gebhart/patrepeval huggingface dataset:
Comprehensive Analysis of MGMT Promoter Methylation: Correlation with MGMT Expression and Clinical Response in GBM (2011)

O⁶-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR = 5.23, 95% CI [2.089-13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR = 3.076, 95% CI [1.301-7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting.
Potassium conductances underlying repolarization and after‐hyperpolarization in rat CA1 hippocampal interneurones. (1995)

1. The roles of multiple potassium conductances underlying action potential repolarization and after-hyperpolarization (AHP) in visually identified st. oriens-alveus (st. O-A) inhibitory interneurones of neonatal rat CA1 hippocampal slices were determined using whole-cell patch clamp techniques. 2. 4-Aminopyridine dose-dependently prolonged the action potential repolarization. The effects of 4-AP persisted in Ca(2+)-free conditions. Action potentials evoked from hyperpolarized potentials possessed an increased rate of repolarization. These data suggest an involvement of the rapidly activating transient current, IA, in spike repolarization. 3. Action potential duration was increased in the presence of Ca(2+)-free, Cd(2+)-containing solution, iberiotoxin or 1 mM TEA. The fast component of the AHP was attenuated by these agents suggesting that the Ca(2+)-activated K+ conductance, IC, underlies both the spike repolarization and fast AHP. 4. In Ca(2+)-free conditions, TEA (> 1 mM) dose-dependently prolonged the action potential duration by blocking a late conductance in action potential repolarization, suggesting a role for the sustained current, IK. 5. The slow AHP was attenuated by Ca(2+)-free medium, apamin or the Ca2+ chelator EGTA, suggesting a role for the Ca(2+)-activated K+ conductance, IAHP. 6. We conclude that action potential repolarization and AHP of st. O-A interneurones result from the activation of pharmacologically distinct, temporally overlapping potassium conductances. These findings are discussed with reference to the voltage clamp data presented in the preceding manuscript.
Blockade of Wnt Signaling Inhibits Angiogenesis and Tumor Growth in Hepatocellular Carcinoma (2009)

Aberrant activation of Wnt signaling plays an important role in hepatocarcinogenesis. In addition to direct effects on tumor cells, Wnt signaling might be involved in the organization of tumor microenvironment. In this study, we have explored whether Wnt signaling blockade by exogenous expression of Wnt antagonists could inhibit tumor angiogenesis and control tumor growth. Human Wnt inhibitory factor 1 (WIF1) and secreted frizzled-related protein 1 (sFRP1) were each fused with Fc fragment of human IgG1 to construct fusion proteins WIF1-Fc and sFRP1-Fc. The recombinant adenoviral vectors carrying WIF1-Fc and sFRP1-Fc driven by cytomegalovirus promoter were constructed. Ad-WIF1-Fc or Ad-sFRP1-Fc induced the expression and correct conformation of WIF1-Fc and sFRP1-Fc fusion proteins. These molecules caused down-regulation of E2F1, cyclin D1, and c-myc and promoted cell apoptosis in hepatocellular carcinoma cells. Treatment of established hepatocellular carcinoma tumors with Ad-WIF1-Fc and/or Ad-sFRP1-Fc resulted in significant inhibition of tumor growth and prolonged animal survival. The antineoplastic effect was associated with increased apoptosis of tumor cells, reduced microvessel density, and decreased expression of vascular endothelial growth factor and stromal cell-derived factor-1. Tube formation and migration of human microvascular endothelial cells and mouse endothelial progenitor cells (EPC) were significantly inhibited by both WIF1-Fc and sFRP1-Fc. In addition, these molecules blocked EPC differentiation and caused EPC apoptosis. Our data indicate that Wnt antagonists WIF1-Fc and sFRP1-Fc inhibit Wnt signaling and exert potent antitumor activity by increasing the apoptosis rate in tumor cells and by impairing tumor vascularization.
Implementation Of A Prototype Digital Optical Cellular Image Processor (DOCIP) (1989)

A processing element of a prototype digital optical cellular image processor (DOCIP) is implemented to demonstrate a particular parallel computing and interconnection architecture. This experimental digital optical computing system consists of a 2-D array of 54 optical logic gates, a 2-D array of 53 subholograms to provide interconnections between gates, and electronic input/output interfaces. The multi-facet interconnection hologram used in this system is fabricated by a computer-controlled optical system to offer very flexible interconnections.
Stepwise DNA condensation by a histone-mimic peptide-coated M12L24 spherical complex (2014)

A nanosized M12L24 coordination sphere mimicking a histone-octamer, in size and charge density, was studied as an artificial DNA compaction core. It triggered a stepwise condensation process in a similar manner to that of the natural system. “Beads-on-a-string” and “multistrand aggregation” intermediates were clearly observed by atomic force microscopy (AFM) and dynamic light scattering (DLS) studies during the condensation process.
Diabetes mellitus. Prevention of amputation (1994)

Fifteen percent of individuals with diabetes will likely develop foot ulcers in their lifetime, and approximately 15% to 20% of these ulcers are estimated to result in lower extremity amputation. Techniques to prevent lower extremity amputation range from the simple but often neglected foot inspection to complicated vascular and reconstructive foot surgery. Appropriate management can prevent and heal diabetic foot ulcers, thereby greatly decreasing the amputation rate and medical care costs. Prevention is the key to treatment. The author discusses general guidelines for foot screening and identifies three specific goals for prevention of amputation: 1) identification of at risk individuals needing prevention and the specific factors placing them at risk; 2) protection of the foot against the adverse effects of external forces (pressure, friction, and shear); and 3) reduction of the incidence of diabetic foot ulcers through educational programs.
Nuclear Receptors TR2 and TR4 Recruit Multiple Epigenetic Transcriptional Corepressors That Associate Specifically with the Embryonic β-Type Globin Promoters in Differentiated Adult Erythroid Cells (2011)

Nuclear receptors TR2 and TR4 (TR2/TR4) were previously shown to bind in vitro to direct repeat elements in the mouse and human embryonic and fetal β-type globin gene promoters and to play critical roles in the silencing of these genes. By chromatin immunoprecipitation (ChIP) we show that, in adult erythroid cells, TR2/TR4 bind to the embryonic β-type globin promoters but not to the adult β-globin promoter. We purified protein complexes containing biotin-tagged TR2/TR4 from adult erythroid cells and identified DNMT1, NuRD, and LSD1/CoREST repressor complexes, as well as HDAC3 and TIF1β, all known to confer epigenetic gene silencing, as potential corepressors of TR2/TR4. Coimmunoprecipitation assays of endogenous abundance proteins indicated that TR2/TR4 complexes consist of at least four distinct molecular species. In ChIP assays we found that, in undifferentiated murine adult erythroid cells, many of these corepressors associate with both the embryonic and the adult β-type globin promoters but, upon terminal differentiation, they specifically dissociate only from the adult β-globin promoter concomitant with its activation but remain bound to the silenced embryonic globin gene promoters. These data suggest that TR2/TR4 recruit an array of transcriptional corepressors to elicit adult stage-specific silencing of the embryonic β-type globin genes through coordinated epigenetic chromatin modifications.
Mutants of Streptococcus suis types 1 and 2 impaired in expression of muramidase-released protein and extracellular protein induce disease in newborn germfree pigs (1996)

The contribution of muramidase-released protein (MRP) and extracellular factor (EF) to the virulence of Streptococcus suis type 1 and 2 infections was studied. For that aim, we constructed mutants of S. suis types 1 and 2 by inactivating the genes encoding MRP and EF. Moreover, we changed a type 2 strain producing the 110-kDa EF protein into a strain producing a modified protein (EF*) of increased molecular mass. The chromosomally located mrp and epf genes were inactivated by replacement recombination by using nonreplicative plasmids. Newborn germfree pigs were inoculated with pathogenic type 1 and 2 strains and with the isogenic mutant strains. Wild-type as well as mutant strains induced fever, specific signs of disease, and lesions. Moreover, all mutant strains could be reisolated from the central nervous system of infected pigs. These results showed that inactivation or alteration of the mrp and epj genes had no measurable effect on the pathogenicity of S. suis types 1 and 2.
Role of Tissue Factor in Cancer (2009)

Tissue factor (TF) is a transmembrane glycoprotein that localizes the coagulation serine protease factor VII/VIIa (FVII/VIIa) to the cell surface. The primary function of TF is to activate the clotting cascade. The TF:FVIIa complex also activates cells by cleavage of a G-protein coupled receptor called protease-activated receptor 2 (PAR2). TF is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, metastasis, tumor growth, and tumor angiogenesis. For instance, tumor cells release TF-positive procoagulant microparticles into the circulation and these may trigger venous thromboembolism in patients with cancer. TF on circulating tumor cells also leads to the coating of the cells with fibrin that traps them within the microvasculature and facilitates hematogenous metastasis. In addition, TF:FVIIa-dependent activation of PAR2 on tumor cells increases tumor growth via an undefined mechanism. One possibility is that PAR2-dependent signaling increases the expression of proangiogenic proteins. Other studies have reported that endothelial cells in the tumor vasculature express TF and this may enhance angiogenesis. These results suggest that inhibition of TF should reduce several pathologic pathways that increase tumor growth and metastasis. This would represent a novel approach to anticancer therapy. Initial studies using inhibitors of the TF:FVIIa complex in mouse tumor models have produced encouraging results. Nevertheless, additional studies are needed to determine if this strategy can be successfully translated to the treatment of cancer patients.
Synthetic Analogues of Residues 1-34 of Human Parathyroid Hormone: Influence of Residue Number 1 on Biological Potency

in Vitro (1975)

A biologically active tetratriacontapeptide of human parathyroid hormone, hPTH (1-34), has been synthesized together with a series of structural analogues involving changes at the amino-terminal residue. Acetylation of the terminal amino group results in a marked reduction in the biological potency as measured in the in vitro rat renal adenylyl cyclase assay. Deletion of the terminal amino group results in a loss of biological activity. Substitution of the amino-terminal serine residue with glycine gives a lowered potency whereas substitution with alanine results in a 2-5-fold increase in biological activity in the in vitro assay. The results are compared with the findings previously reported for a series of amino-terminal analogues of the bovine PTH 1-34 peptide.
Ectopic Expression of Inhibitors of Protein Phosphatase Type 1 (PP1) Can Be Used to Analyze Roles of PP1 in Drosophila Development (2003)

We have identified two proteins that bind with high specificity to type 1 serine/threonine protein phosphatase (PP1) and have exploited their inhibitory properties to develop an efficient and flexible strategy for conditional inactivation of PP1 in vivo. We show that modest overexpression of Drosophila homologs of I-2 and NIPP1 (I-2Dm and NIPP1Dm) reduces the level of PP1 activity and phenotypically resembles known PP1 mutants. These phenotypes, which include lethality, abnormal mitotic figures, and defects in muscle development, are suppressed by coexpression of PP1, indicating that the effect is due specifically to loss of PP1 activity. Reactivation of I-2Dm:PP1c complexes suggests that inhibition of PP1 activity in vivo does not result in a compensating increase in synthesis of active PP1. PP1 mutants enhance the wing overgrowth phenotype caused by ectopic expression of the type II TGF beta superfamily signaling receptor Punt. Using I-2Dm, which has a less severe effect than NIPP1Dm, we show that lowering the level of PP1 activity specifically in cells overexpressing Punt is sufficient for wing overgrowth and that the interaction between PP1 and Punt requires the type I receptor Thick-veins (Tkv) but is not strongly sensitive to the level of the ligand, Decapentaplegic (Dpp), nor to that of the other type I receptors. This is consistent with a role for PP1 in antagonizing Punt by preventing phosphorylation of Tkv. These studies demonstrate that inhibitors of PP1 can be used in a tissue- and developmental-specific manner to examine the developmental roles of PP1.
Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition (2016)

"Training" the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvβ6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8(+) cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.
Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death (2003)

Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of a polyglutamine (polyQ) repeat in ataxin-2, the SCA2 gene product. In contrast to other polyQ diseases, intranuclear inclusions are not prominent in SCA2. In animal models with expression of mutant ataxin-2 targeted to Purkinje cells, neuronal dysfunction and morphologic changes are observed without the formation of intranuclear aggregates. In this report, we investigated the mechanisms underlying SCA2 pathogenesis using cellular models. We confirmed that the SCA2 gene product, ataxin-2, was predominantly located in the Golgi apparatus. Deletion of ER-exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 and TUNEL-positive cells. These results suggest a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. The formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2.
Concepts and Technologies of Selected Seed Treatments (1990)

Beneficial microbes in the microbiome of plant roots improve plant health. Induced systemic resistance (ISR) emerged as an important mechanism by which selected plant growth–promoting bacteria and fungi in the rhizosphere prime the whole plant body for ...Read More
Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency (2015)

Panitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.
Thermal Management of On-Chip Caches Through Power Density Minimization (2006)

Various architectural power reduction techniques have been proposed for on-chip caches in the last decade. However, these techniques mostly ignore the effects of temperature on the power consumption. In this paper, first we show that these power reduction techniques can be suboptimal when thermal effects are considered. Particularly, we propose a thermal-aware cache power-down technique that minimizes the power density of the active parts by turning off alternating rows of memory cells instead of entire banks. The decrease in the power density lowers the temperature, which in return, reduces the leakage of the active parts. Simulations based on SPEC2000 benchmarks in a 70nm technology show that the proposed thermal-aware architecture can reduce the total energy consumption by 53% compared to a conventional cache, and 14% compared to a cache architecture with thermal-unaware power reduction scheme. Second, we show a block permutation scheme that can be used during the design of caches to maximize the distance between blocks with consecutive addresses. By maximizing the distance between consecutively accessed blocks, we minimize the power density of the hot spots in the cache, and hence reduce the peak temperature. This, in return, results in an average leakage power reduction of 8.7% compared to a conventional cache without affecting the dynamic power and the latency. Overall, both of our architectures add no extra run-time penalty compared to the thermal-unaware power reduction schemes, yet they reduce the total energy consumption of a conventional cache by 53% and 5.6% on average, respectively.
Nanoarray of Polycyclic Aromatic Hydrocarbons and Carbon Nanotubes for Accurate and Predictive Detection in Real-World Environmental Humidity (2011)

In the present work, we introduce a cross-reactive array of synthetically designed polycyclic aromatic hydrocarbons (PAH) and single-walled carbon nanotube (SWCNT) bilayers and demonstrate the huge potential of the array in discriminating between polar and nonpolar volatile organic compounds (VOCs), as well as between the different VOCs from each subgroup. Using appropriate combinations of PAH/SWCNT sensors, we demonstrate that high sensitivity and accuracy values can be obtained for discriminating polar and nonpolar VOCs in samples with variable humidity levels (5-80% RH). The same array of sensors exhibited self-learning capabilities that facilitated exchanging information about environmental properties under observation. The results presented here could lead to the development of a cost-effective, lightweight, low-power, and non-invasive tool for a widespread detection of VOCs in real-world environmental, security, food, health, and other applications.