoter Methylation in Transgenic Pigs (2009)

Transgenic animals have been used for years to study gene function, produce important proteins, and generate models for the study of human diseases. However, inheritance and expression instability of the transgene in transgenic animals is a major limitation. Copy number and promoter methylation are known to regulate gene expression, but no report has systematically examined their effect on transgene expression. In the study, we generated two transgenic pigs by somatic cell nuclear transfer (SCNT) that express green fluorescent protein (GFP) driven by cytomegalovirus (CMV). Absolute quantitative real-time PCR and bisulfite sequencing were performed to determine transgene copy number and promoter methylation level. The correlation of transgene expression with copy number and promoter methylation was analyzed in individual development, fibroblast cells, various tissues, and offspring of the transgenic pigs. Our results demonstrate that transgene expression is associated with copy number and CMV promoter methylation in transgenic pigs.
Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity (2008)

Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (gamma-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNA-dependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity.
Astrocytes in Alzheimer's disease gray matter express alpha 1-antichymotrypsin mRNA. (1989)

The serine protease inhibitor alpha 1-antichymotrypsin (ACT) has been shown to be tightly associated with the amyloid found in plaque cores and blood vessels in the brains of patients with Alzheimer's disease (AD). Although the ACT found in plaques could be derived from the high levels of ACT in serum, previous Northern analysis revealed that ACT mRNA is produced locally in AD gray matter at much higher levels than in control gray matter. To determine which brain cells express ACT mRNA, we conducted in situ hybridization with 35S-labeled cRNA probes on hippocampal sections from four AD and three control cases. To identify astrocytes unequivocally, some of the hybridized sections were immunostained for glial fibrillary acidic protein, which is astrocyte-specific. Our results showed numerous astrocytes that were intensely labeled by the probe for ACT mRNA throughout the subicular gray matter of the AD cases. In contrast, astrocytes in control gray matter were rarely labeled by the probe for ACT mRNA. Examination of plaque cores in the AD subiculum showed that some astrocytes intensely labeled by the probe for ACT mRNA were closely associated with virtually every plaque core. Our results also showed many astrocytes in both AD and control white matter that were intensely labeled by the probe for ACT mRNA, and a small fraction of the astrocytes in a juvenile cerebellar astrocytoma that we examined were found to produce high levels of ACT mRNA. In every area in which astrocytes expressing ACT mRNA were found, astrocytes producing no detectable ACT message were also present. Our findings indicate that astrocytes produce the increased ACT mRNA in AD gray matter observed by Northern analysis, but they also show that ACT mRNA expression by astrocytes is not unique to AD. The presence of astrocytes expressing ACT mRNA near, and extending processes towards, plaque cores strongly suggests that some if not all of the ACT associated with amyloid plaque cores is produced by astrocytes surrounding the cores.