gebhart/patrepeval huggingface dataset:
Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers (2011)

To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ~200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor-normal pairs.
Effect of a 5‐HT1 receptor agonist, CP‐122,288, on oedema formation induced by stimulation of the rat saphenous nerve (1995)

Neurogenic oedema formation in the rat hind paw skin induced by electrical stimulation of the saphenous nerve and measured by extravasation of [ I25 I]‐albumin, was inhibited by the 5‐HT 1B receptor agonist, CP‐93,129, and the novel, tryptamine analogue, CP‐122,288. Significant inhibition of up to 66% of control was observed with CP‐122,288 (2 × 10 14 ‐2 × 10 −7 mol kg −1 ) and CP‐93,129 (5 × 10 −7 ‐5 × 10 −6 mol kg −1 ), with the minimum effective dose for CP‐122,288 being about 10 7 fold less than that for CP‐93,129. Oedema formation induced by the intradermal administration of exogenous mediators (substance P and histamine) in rat dorsal skin was not inhibited by CP‐122,288 (2 × 10 −10 mol kg −1 ). These results suggest that CP‐122,288 is a potent inhibitor of neurogenic inflammation in rat skin and that the effect may be due to a prejunctional inhibition of neuropeptide release.
Single‐cell sequencing and mini‐sequencing for preimplantation genetic diagnosis (2003)

There is increasing interest in the use of preimplantation genetic diagnosis (PGD) as an alternative to routine prenatal diagnosis. However, the costs associated with development and testing of new PGD protocols have forced some PGD centres to limit the number of diseases for which PGD is offered. One of the main factors in the design of new protocols, which affects cost and accuracy, is the choice of the mutation-detection technique. We have assessed the reliability of DNA sequencing and mini-sequencing for clinical diagnosis at the single-cell level and have found them to be rapid and accurate. Extensive optimisation for individual mutations is not usually necessary when employing these versatile techniques and consequently a smaller investment of time and resources should be required during development of new protocols. Additionally, we report single-cell protocols for the diagnoses of cystic fibrosis, sickle cell anaemia and beta-thalassaemia, which utilise mini-sequencing. Unlike most mutation-detection techniques, mini-sequencing permits analysis of very small DNA fragments. Small amplicons experience low allele dropout (ADO) rates, and consequently this approach could potentially improve the reliability of PGD.
Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. (2002)

The PRL family oncogenic phosphatases are attractive targets for developing inhibitors as anticancer therapeutics given their potentially pathogenic role in human malignancies. Herein we demonstrate that pentamidine, an anti-protozoa drug with an unknown mechanism of action, is an inhibitor of PRLs with anticancer potential. Pentamidine at its therapeutic doses inhibited recombinant PRL phosphatases in vitro and inactivated ectopically expressed PRLs in NIH3T3 transfectants with an effective duration more than 24 h after a pulse cell treatment. The drug had in vitro growth-inhibitory activity against human cancer cell lines that express the endogenous PRLs. Pentamidine at a tolerable dose markedly inhibited the growth of WM9 human melanoma tumors in nude mice coincident with the induction of tumor cell necrosis and is capable of inactivating ectopically expressed PRL-2 in the cancer cells. These observations suggest the potential of pentamidine in anticancer therapies and may provide a basis for developing novel PTPase-targeted therapeutics.
Real-time monitoring of circadian clock oscillations in primary cultures of mammalian cells using Tol2 transposon-mediated gene transfer strategy (2010)

The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between circadian oscillator and physiological functions in peripheral tissues. However, it is still difficult to investigate the molecular oscillator in primary culture cells. In this study, we used a novel Tol2 transposon based Dbp promoter or Bmal1 promoter driven luciferase reporter vector system to detect and analyze the intrinsic molecular oscillator in primary culture cells (mouse embryonic fibroblasts, fetal bovine heart endothelial cells and rat astrocytes). The results showed circadian molecular oscillations in all examined primary culture cells. Moreover, the phase relationship between Dbp promoter driven and Bmal1 promoter driven molecular rhythms were almost anti-phase, which suggested that these reporters appropriately read-out the intrinsic cellular circadian clock. Our results indicate that gene transfer strategy using the Tol2 transposon system of a useful and safe non-viral vector is a powerful tool for investigating circadian rhythms in peripheral tissues.
Melatonin Receptor Ligands:  Synthesis of New Melatonin Derivatives and Comprehensive Comparative Molecular Field Analysis (CoMFA) Study (1998)

The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.
Binding of divalent cations to dipalmitoylphosphatidylcholine bilayers and its effect on bilayer interaction (1981)

We have confirmed that CaCl2 swells the multilayer lattice formed by dipalmitolyphosphatidylcholine (DPPC) in an aqueous solution. Specifically, at room temperature 1 mM CaCl2 causes these lipid bilayers to increase their separation, dw, from 19 A in pure water to greater than 90 A. CaCl2 concentrations greater than 4 mM cause less swelling. We have measured the net repulsive force between the bilayers in 30 mM CaCl2 at T = 25 degrees C (below the acyl chain freezing temperature). For interbilayer separations between 30 and 90 A, the dominant repulsion between bilayers is probably electrostatic; Ca2+ binds to DPPc lecithin bilayers, imparting a charge to them. The addition of NaCl to CaCl2 solutions decreases this repulsion. For dw less than 20 A, the bilayer repulsion appears to be dominated by the "hydration forces" observed previously between both neutral and charged phospholipids. From the electrostatic repulsive force, we estimate the extent of Ca2+ binding to the bilayer surface. The desorption and bound Ca2+, apparent when bilayers are pushed together, is more rapid than one would expect if an association constant governed Ca2+ binding. The association affinity does not appear to be a fixed quantity but rather a sensitive function of ionic strength and bilayer separation.
Optimizing cost and performance in online service provider networks (2010)

We present a method to jointly optimize the cost and the performance of delivering traffic from an online service provider (OSP) network to its users. Our method, called Entact, is based on two key techniques. First, it uses a novel route-injection mechanism to measure the performance of alternative paths that are not being currently used, without disturbing current traffic. Second, based on the cost, performance, traffic, and link capacity information, it computes the optimal cost vs. performance curve for the OSP. Each point on the curve represents a potential operating point for the OSP such that no other operating point offers a simultaneous improvement in cost and performance. The OSP can then pick the operating point that represents the desired trade-off (e.g., the sweet spot). We evaluate the benefit and overhead of Entact using trace-driven evaluation in a large OSP with 11 geographically distributed data centers. We find that by using Entact this OSP can reduce its traffic cost by 40% without any increase in path latency and with acceptably low overheads.
Circulating microRNAs in Alzheimer’s disease: the search for novel biomarkers (2013)

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. While advancements have been made in understanding the genetic and molecular basis of AD, the clinical diagnosis of AD remains difficult, and post-mortem confirmation is often required. Furthermore, the onset of neurodegeneration precedes clinical symptoms by approximately a decade. Consequently, there is a crucial need for an early and accurate diagnosis of AD, which can potentially lead to strategies that can slow down or stop the progression of neurodegeneration and dementia. Recent advances in the non-coding RNA field have shown that microRNAs (miRNAs) can function as powerful biomarkers in human diseases. Studies are emerging suggesting that circulating miRNAs in the cerebrospinal fluid and blood serum have characteristic changes in AD patients. Whether miRNAs can be used in AD diagnosis, alone or in combination with other AD biomarkers (e.g., amyloid and tau), warrants further investigation.
Comparative Immunohistochemical Study of Four Monoclonal Antibodies Directed Against Ovarian Carcinoma-Associated Antigens (1991)

The monoclonal antibodies OC 125, OV-TL 3, MOv 18, and OV-TL 23, which are directed against distinct ovarian carcinoma-associated antigens, are assessed in the present study for their diagnostic value. The expression of the antigens defined by these was studied in serial sections from 80 ovarian carcinomas and 103 nonovarian carcinomas obtained from 183 patients, using the immunoperoxidase technique. Immunoelectron microscopy demonstrated that the antigens were all localized on the tumor cell membrane. OC 125, OV-TL 3, and MOv 18 reacted positively with approximately 90% of the ovarian carcinoma samples (n = 80), whereas OV-TL 23 stained 76% of these samples. OC 125, OV-TL 3, and MOv 18 were also reactive with a majority of carcinomas derived from the cervix, endometrium and fallopian tube, while OV-TL 23 reactivity was primarily restricted to ovarian carcinomas. OC 125 and OV-TL 3 reacted respectively with 11% and 14% of the nongynecologic carcinomas tested (n = 64). Positive cases included breast, colon, and lung carcinomas. The antibodies MOv 18 and OV-TL 23 were found less reactive with nongynecologic carcinomas.
Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes (2004)

Exenatide significantly reduced HbA(1c) in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.
Graph Attention Networks (2017)

We present graph attention networks (GATs), novel neural network architectures that operate on graph-structured data, leveraging masked self-attentional layers to address the shortcomings of prior methods based on graph convolutions or their approximations. By stacking layers in which nodes are able to attend over their neighborhoods' features, we enable (implicitly) specifying different weights to different nodes in a neighborhood, without requiring any kind of costly matrix operation (such as inversion) or depending on knowing the graph structure upfront. In this way, we address several key challenges of spectral-based graph neural networks simultaneously, and make our model readily applicable to inductive as well as transductive problems. Our GAT models have achieved or matched state-of-the-art results across four established transductive and inductive graph benchmarks: the Cora, Citeseer and Pubmed citation network datasets, as well as a protein-protein interaction dataset (wherein test graphs remain unseen during training).
Induction of the P2z/P2X7 nucleotide receptor and associated phospholipase D activity by lipopolysaccharide and IFN-γ in the human THP-1 monocytic cell line (1996)

The activation of phospholipase D (PLD) was used as a marker for P2z nucleotide receptor (P2zR) activity in the human THP-1 monocytic cell line. While untreated THP-1 cells displayed little PLD response to the P2zR agonist 3'-O-(4-benzoyl)benzoyl (Bz)ATP, treatment with either IFN-gamma or bacterial LPS induced a BzATP-mediated stimulation of PLD activity. Treatment of cells with combinations of IFN-gamma and LPS resulted in synergistic induction. P2z receptors mediated these effects because: 1) reduction of extracellular divalent cation concentration increased agonist potency; 2) only BzATP or ATP acted as agonist nucleotides; 3) oxidized ATP, an inhibitor of the P2z receptor, abolished the response. The P2zR-stimulated PLD was rapidly activated (t(1/2) = 1.5 min), completely inhibited by KN-62, a calcium-calmodulin kinase II inhibitor, and only partially repressed by bisindolylmaleimide, a protein kinase C inhibitor. The P2zR-mediated PLD activity was distinguished from phorbol ester-stimulated PLD activity because the latter was slowly activated (t(1/2) > 15 min), unaffected by oxidized ATP or KN-62, and completely inhibited by bisindolylmaleimide. IFN-gamma and LPS treatment also synergistically induced P2zR-dependent changes in membrane permeability and cytolysis, as indicated by BzATP-mediated Ca2+ influx, ethidium bromide uptake, and lactate dehydrogenase release. Finally, IFN-gamma and LPS synergistically up-regulated mRNA encoding the P2X7 receptor, a recently cloned ATP-gated channel that exhibits a P2zR phenotype.
Antiproliferative Effects of Interferons -α and -β in Combination with 5-Fluorouracil, Cisplatin, and Cis - and Trans -Retinoic Acid in Three Human Lung Carcinoma Cell Lines (1993)

We assessed the antiproliferative effect of human recombinant interferon -alpha (IFN-alpha) or -beta in combination with 5-fluorouracil (5-FU), cisplatin, or cis- or trans-retinoic acid on two human nonsmall cell lung carcinoma cell lines (SK-LU-1 and SK-MES-1) and on one human small cell lung carcinoma cell line (NCI-H69). Results were obtained by direct cell count and/or by the clonigenic assay. The three cell lines differed in their sensitivities to the antiproliferative effects of the different agents. However, both NSCLC cell lines were more responsive to IFN-beta than to IFN-alpha. The SK-MES cell line was more resistant to both IFNs than the SK-LU-1. The NCI-H69 cells were resistant to all the drugs tested, except trans-retinoic acid. The dose and time of exposure were found to be important factors in the case of IFNs and cytotoxic agents, with lower surviving fractions obtained with the higher doses and longer exposures. This finding, however, did not hold true for the retinoic acids, which showed no antiproliferative effect. Within the sensitivity of our system, we did not identify any synergistic interaction in any of the cell lines with IFN-alpha or IFN-beta and 5-FU or cisplatin. A slight synergistic interaction was observed with IFN and cis- or trans-retinoic acid in the SK-LU-1 cell line which was not thought to be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibitors of metabolism rescue cell death in Huntington's disease models (2007)

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder. HD is caused by polyglutamine expansions in the huntingtin (htt) protein that result in neuronal loss and contribute to HD pathology. The mechanisms of neuronal loss in HD are elusive, and there is no therapy to alleviate HD. To find small molecules that slow neuronal loss in HD, we screened 1,040 biologically active molecules to identify suppressors of cell death in a neuronal cell culture model of HD. We found that inhibitors of mitochondrial function or glycolysis rescued cell death in this cell culture and in in vivo HD models. These inhibitors prevented cell death by activating prosurvival ERK and AKT signaling but without altering cellular ATP levels. ERK and AKT inhibition through the use of specific chemical inhibitors abrogated the rescue, whereas their activation through the use of growth factors rescued cell death, suggesting that this activation could explain the protective effect of metabolic inhibitors. Both ERK and AKT signaling are disrupted in HD, and activating these pathways is protective in several HD models. Our results reveal a mechanism for activating prosurvival signaling that could be exploited for treating HD and possibly other neurodegenerative disorders.
Pretargeted radioimmunotherapy of cancer: progress step by step. (2003)

To enhance the therapeutic efficacy of radioimmunotherapy of cancer, several pretargeting strategies have been developed. In pretargeted radioimmunotherapy, the tumor is pretargeted with an antibody construct that has affinity for the tumor-associated antigen on the one hand and for a radiolabeled hapten on the other. The radiolabeled hapten is administered in a later phase, preferably after the antibody construct has cleared from the circulation. In pretargeted radioimmunotherapy, 2 main approaches can be distinguished: pretargeting strategies based on the avid interaction between streptavidin (SA) or avidin and biotin, and pretargeting strategies based on the use of bispecific antibodies. In pretargeting strategies based on biotin and SA or avidin, the use of a clearing agent that could remove the pretargeting construct from the circulation markedly improved the targeting of the radiolabeled biotin to the tumor. Thus, multistep injection schemes in which 3-5 different agents are subsequently injected were developed. In bispecific antibody-based pretargeting strategies, the use of bivalent haptens improved the efficacy of the tumor targeting, and a 2-step pretargeted radioimmunotherapy strategy is now being tested in cancer patients. Preclinical studies as well as studies on cancer patients have shown that these pretargeting strategies can result in higher radiation doses to the tumor than can directly radiolabeled antitumor antibodies. Here, the development and state of the art of the most effective approaches for pretargeted radioimmunotherapy are reviewed.
The products of the yeast MMS2 and two human homologs (hMMS2 and CROC- 1) define a structurally and functionally conserved Ubc-like protein family (1998)

Eukaryotic genes encoding ubiquitin-congugating enzyme (Ubc)-like proteins have been isolated from both human and yeast cells. The CROC-1 gene was isolated by its ability to transactivate c- fos expression in cell culture through a tandem repeat enhancer sequence. The yeast MMS2 gene was cloned by its ability to complement the methyl methanesulfonate sensitivity of the mms2-1 mutant and was later shown to be involved in DNA post-replication repair. We report here the identification of a human MMS2 ( hMMS2 ) cDNA encoding a novel human Ubc-like protein. hMMS2 and CROC-1 share >90% amino acid sequence identity, but their DNA probes hybridize to distinct transcripts. hMMS2 and CROC-1 also share approximately 50% identity and 75% similarity with the entire length of yeast Mms2. Unlike CROC-1 , whose transcript appears to be elevated in all tumor cell lines examined, the hMMS2 transcript is only elevated in some tumor cell lines. Collectively, these results indicate that eukaryotic cells may contain a highly conserved family of Ubc-like proteins that play roles in diverse cellular processes, ranging from DNA repair to signal transduction and cell differentiation. The hMMS2 and CROC-1 genes are able to functionally complement the yeast mms2 defects with regard to sensitivity to DNA damaging agents and spontaneous mutagenesis. Conversely, both MMS2 and hMMS2 were able to transactivate a c- fos - CAT reporter gene in Rat-1 cells in a transient co-transfection assay. We propose that either these proteins function in a common cellular process, such as DNA repair, or they exert their diverse biological roles through a similar biochemical interaction relative to ubiquitination.