gebhart/patrepeval huggingface dataset:
515 A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours (2021)

<h3>Background</h3> MTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage which has shown promising clinical activity as monotherapy and combination therapy with tyrosine kinase inhibitors in hepatocellular carcinoma (HCC). Immunosuppressive myeloid cells are associated with worse outcomes to checkpoint inhibitors. Pre-clinical data have shown that MTL-CEBPA potentiates the oncological effect of PD-1 inhibitors. <h3>Methods</h3> This phase 1A/B, first-in-human, open-label, multicenter study evaluates the safety, tolerability, PK, and efficacy of MTL-CEBPA in combination with a pembrolizumab in adult patients with advanced solid tumours across 3 dose cohorts (70mg/98mg/130mg/m2 MTL-CEBPA once weekly for 3 consecutive weeks with final week break per cycle, with 200mg pembrolizumab every 3 weeks). The primary endpoint is safety and ORR; key secondary endpoints include PK, CR rate &amp; DCR. Key inclusion criteria: Patients with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available, measurable disease, ECOG PS &lt;2, life expectancy &gt;3 months. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). <h3>Results</h3> 10 pts (3 men, 7 women; median age 50.5yrs), all with different tumor types (1 each of triple negative breast, methothelioma, squamous thymic, cholangiocarcinoma, eccrine, fibrolamellar hepatocellular, colorectal, pancreatic and 2 platinum resistant high-grade serous ovarian). 4 pts had ≥4 prior lines of treatment. All pts reported treatment-related AEs, 7 pts reported AEs considered related to MTL-CEBPA only and all were grade 1 or 2. The most common was nausea (n=3) followed by anaemia, headache, insomnia, neutropenia, pyrexia, transaminase increase and ventricular extrasystole (all n=1). Five pts reported AEs considered related to pembrolizumab only, 2AEs in 1 pt only were grade 3 (ALT and AST increases) There were no DLTs, SAEs or AEs leading to discontinuation or to death in the study. Tumor response was evaluated in 9 pts. 2 pts had a PR (epithelioid mesothelioma at 2 months with 83% tumour reduction, pt ongoing at 9 months &amp; serous ovarian cancer at 2 months with 69% reduction in tumour, pt progressed at 6 months). Three pts had SD, 4 pts had PD as BOR, and 4 pts are continuing to receive treatment. <h3>Conclusions</h3> MTL-CEBPA in combination with pembrolizumab demonstrated manageable toxicity at the dose levels tested and has shown antitumor activity. MTD was not reached and RP2D was determined at 130mg/m2 on day 1, 8 and 15 of a 28 day cycle. Enrolment into the dose expansion is ongoing. <h3>Trial Registration</h3> This study was registered with ClinicalTrials.gov, number NCT04105335. <h3>Ethics Approval</h3> The study was approved by the North East - Newcastle &amp; North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.
Early Activation of Metalloproteinases after Experimental Myocardial Infarction Occurs in Infarct and Non-infarct Zones (1998)

The collagen matrix of the heart forms a network linking muscle fibers, muscle bundles, and intramyocardial blood vessels. Collagen turnover in the heart is normally a dynamic process that involves both collagen synthesis and degradation. Collagen breakdown generally involves its chemical digestion by matrix metalloproteinases (MMPs) which are activated in tissue repair, wound healing, and myocardial ischemia. We studied activation of MMPs by zymography in infarct (anterolateral wall) and non-infarct (septum) zones of rat hearts following coranary artery ligation, as well as in sham operated rats. Rats were sacrificed at 30 minutes, 1 hour, 2 hours, 4 hours, and 24 hours post infarction (six hearts for each time period). MMP activity was detected at different molecular weights, with bands at 54 kDa (MMP-1), 62 kDa (MMP-2), and 92 kDa (MMP-9) being the most prominent. MMP activities were indexed by densitometer optical reading. Activity was detected as early as 1 hour post infarct in the MI and remote zones at the 54 kDa (MMP-1) ( p < 0.01) and 62 kDa bands (MMP-2) ( p < 0.001), and at 2 hours post infarct in the infarct zone only at 92 kDa (MMP-9) ( p < 0.05). MMPs are activated early after infarction both in the infarct and importantly, non-infarct zones. This may contribute to collagen breakdown, infarct expansion, and left ventricular remodeling, known to occur early after infarction in experimental and clinical settings.
Orexigenic effect of the melanocortin MC4receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1receptor selective antagonists (2000)

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]D-argininam ide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2(diphenyl acetyl)-argininamidetrifluoroacetate (BIBO3304), and decapeptide [D-Tyr(27,36)D-Thr32]NPY(27-36), after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr(27,36)D-Thr32]NPY(27-36) was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.
Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles (2007)

Posttranslational modification through palmitoylation regulates protein localization and function. In this study, we identify a role for the Drosophila melanogaster palmitoyl transferase Huntingtin-interacting protein 14 (HIP14) in neurotransmitter release. hip14 mutants show exocytic defects at low frequency stimulation and a nearly complete loss of synaptic transmission at higher temperature. Interestingly, two exocytic components known to be palmitoylated, cysteine string protein (CSP) and SNAP25, are severely mislocalized at hip14 mutant synapses. Complementary DNA rescue and localization experiments indicate that HIP14 is required solely in the nervous system and is essential for presynaptic function. Biochemical studies indicate that HIP14 palmitoylates CSP and that CSP is not palmitoylated in hip14 mutants. Furthermore, the hip14 exocytic defects can be suppressed by targeting CSP to synaptic vesicles using a chimeric protein approach. Our data indicate that HIP14 controls neurotransmitter release by regulating the trafficking of CSP to synapses.
A Simple Strategy for Constructing Hierarchical Composite Electrodes of PPy‐Posttreated 3D‐Printed Carbon Aerogel with Ultrahigh Areal Capacitance over 8000 mF cm–2 (Adv. Mater. Technol. 7/2022) (2022)

3D-Printed Carbon Aerogel Electrodes In article number 2101325, Bin Zhou, Ai Du, and co-workers demonstrate a simple strategy to design the hierarchically porous 3D-printed carbon aerogel (CA) electrodes via combining direct ink writing, freezing drying, carbonization and polypyrrole (PPy) posttreatment. The improved wettability and contact conductivity of CA electrodes lead to an extremely high areal capacitance up to 8126 mF cm−2. This simple strategy may provide a novel insight to dramatically boost energy storage properties of supercapacitor electrodes and their functionalization.
Script (1985)

In this paper, we introduce a new abstraction mechanism, called a script , which hides the low-level details that implement patterns of communication . A script localizes the communication between a set of roles (formal processes), to which actual processes enroll in order to participate in the action of the script. The paper discusses the addition of scripts to the languages CSP and Ada, as well as to a shared-variable language with monitors.
Thermal energy suppresses mutational defects in DNA unwinding at a yeast replication origin. (1990)

Yeast replication origins contain a DNA sequence element whose biological activity correlates with hypersensitivity to single-strand-specific nucleases in negatively supercoiled plasmids. By using two-dimensional gel electrophoresis of plasmid topoisomers, we demonstrate that thermodynamically stable origin unwinding accounts for the nuclease hypersensitivity and, furthermore, that increased thermal energy facilitates stable origin unwinding in vitro. In living cells, increased thermal energy can suppress origin mutations that raise the free-energy cost for unwinding the nuclease-hypersensitive element. Specifically, mutational defects in autonomously replicating sequence (ARS)-mediated plasmid replication are less severe in cells grown at 30 degrees C as compared to 23 degrees C. Our findings indicate that the energetics of DNA unwinding at the nuclease-hypersensitive element are biologically important. We call the nuclease-hypersensitive sequence the DNA unwinding element (DUE) and propose that it serves as the entry site for yeast replication enzymes into the DNA helix.
Hydrophilic domain structure in polymer exchange membranes: Simulations of NMR spin diffusion experiments to address ability for model discrimination (2017)

ABSTRACT We detail the development of a flexible simulation program (NMR_DIFFSIM) that solves the nuclear magnetic resonance (NMR) spin diffusion equation for arbitrary polymer architectures. The program was used to explore the proton ( 1 H) NMR spin diffusion behavior predicted for a range of geometrical models describing polymer exchange membranes. These results were also directly compared with the NMR spin diffusion behavior predicted for more complex domain structures obtained from molecular dynamics (MD) simulations. The numerical implementation and capabilities of NMR_DIFFSIM were demonstrated by evaluating the experimental NMR spin diffusion behavior for the hydrophilic domain structure in sulfonated Diels‐Alder Poly(Phenylene) (SDAPP) polymer membranes. The impact of morphology variations as a function of sulfonation and hydration level on the resulting NMR spin diffusion behavior were determined. These simulations allowed us to critically address the ability of NMR spin diffusion to discriminate between different structural models, and to highlight the extremely high fidelity experimental data required to accomplish this. A direct comparison of experimental double‐quantum‐filtered 1 H NMR spin diffusion in SDAPP membranes to the spin diffusion behavior predicted for MD‐proposed morphologies revealed excellent agreement, providing experimental support for the MD structures at low to moderate hydration levels. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56 , 62–78
Relay with Side Information (2007)

This paper establishes necessary and sufficient conditions for reliable transmission of a source over a relay channel when source side information is available non-causally (a) only at the receiver, (b) only at the relay, or (c) at both the relay and the receiver. For the cases of side information only at the receiver and at both the relay and the receiver, we establish tight necessary and sufficient conditions that apply to any relay channel and show that source-channel separation is optimal. When side information is available only at the relay, we establish a necessary condition for reliable transmission and show that it is tight for the class of degraded relay channels and that source-channel separation is optimal in this case.
Variance Analysis of Frequency Response Function Measurements Using Periodic Excitations (2005)

The influence of disturbing noise and nonlinear distortions on frequency response function measurements using periodic excitations has been studied in detail in the literature. A variance analysis method has been developed that allows one to detect and quantify the nonlinear distortions and the disturbing noise. In this paper, the variance analysis is generalized to detect and quantify the following nonstationary disturbances: 1) nonsynchronous periodic signals, for example, the 50 Hz mains and its harmonics, and 2) nonstationary behavior of the device under test, for example, phase or frequency modulation.
Gene Therapy and Cell-Based Therapies for Therapeutic Angiogenesis in Peripheral Artery Disease (2013)

Gene therapy and cell-based therapy have emerged as novel therapies to promote therapeutic angiogenesis in critical limb ischemia (CLI) caused by peripheral artery disease (PAD). Although researchers initially focused on gene therapy using proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factors (HGF), cell therapy using bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (BMMSCs), G-CSF-mobilized peripheral blood mononuclear cells (M-PBMNCs), and endothelial progenitor cells (EPCs) have also been extensively studied. Based on the elaborate studies and favorable results of basic research, some clinical phase I/II trials have been performed, and the results demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI. However, the phase 3 clinical trials have thus far been limited to gene therapy using the HGF gene. Further studies using well-designed larger placebo-controlled and long-term randomized control trials (RCTs) will clarify the effectiveness of gene therapy and cell-based therapy for the treatment of CLI. Furthermore, the development of efficient gene transfer systems and effective methods for keeping transplanted cells healthy will make these novel therapies more effective and ease the symptoms of CLI.
Synthesis of N4amG as a novel probe for cell nucleus activity assessment (2013)

1173 Objectives Uptake of F-18 FDG in highly glycolytic areas could not differentiate infection and/or inflammation which cause false positive results. An alternative way is to target cell proliferation via nucleoside analogues. This study was aimed to synthesis a guanine analog for cell nucleus activity assessment. Methods N4-Guan is synthesized through a 9-step reaction. The hydroxyl groups of penciclovir was selectively protected. The unprotected hydroxyl group was converted to an amino group. The carboxyl acid group of the N4 mono-acid was reacted with amino-penciclovir to form amide linage. N4amG was obtained after deprotection and purification. Radiolabeling of N4amG with Tc-99m was performed in a standard manner. Cell uptake assay and cytoplasm/nucleus isolation was performed using breast cancer cell line. Biodistribution and planar imaging (n=3/time interval) of Tc-99m N4amG were conducted in breast tumor-bearing rats from 0.5-4hrs. Computer outlined region of interest (counts per pixel) was used to determine tumor-to-muscle (T/M) count density ratios. Dosimetry estimates were computed from respective biodistribution data using Olinda software. Results Mass spectronmetry, NMR and HPLC analysis for N4amG were performed to determine the structure. The purity was >97%. The total synthetic yield was 6%. Radiochemical purity of Tc-99m N4amG determined by ITLC was >95% (in saline). There was 2.3%ID uptake in cytoplasm and 1.5%ID in nucleus after 4 hours incubation indicated Tc-99m N4amG was involved in cell nucleus activity. In the breast tumor-bearing rat planar imaging from 0.5-4 hours, T/M ratio was 3.65+0.18 to 5.02+0.41. In the rat biodistribution from 0.5-4hrs, tumor, tumor/blood and tumor/muscle count density ratios were 0.32+0.06 to 0.43+0.04, 0.29+0.02 to 0.52+0.02 and 3.24+0.38to 4.30+0.59, respectively. Tc-99m N4amG showed total rad absorbed by each organ was below the proposed annual and total limits after dosimetry estimation. Conclusions Our data indicate that it is feasible to assess tumor nucleus activity with Tc-99m N4amG.
Supercritical Density Modifications of a Laser-Produced Plasma Due to Resonant Cavity Fields (1979)

A laser plasma is produced at the center of a cylindrical cavity while radio-frequency excitation of moderate power is supplied near the TM011 and TE111 vacuum-mode frequencies. Probe and particle collector measurements show density modification of the plasma during its decay due to resonances excited by the RF source. The magnitudes of these density changes are found to be near and exceeding critical (ωp = ωRF) density.
Dual Use Applications to Electronic Fee Collection (2012)

Traffic infrastructure requires huge investments and long construction periods what asks for a strong focus in optimizing already available traffic ways and a comprehensive planning of new ones. To maximize the efficiency and capacity of goods transportation as well as individual traffic is a major goal of traffic engineering and management. The challenge is to fit a rapidly growing traffic volume into a transportation network which capacity is increasing at a much lower level and to consider constraints like environmental protection and road safety. This paper deals with an approach of dual using applications originally introduced for Electronic Fee Collection (EFC). For the purpose of traffic data gathering and analysis a Telematics Platform is introduced which offers data out of the EFC context to any interested party for a more comprehensive traffic management based on higher quality data. Further it is shown that EFC compliance check infrastructure can be dual used for increasing road safety, allowing for enhanced security on roads.
Detecting Changes and Avoiding Catastrophic Forgetting in Dynamic Partially Observable Environments (2020)

The ability of an agent to detect changes in an environment is key to successful adaptation. This ability involves at least two phases: learning a model of an environment, and detecting that a change is likely to have occurred when this model is no longer accurate. This task is particularly challenging in partially observable environments, such as those modeled with partially observable Markov decision processes (POMDPs). Some predictive learners are able to infer the state from observations and thus perform better with partial observability. Predictive state representations (PSRs) and neural networks are two such tools that can be trained to predict the probabilities of future observations. However, most such existing methods focus primarily on static problems in which only one environment is learned. In this paper, we propose an algorithm that uses statistical tests to estimate the probability of different predictive models to fit the current environment. We exploit the underlying probability distributions of predictive models to provide a fast and explainable method to assess and justify the model's beliefs about the current environment. Crucially, by doing so, the method can label incoming data as fitting different models, and thus can continuously train separate models in different environments. This new method is shown to prevent catastrophic forgetting when new environments, or tasks, are encountered. The method can also be of use when AI-informed decisions require justifications because its beliefs are based on statistical evidence from observations. We empirically demonstrate the benefit of the novel method with simulations in a set of POMDP environments.
Supplementary Figure Legends and Supplementary Tables from A Four-Gene Promoter Methylation Marker Panel Consisting of <i>GREM1, NEURL, LAD1,</i> and <i>NEFH</i> Predicts Survival of Clear Cell Renal Cell Cancer Patients (2023)

&lt;p&gt;File containing Supplementary Tables S1-S7 and Legends to Supplementary Figures S1-S4. Supplementary Table S1. Primers for promoter methylation analysis by MSP of the 43 candidate genes. Supplementary Table S2. Primers for mRNA expression analysis by qRT-PCR for 22 genes. Supplementary Table S3. Candidate gene selection. Supplementary Table S4. Validation of expression microarrays and MBD-NGS by MSP. Supplementary Table S5. Candidate gene promoter methylation associated with patient and tumor characteristics - hospital-based series. Supplementary Table S6. Hazard ratio's with 95% confidence intervals and p-values, including model fit according to Harrell's C and AIC, for the single markers, all possible two- and three-marker panels, and the four-marker panel for both the age- and sex-adjusted models and the multivariable models in the hospital-based series. Supplementary Table S7. Hazard ratio's with 95% confidence intervals and p-values, including model fit according to Harrell's C and AIC, for the single markers, all possible two- and three-marker panels, and the four-marker panel for both the age- and sex-adjusted models and the multivariable models in the population-based series. Supplementary Figure S1. Methylation analysis of GREM1, LAD1, NEFH and NEURL by methylation-specific PCR (MSP) in the hospital- and population-based series and in the TCGA series. Supplementary Figure S2. Validation of up-regulation of gene expression after demethylation with DAC by qRT-PCR for 22 genes. Supplementary Figure S3. Cause-specific overall survival curves for candidate genes in hospital-based ccRCC series (related to Supplementary Table S5). Supplementary Figure S4. Cause-specific overall survival curves for GREM1, LAD1, NEFH, and NEURL in hospital- and population-based ccRCC series (related to Table 1 and Table 2).&lt;/p&gt;
Freeze-Casting Produces a Graphene Oxide Aerogel with a Radial and Centrosymmetric Structure (2018)

We report the assembly of graphene oxide (G-O) building blocks into a vertical and radially aligned structure by a bidirectional freeze-casting approach. The crystallization of water to ice assembles the G-O sheets into a structure, a G-O aerogel whose local structure mimics turbine blades. The centimeter-scale radiating structure in this aerogel has many channels whose width increases with distance from the center. This was achieved by controlling the formation of the ice crystals in the aqueous G-O dispersion that grew radially in the shape of lamellae during freezing. Because the shape and size of ice crystals is influenced by the G-O sheets, different additives (ethanol, cellulose nanofibers, and chitosan) that can form hydrogen bonds with H<sub>2</sub>O were tested and found to affect the interaction between the G-O and formation of ice crystals, producing ice crystals with different shapes. A G-O/chitosan aerogel with a spiral pattern was also obtained. After chemical reduction of G-O, our aerogel exhibited elasticity and absorption capacity superior to that of graphene aerogels with "traditional" pore structures made by conventional freeze-casting. This methodology can be expanded to many other configurations and should widen the use of G-O (and reduced G-O and "graphenic") aerogels.