gebhart/patrepeval huggingface dataset:
Abstract 4086: Location matters: The impact of the location of CpG sites on the specificity of methylation biomarkers for HCC (2012)

Abstract Hepatocellular carcinoma (HCC) is the second fastest growing cancer and one of the top 10 causes of cancer deaths in the United States. The 5-year survival rate is 14%, ranging from 26% among early stage tumors to only 2% in late stage HCC. The only available biomarker for screening, serum alpha-fetoprotein (AFP), has a low sensitivity of detection (40%-60%), so the need for a better detection method is urgent. Given the heterogeneous nature of HCC, a panel of genetic and epigenetic biomarkers would be needed to obtain high sensitivity for the early diagnosis of HCC. In the course of assembling a panel of epigenetic markers for HCC, we noticed variable HCC specificity of three extensively studied potential methylation biomarkers, APC, GSTP1, and RASSF1A. We hypothesized that the specificity of promoter methylation of the tumor suppressor genes APC, GSTP1, and RASSF1A as a biomarker for HCC could depend upon the location of the CpG sites analyzed. To test this hypothesis, we used bisulfite-PCR sequencing to compare the methylation status of the promoter region of these three genes in DNA isolated from HCC, matched adjacent non-HCC, cirrhosis, hepatitis, and normal liver. We identified HCC-specific CpG methylation sites and unique liver-specific methylation patterns in the promoter region of the APC (Jain et. al, PloSOne 2011) and GSTP1 genes and in a more HCC-specific promoter region (p &amp;lt; 0.05 by Fisher's exact test) of the RASSF1A gene. Together, these results proved our hypothesis and provided an interpretation for the variability in the literature. Using PCR-based technology, we have developed assays for a panel of genetic and epigenetic markers for liver cancer screening. These assays were first tested in tissue to determine their ability to distinguish HCC (n=120) from cirrhosis (n=35) and hepatitis (n=35). The AUROC is 0.809 for mAPC, 0.756 for mGSTP1, 0.887 for mRASSF1, and 0.733 for TP53. When combined, this panel of DNA markers had an AUROC of 0.931 and identified 90% of AFP-negative tumors. This study clearly demonstrates (1) the importance of location of CpG site methylation for HCC specificity and the way in which liver-specific DNA methylation should be considered when an epigenetic DNA marker is studied for detection of HCC and (2) the potential of a sensitive DNA test for HCC screening. An analysis of the performance of this panel of markers in peripherals (blood and urine) for HCC screening is in progress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4086. doi:1538-7445.AM2012-4086
Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model (2023)

Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing <i>N</i>-methyl-d-Aspartate receptors is thought to play a key role in mechanisms underlying cellular adaptation that takes place in the development of analgesic tolerance. Herein, we describe a novel GluN2B-selective negative allosteric modulator, <b>EU93-108</b>, that shows high potency and brain penetrance. We describe the structural basis for binding at atomic resolution. This compound possesses intrinsic analgesic properties in the rodent tail immersion test. EU93-108 has an acute and significant anodyne effect, whereby morphine when combined with EU93-108 produces a higher tail flick latency compared to that of morphine alone. These data suggest that engagement of GluN2B as a target has utility in the treatment of pain, and EU93-108 could serve as an appropriate tool compound to interrogate this hypothesis. Future structure-activity relationship work around this scaffold could give rise to compounds that can be co-administered with opioids to diminish the onset of tolerance due to chronic opioid use, thereby modifying their utility.
Room Temperature Difluoro-Tolane and Diphenyl-Diacetylene Liquid Crystals with Negative Dielectric Anisotropy (1997)

Abstract Several laterally difluorinated tolane and diphenyl-diacetylene liquid crystals were synthesized and their physical properties evaluated. These compounds exhibit low melting temperature, small heat fusion enthalpy and large negative dielectric anisotropy. Their potential applications are in the high contrast displays using a homeotropic cell and for infrared spatial light modulators.
Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. III. Impact of modifications to the macrocycle isobutyryl ester position (2019)

Abstract BACKGROUND Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK‐2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK‐2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. RESULTS Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici , Leptosphaeria nodorum , Pyricularia oryzae and Ustilago maydis . Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC 50 1.44 nM) and the n ‐butyl, 1‐Me‐propyl, 3,3‐diMe‐propyl and 2‐ c ‐propyl propyl ethers (IC 50 values = 1.08, 1.14, 1.15 &amp; 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy ( E solv ) and critical packing parameters ( vsurf_CP ) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC 50 3.36 nM, Z. tritici EC 50 12 μg L −1 ) showing the strongest Z. tritici activity in protectant tests. CONCLUSIONS Substitution of the isobutyryl ester group of UK‐2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry
Acute Hemodynamic Effects of Single‐Dose Sildenafil When Added to Established Bosentan Therapy in Patients With Pulmonary Arterial Hypertension: Results of the COMPASS‐1 Study (2009)

This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (>or=18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21%, -8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (-15%; 95% confidence limits: -21%, -10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds.
Hematopoietic Development from Human Embryonic Stem Cells (2007)

The most common human cell-based therapy applied today is hematopoietic stem cell (HSC) transplantation. HSCs can be defined by two essential properties: self-renewal and multilineage hematopoietic differentiation. These combined HSC properties allow them to differentiate into all blood cell types (multilineage) in a sustained manner for the lifetime of the animal, which requires their ability to make cellular copies of themselves (self-renewal). These features can be tested by transplantation from donor to recipient and provide a functional basis to define and identify HSCs. Currently, human bone marrow (BM), mobilized peripheral blood, and umbilical cord blood (CB) represent the major sources of transplantable HSCs, but their availability for use is limited by both quantity and compatibility. Although increasing evidence suggests that somatic HSCs can be expanded to meet current needs, their in vivo potential is concomitantly compromised after ex vivo culture. Pluripotent human embryonic stem cells (hESCs) may provide an alternative. hESCs possess indefinite proliferative capacity in vitro, and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures. In most cases, hESC-derived hematopoietic cells show similar clonogenic progenitor capacity and primitive phenotype to somatic sources of hematopoietic progenitors, but possess limited in vivo repopulating capacity when transplanted into immunodeficient mice. Although this suggests HSC function can be derived from hESCs, the efficiency and quality of these cells must be characterized using surrogate models for potential clinical applications.
Exon 11 Skipping of E-Cadherin RNA Downregulates Its Expression in Head and Neck Cancer Cells (2011)

E-cadherin is an important tumor suppressor gene whose expression is lost when cells acquire a metastatic phenotype. We analyzed the role of E-cadherin missplicing as a mechanism of its downregulation by analyzing a misspliced E-cadherin transcript that lacks exon 11 of this gene. This results in a frameshift and a premature termination codon that targets this transcript for degradation. Tumor tissues, including breast (20%, n = 9), prostate (30%, n = 9) and head and neck (75%, n = 8) cancer, express the exon 11-skipped transcripts (vs. nonmalignant controls) and its levels inversely correlate with E-cadherin expression. This is a novel mechanism of E-cadherin downregulation by missplicing in tumor cells, which is observed in highly prevalent human tumors. In the head and neck cancer model, nontumorigenic keratinocytes express exon 11-skipped splice product two- to sixfold lower than the head and neck tumor cell lines. Mechanistic studies reveal that SFRS2 (SC35), a splicing factor, as one of the regulators that increases missplicing and downregulates E-cadherin expression. Furthermore, this splicing factor was found to be overexpressed in 5 of 7 head and neck cell lines and primary head and neck tumors. Also, methylation of E-cadherin gene acts as a regulator of this aberrant splicing process. In 2 head and neck cell lines, wild-type transcript expression increased 16- to 25-folds, whereas the percentage of exon 11-skipped transcripts in both the cell lines decreased five- to 30-folds when cells were treated with a hypomethylating agent, azacytidine. Our findings reveal that promoter methylation and an upregulated splicing factor (SFRS2) are involved in the E-cadherin missplicing in tumors.
Role of cytokine in inflammatory response. (1993)

There is a considerable body of evidence that inflammatory response is mediated by various cytokines. IL-5 is one of inflammatory cytokines. The study of IL-5 has been originated in the search for one of the B cell growth and differentiation factors, named T cell-replacing factor (TRF), that induces antigen-stimulated B cells to differentiate into plasma cells. Eosinophil differentiation factor (EDF) has been known as a diffusible factor from thoracic duct lymphocytes of parasite-infected rats. The cDNA cloning and mAb against IL-5 enable us to identify this molecule as a cytokine (TRF/EDF) that has pleiotropic activity in vitro on various target cells besides B cells and eosinophils. The IL-5 transgenic mice show not only polyclonal B cell activation represented by enhanced serum levels of IgM, IgA, and IgE and autoantibody production, but also massive eosinophilia in peripheral blood and eosinophil infiltration into various tissues.The pleiotropic activity of IL-5 on target cells is directly dependent on initial binding to specific cell-surface receptor (IL-5R) . IL-5 interacts with target cells with biphasic equilibrium binding kinetics, reflecting two classes of binding sites with high and low affinity. We carried out the cloning of the cDNA for the IL-5Rα chain which found IL-5 with low affinity by itself. The IL-5Rα chain associates with the β chain which can convert low affinity IL-5R to the high affinity. The β chain of IL-5R, that does not bind either IL-5, IL-3, or GM-CSF by itself is shared among IL-5R, IL-3R, and GM-CSFR.These results can imply why IL-5, IL-3, and GM-CSF are eosinophil-poietin, but can not explain why IL-5 preferentially induces eosinophil production. IL-5 specific signalling may be transduced through IL-5Rα chain. We need further experimentation to give definite answer on these issues.
A Study of Errant Pipeline Flushes Caused by Value Misspeculation (2004)

Value speculation has been proposed as a technique that can overcome true data dependencies, hide memory latencies, and expose higher degrees of instruction level parallelism (ILP). Branch direction prediction and target address prediction are two widely used control speculation techniques aimed at providing a steady stream of instructions to the instruction window. In this paper we consider a load value predictor used together with an aggressive branch predictor microarchitecture and investigate the effects of load value misspeculations on branch resolution. We study the performance impact of the interaction of these mechanisms and characterize the occurence of these events in a multiple issue, out-of-order, superscalar pipeline. We perform execution-driven studies using integer benchmarks taken from the SPECint2000, SPECint95 and Olden suites. We show that IPC can deteriorate by as much as 4.7% due to unnecessary pipeline flushes caused by branch resolutions that use speculative data. This paper also proposes a mechanism that can prevent these unnecessary squashes from occurring.
Projection-Based Wavelet Denoising [Lecture Notes] (2015)

In this lecture note, we describe a wavelet domain denoising method consisting of making orthogonal projections of wavelet (subbands) signals of the noisy signal onto an upside down pyramid-shaped region in a multidimensional space. Each horizontal slice of the upside down pyramid is a diamond shaped region and it is called an -ball. The upside down pyramid is called the epigraph set of the -norm cost function. We show that the method leads to soft-thresholding as in standard wavelet denoising methods. Orthogonal projection operations automatically determine the soft-threshold values of the wavelet signals.
DeMOR (2008)

Model order reduction is an efficient technique to reduce the system complexity while producing a good approximation of the input-output behavior. However, the efficiency of reduction degrades as the number of ports increases, which remains a long-standing problem. The reason for the degradation is that existing approaches are based on a centralized framework, where each input-output pair is implicitly assumed to be equally interacted and the matrix-valued transfer function has to be assumed to be fully populated. In this paper, a decentralized model order reduction scheme is proposed, where a multi-input multi-output (MIMO) system is decoupled into a number of subsystems and each subsystem corresponds to one output and several dominant inputs. The decoupling process is based on the relative gain array (RGA), which measures the degree of interaction of each input-output pair. Our experimental results on a number of interconnect circuits show that most of the input-output interactions are usually insignificant, which can lead to extremely compact models even for systems with massive ports. The reduction scheme is very amenable for parallel computing as each decoupled subsystem can be reduced independently.
Supplementary Figure S1 from Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer (2023)

Supplementary Figure S1 from Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer
Dual-Surface-Modified Reverse-Selective Membranes (2007)

The reverse selectivity of inorganic membranes can be enhanced by surface modification using long hydrocarbon chain silanes. Improvements in n-C4H10 selectivity of Vycor porous glass over N2 and CH4 were obtained by sequentially modifying it with a C18 monochlorosilane (OCS) followed by a C18 trichlorosilane (ODS). The membranes were tested for pure and mixed gases at different feed pressures. The dual-modified membranes have higher ideal, or pure-gas, selectivities than membranes modified using OCS alone. The n-C4H10/N2 and n-C4H10/CH4 ideal selectivities for the dual-modified membrane were 88 and 35, respectively, as compared to values of 13 and 7, respectively, for the OCS-modified membrane. Adsorption experiments showed an increase in the relative adsorption of n-C4H10 over N2 and CH4 after dual surface modification of Vycor glass. Nuclear magnetic resonance, X-ray photoelectron spectroscopy, and thermogravimetric analysis techniques were used to confirm the presence of silanes on the surface of the substrates. A high flux of n-butane was measured for a dual-modified membrane fabricated using a 5 nm pore diameter γ-alumina ultrafilter substrate. The mixed-gas n-butane permeance for this membrane was 2 × 10-4 cm3(STP) cm-2 cm Hg-1 s-1 (6.7 × 10-8 mol m-2 s-1 Pa-1).
Assessing the Causal Effect of Policies: An Example Using Stochastic Interventions (2013)

Assessing the causal effect of an exposure often involves the definition of counterfactual outcomes in a hypothetical world in which the stochastic nature of the exposure is modified. Although stochastic interventions are a powerful tool to measure the causal effect of a realistic intervention that intends to alter the population distribution of an exposure, their importance to answer questions about plausible policy interventions has been obscured by the generalized use of deterministic interventions. In this article, we follow the approach described in Díaz and van der Laan (2012) to define and estimate the effect of an intervention that is expected to cause a truncation in the population distribution of the exposure. The observed data parameter that identifies the causal parameter of interest is established, as well as its efficient influence function under the non-parametric model. Inverse probability of treatment weighted (IPTW), augmented IPTW and targeted minimum loss-based estimators (TMLE) are proposed, their consistency and efficiency properties are determined. An extension to longitudinal data structures is presented and its use is demonstrated with a real data example.
Sparse Vector Transmission: An Idea Whose Time Has Come (2020)

In recent years, we are witnessing bewildering variety of automated services and applications of vehicles, robots, sensors, and machines powered by the artificial intelligence technologies. Communication mechanism associated with these services is dearly distinct from human-centric communications. One important feature for the machine-centric communications is that the amount of information to be transmitted is tiny. In view of the short packet transmission, relying on today's transmission mechanism would not be efficient due to the waste of resources, large decoding latency, and expensive operational cost. In this article, we present an overview of the sparse vector transmission (SVT), a scheme to transmit a short-sized information after the sparse transformation. We discuss basics of SVT, two distinct SVT strategies, viz., frequency-domain sparse transmission and sparse vector coding with detailed operations, and also demonstrate the effectiveness in realistic wireless environments.
Mechanism of Action of 2-Mercapto-1(β-4-pyridethyl)benzimidazole: A Reversible Inhibitor of Interferon Activity (1970)

2-mercapto-1(beta-4-pyridethyl)benzimidazole (MPB) inhibited the development of antiviral activity induced by interferon in chick cells. The MPB effect was reversed by washing the cells. The action of MPB was on a step immediately following interferon binding but before the cellular RNA and protein synthesis that appear to be required for interferon action. The step blocked by MPB possibly involves cellular phospholipid synthesis.
Six cases of squamous cell carcinoma of the stomach of the horse (1982)

Six cases of squamous cell carcinoma of the stomach in horses seen at the New York State College of Veterinary Medicine are compared with 15 similar cases reported previously. Clinical signs included anorexia in all cases, emaciation, fever, anaemia and/or palpable abdominal masses in 3, colic in 2 and dysphagia in one case. Haematological studies revealed normochromic, normocytic anaemia in 3 and absolute neutrophilia in 5 cases. Peritoneal fluid analysis was performed in 4 cases and revealed slightly to moderately elevated total protein concentrations in 3 and a markedly elevated number of white blood cells in 2 cases. Exploratory laparotomy, performed in 3 cases, was essential for a definitive diagnosis. The data presented here suggest that squamous cell carcinoma of the equine stomach may be increasing in frequency and demonstrate the need for prospective epidemiological studies.