gebhart/patrepeval huggingface dataset:
Identification of a Small Molecule with Synthetic Lethality for K-Ras and Protein Kinase C Iota (2008)

K-Ras mutations are frequently found in various cancers and are associated with resistance to treatment or poor prognosis. Similarly, poor outcomes have recently been observed in cancer patients with overexpression of protein kinase C iota (PKCiota), an atypical protein kinase C that is activated by oncogenic Ras protein and is required for K-Ras-induced transformation and colonic carcinogenesis in vivo. Thus far, there is no effective agent for treatment of cancers with K-Ras mutations or PKCiota overexpression. By synthetic lethality screening, we identified a small compound (designated oncrasin-1) that effectively kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations. The cytotoxic effects correlated with apoptosis induction, as was evidenced by increase of apoptotic cells and activation of caspase-3 and caspase-8 upon the treatment of oncrasin-1 in sensitive cells. Treatment with oncrasin-1 also led to abnormal aggregation of PKCiota in the nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1-induced apoptosis was blocked by siRNA of K-Ras or PKCiota, suggesting that oncrasin-1 is targeted to a novel K-Ras/PKCiota pathway. The in vivo administration of oncrasin-1 suppressed the growth of K-ras mutant human lung tumor xenografts by >70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity. Our results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents, which effectively kill K-Ras mutant cancer cells.
Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF (2011)

The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.
Selenium Capture Using Sorbent Powders:  Mechanism of Sorption by Hydrated Lime (1996)

This study investigates the potential of mineral sorbents to capture selenium which is sufficiently volatile to occur in the flue gas in vapor state. The sorption studies are conducted in a high-temperature reactor using SeO2 as the source of selenium. In both high (800−1000 °C) and medium-temperature (400−700 °C) range, hydrated lime exhibits superior selenium sorption capability compared to other sorbent powders. The results show that the mechanism of capture by Ca(OH)2 is not a simple physical adsorption process but seems to involve a chemical reaction between CaO and SeO2. The medium temperature range of 400−600 °C is favorable for the reaction to occur and leads to high selenium sorption. At higher temperatures, thermodynamic equilibrium aids dissociation of the reaction product, and the amount of metal capture reduces drastically with increasing temperature. XRD studies further confirm that calcium selenite is the dominant reaction product.
Oasis®: an innovative alternative dressing for chronic wounds (2001)

Chronic wounds in patients with multiple systemic factors present a significant clinical challenge for clinicians. Oasis Wound Dressing is derived from porcine small intestine which, when placed in a non-infected wound, stimulates new tissue and an absorbable, natural template for the growth of new tissue. Emerging evidence suggests that it is beneficial for patients with chronic, non-healing wounds complicated by multiple systemic factors.
Respiratory syncytial virus--how soon will we have a vaccine? (1995)

Xq28.18 This site (FraX-E) is folate sensitive. Cytogenetically it is virtually indistinguishable from FraX-A. The molecular abnormality in FraX-E does appear to expand through generations though perhaps not as consistently as in FraX-A.19 Mental retardation is usually mild. Individuals have amplifications of a GCC repeat.20 A third fragile site, FraX-F, has been identified in Xq27-q28.21 Using fluorescent in situ hybridisation (FISH) the site has been shown to lie distal to FraX-A and on July 11, 2023 by guest.
Influence of graded dehydration on hyperthermia and cardiovascular drift during exercise (1992)

This investigation determined the effect of different rates of dehydration, induced by ingesting different volumes of fluid during prolonged exercise, on hyperthermia, heart rate (HR), and stroke volume (SV). On four different occasions, eight endurance-trained cyclists [age 23 +/- 3 (SD) yr, body wt 71.9 +/- 11.6 kg, maximal O2 consumption 4.72 +/- 0.33 l/min] cycled at a power output equal to 62-67% maximal O2 consumption for 2 h in a warm environment (33 degrees C dry bulb, 50% relative humidity, wind speed 2.5 m/s). During exercise, they randomly received no fluid (NF) or ingested a small (SF), moderate (MF), or large (LF) volume of fluid that replaced 20 +/- 1, 48 +/- 1, and 81 +/- 2%, respectively, of the fluid lost in sweat during exercise. The protocol resulted in graded magnitudes of dehydration as body weight declined 4.2 +/- 0.1, 3.4 +/- 0.1, 2.3 +/- 0.1, and 1.1 +/- 0.1%, respectively, during NF, SF, MF, and LF. After 2 h of exercise, esophageal temperature (Tes), HR, and SV were significantly different among the four trials (P < 0.05), with the exception of NF and SF. The magnitude of dehydration accrued after 2 h of exercise in the four trials was linearly related with the increase in Tes (r = 0.98, P < 0.02), the increase in HR (r = 0.99, P < 0.01), and the decline in SV (r = 0.99, P < 0.01). LF attenuated hyperthermia, apparently because of higher skin blood flow, inasmuch as forearm blood flow was 20-22% higher than during SF and NF at 105 min (P < 0.05). There were no differences in sweat rate among the four trials. In each subject, the increase in Tes from 20 to 120 min of exercise was highly correlated to the increase in serum osmolality (r = 0.81-0.98, P < 0.02-0.19) and the increase in serum sodium concentration (r = 0.87-0.99, P < 0.01-0.13) from 5 to 120 min of exercise. In summary, the magnitude of increase in core temperature and HR and the decline in SV are graded in proportion to the amount of dehydration accrued during exercise.
Development and Testing of AIDS Vaccines (1988)

Recent advances in delineating the molecular biology of human immunodeficiency virus type 1 (HIV-1) have led to innovative approaches to development of a vaccine for acquired immunodeficiency syndrome (AIDS). However, the lack of understanding of mechanisms of protective immunity against HIV-1, the magnitude of genetic variation of the virus, and the lack of effective animal models for HIV-1 infection and AIDS have impeded progress. The testing of AIDS vaccines also presents challenges. These include liability concerns over vaccine-related injuries; identification of suitable populations for phase 3 efficacy studies; balancing the ethical obligation to counsel research subjects to avoid high-risk behavior with the necessity to obtain vaccine efficacy data; and the effect of vaccine-induced seroconversion on the recruiting and welfare of trial volunteers. Several candidate AIDS vaccines are nevertheless currently under development, and some are undergoing phase 1 clinical trials. Rapid progress will depend on continued scientific advancement in conjunction with maximum use of resources, open information and reagent exchange, and a spirit of international collaboration.
Dependence of Interface State Density on Silicon Thermal Oxidation Process Variables (1979)

The structural or intrinsic type of interface state charge, related to thermal oxidation and annealing processes, has been characterized with respect to silicon thermal oxidation variables using quasistatic C‐V techniques. Those variables include oxidation ambient (, , ), annealing/cooling ambient (, , Ar), oxidation temperature (800°–1200°C), silicon type (p‐ and n‐type), and orientation [(111) and (100)]. Oxides (1200–2200Å thick) annealed and cooled from any oxidation temperature in nitrogen or argon exhibit large interface state densities as oxidized. However after a low temperature hydrogen anneal these densities are lower than those of comparable oxygen‐cooled oxides. Interface state densities of oxides cooled in oxygen vary inversely with oxidation temperature before and after postmetallization anneals. This temperature relationship is very similar to that reported previously for oxide fixed charge and helps to substantiate a model based on a common origin of interface states and oxide fixed charge.
Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies (2007)

Chimeric T-cell receptors (ChTCR), are a fascinating technological step in the field of immunotherapy for orienting the activity of immune cells towards specific molecular targets expressed on the cell surface of various tumors, including hematologic malignancies. The main characteristics of ChTCR are their ability to redirect T-cell specificity and their killing/effector activity toward a selected target in a non MHC-restricted manner, exploiting the antigen binding properties of monoclonal antibodies. ChTCR are, in fact, artificial T-cell receptors constituted by an antigen-recognizing antibody molecule linked to a T-cell triggering domain. Various hematologic malignancies represent optimal targets for the exploitation of ChTCR, because of the bright expression of specific antigens on the surface of tumor cells. Thus, CD19 and CD20 have been targeted for B-cell lymphoid tumors (acute lymphoblastic leukemia-ALL, lymphomas and chronic lymphocytic leukemia-CLL), CD33 for myeloid leukemia, and CD30 for lymphomas. Even though technical and safety progresses are still needed to improve the profile of gene transfer and protein expression of ChTCR, phase 1 trials will be carried out in the near future to demonstrate the feasibility of their clinical translation and, it is be hoped, give preliminary indications about their anti-tumor efficacy.
Vascular Endothelial Growth Factor Induces Endothelial Fenestrations In Vitro (1998)

Vascular endothelial growth factor (VEGF) is an important regulator of vasculogenesis, angiogenesis, and vascular permeability. In contrast to its transient expression during the formation of new blood vessels, VEGF and its receptors are continuously and highly expressed in some adult tissues, such as the kidney glomerulus and choroid plexus. This suggests that VEGF produced by the epithelial cells of these tissues might be involved in the induction or maintenance of fenestrations in adjacent endothelial cells expressing the VEGF receptors. Here we describe a defined in vitro culture system where fenestrae formation was induced in adrenal cortex capillary endothelial cells by VEGF, but not by fibroblast growth factor. A strong induction of endothelial fenestrations was observed in cocultures of endothelial cells with choroid plexus epithelial cells, or mammary epithelial cells stably transfected with cDNAs for VEGF 120 or 164, but not with untransfected cells. These results demonstrate that, in these cocultures, VEGF is sufficient to induce fenestrations in vitro. Identical results were achieved when the epithelial cells were replaced by an epithelial-derived basal lamina-type extracellular matrix, but not with collagen alone. In this defined system, VEGF-mediated induction of fenestrae was always accompanied by an increase in the number of fused diaphragmed caveolae-like vesicles. Caveolae, but not fenestrae, were labeled with a caveolin-1-specific antibody both in vivo and in vitro. VEGF stimulation led to VEGF receptor tyrosine phosphorylation, but no change in the distribution, phosphorylation, or protein level of caveolin-1 was observed. We conclude that VEGF in the presence of a basal lamina-type extracellular matrix specifically induces fenestrations in endothelial cells. This defined in vitro system will allow further study of the signaling mechanisms involved in fenestrae formation, modification of caveolae, and vascular permeability.
Inhibitory Effect of NS‐398, a Selective Cyclooxygenase‐2 Inhibitor, on Azoxymethane‐induced Aberrant Crypt Foci in Colon Carcinogenesis of F344 Rats (1997)

Prostaglandin E2, which is produced by cyclooxygenase (COX) during arachidonic acid metabolism, is considered to be related to colon carcinogenesis. Therefore, the effect of NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide), a COX-2 inhibitor, was examined in azoxymethane (AOM)-induced colon carcinogenesis in rats in this study. In the first experiment, groups 1-3 were treated with AOM (15 mg/kg, s.c.) 3 times at intervals of a week from 5 weeks of age. Groups 2 and 3 were respectively given 1 mg/kg and 10 mg/kg of NS-398 in 5% gum arabic aqueous solution 3 times per week by oral gavage during the experiment. Six weeks after the first exposure to AOM, aberrant crypt foci (ACF) were counted in the colonic mucosa of all rats. The mean occurrence of ACF per length in rats given 1 mg/kg b.w. or 10 mg/kg b.w. of NS-398 was reduced to 65.7% or 52.8%, respectively, of that in rats treated with only AOM. Levels of COX-2 mRNA expression in groups treated with AOM, regardless of NS-398, were slightly higher than that in the group treated with NS-398 alone as judged from reverse transcription-polymerase chain reaction analysis. In the second experiment, the effect of NS-398 at different times, i.e., during initiation and post-initiation, was examined. Treatment with NS-398 in both phases significantly inhibited the appearance of ACF. The results imply that NS-398 might have a chemopreventive potential.
Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells (2012)

Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.
Diagnosis and management of anaemia of chronic disease: current status (2011)

Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future.
Studies on biologically active halogenated compounds. II. Chemical modifications of 6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone and the CNS depressant activities of related compounds. (1979)

A number of derivatives of 6-amino-2-fluoromethyl-3-(o-tolyl)-4 (3H)-quinazolinone (15), a potent muscle relaxant, have been prepared and screened in terms of the loss of righting reflex test and the rotating rod test in mice. Several derivatives with additional fluorine substitution or with repositioning of the fluorine atom exhibited high activities. Other structural modifications included acylation, carbamoylation, and alkoxycarbonylation of the 6-amino group, hydroxylation at the 3-tolyl group, and replacement of the fluorine atom at the 2-fluoromethyl group by oxygen, nitrogen, and sulfur nucleophiles ; these modifications all resulted in loss of activity.
Monte Carlo simulation of topological defects in the nematic liquid crystal matrix around a spherical colloid particle (1997)

We use a Monte Carlo algorithm to simulate the director field around a spherical inclusion in a uniform nematic liquid crystal matrix. The resulting structure crucially depends on the relative strength of the nematic bulk elasticity and the director anchoring on the particle surface. When this anchoring is weak, the director field perturbations are small and have quadrupolar symmetry. With increasing strength of anchoring two topologically nontrivial situations are possible: a dipolar configuration with a satellite point defect (hedgehog) near the particle pole, or a quadrupolar configuration with a ``Saturn ring'' of disclination around the particle equator.
Distribution of prostaglandin IP and EP receptor subtypes and isoforms in platelets and human umbilical artery smooth muscle cells (1998)

Prostaglandins act through specific receptors to stimulate cyclic AMP formation which inhibits platelet activation and relaxes vascular smooth muscle. We have used RT-PCR combined with Southern blot analysis to determine the subtypes of prostaglandin receptor on platelets. Platelets expressed the EP4 rather than the EP2 prostaglandin EP receptor subtype, whereas vascular smooth muscle cells predominantly expressed the EP2 receptor. The IP receptor, which binds prostacyclin and couples to stimulation of adenylyl cyclase, and three isoforms of the inhibitory EP3 receptor were equally expressed in platelets, HEL cells and umbilical artery smooth muscle cells. The EP3-II isoform showed variation in level of expression among the three cell types. As a positive control for the presence of platelet RNA, PCR was performed using primers specific for the alpha chain of the platelet membrane glycoprotein Ib. As a negative control for the absence of T and B cell contamination in the platelet RNA, PCR was performed using primers specific for the cell specific cluster determinants CD2 (a T-cell marker) and CD20 (a B-cell marker). The finding that platelets express both stimulatory and inhibitory prostaglandin receptors provides confirmation of a homeostatic model of regulation of platelet adenylyl cyclase previously proposed.
Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat (2002)

Because of the suggested role of energy consumption and the well-documented role of estrogens in the etiology of breast cancer, we have examined the effect of a 40% restriction of dietary energy consumption on the ability of administered 17beta-estradiol (E2) to induce mammary tumorigenesis in female ACI rats. Experiments herein test the hypothesis that at least part of the inhibitory effect of energy restriction on mammary tumorigenesis is exerted downstream of potential effects of dietary manipulation on the production of estrogens by the ovaries. Ovary-intact ACI rats were fed a control or a 40% energy-restricted diet and were either treated continuously with E2 from subcutaneous Silastic tubing implants or received no hormone treatment. Mammary cancers rapidly developed in E2-treated rats fed the control diet; within 216 days of initiation of E2 treatment 100% of the population at risk exhibited palpable mammary tumors. Dietary energy restriction markedly inhibited E2-induced mammary tumorigenesis, as evidenced by significant reductions in cancer incidence and tumor burden as well as a significant increase in the latency to the appearance of the first palpable cancer. The inhibitory actions of dietary energy restriction on E2-induced mammary tumorigenesis were associated with an inhibition of E2-stimulated mammary cell proliferation. However, this inhibition was insufficient to block induction of lobuloalveolar hyperplasia or appearance of focal regions of atypical epithelial hyperplasia. These data suggest that dietary energy restriction inhibits E2-induced mammary cancer by attenuating or retarding the progression of atypical hyperplasia to carcinoma. Expression of progesterone receptor (PR) was up-regulated within the focal regions of atypical hyperplasia and the carcinomas induced by E2, regardless of whether the rats were fed the control or energy-restricted diet. However, circulating progesterone was reduced by dietary energy restriction, suggesting a possible mechanism for inhibition of mammary tumorigenesis. Dietary energy restriction did not inhibit the ability of administered E2 to induce prolactin (PRL)-producing pituitary tumors and associated hyperprolactinemia, indicating that the inhibitory effects of dietary energy restriction on mammary tumorigenesis are tissue specific and independent of circulating E2 and PRL.
Methodology for Locking Feature Selection in Integral Snap-Fit Assembly (1997)

Abstract While every step in a systematic approach to the design of an assembly for integral attachment using snap-fit features is important, none is more important than the selection of locking features. After all, it is these features that hold the assembly together. Comprised of a latch and catch component, locking pairs must themselves be selected using a systematic approach. This paper presents that approach as a six-step methodology, after defining and describing latch and catch components. It then demonstrates the methodology using a case study taken from real life.