gebhart/patrepeval huggingface dataset:
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer (2011)

The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER is a major clinical challenge. Here, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. In this context, cyclin D1 expression and retinoblastoma tumor suppressor protein (RB) phosphorylation are maintained even with efficient ablation of ER with pure antagonists. These therapy-resistant models recapitulate a key feature of deregulated RB/E2F transcriptional control. Correspondingly, a gene expression signature of RB-dysfunction is associated with luminal B breast cancer, which exhibits a relatively poor response to endocrine therapy. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed. Importantly, PD-0332991 led to a stable cell cycle arrest that was fundamentally distinct from those elicited by ER antagonists, and was capable of inducing aspects of cellular senescence in hormone therapy refractory cell populations. These findings underscore the clinical utility of downstream cytostatic therapies in treating tumors that have experienced failure of endocrine therapy.
Message waiting time performance for meteor-burst communication systems (1989)

The performance is investigated of the meteor-burst channel in terms of the waiting time required to reliably transmit a message of length N bits. Two modulation techniques are considered. The first is the traditional fixed-rate modulation scheme where the modem operates at a constant bit rate whenever the channel is available for message traffic. The second is an adaptive modulation method where the channel symbol rate varies continuously to match the time-varying signal-to-noise ratio at the receiver. Upper and lower bounds on waiting time for the general case are derived using probabilistic arguments. Novel closed-form expressions for waiting time and optimal bit rate are derived for the fixed-rate modem. Bounds on mean waiting time are derived for the adaptive-symbol-rate modem. It is shown that for fixed-rate modems operating at the optimal bit rate and for adaptive modems operating at a minimum bit rate equal to this rate, the improvement in mean waiting time can never exceed a factor of two.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Coherent Filterless Wideband Microwave/Millimeter-Wave Channelizer Based on Broadband Parametric Mixers (2014)

An essential capability in many applications, ranging from commercial, surveillance and defense, is to analyze the spectral content of intercepted microwave and millimeter-wave signals over a very wide bandwidth in real-time and with high resolution. A range of photonic schemes have been introduced for the real-time processing of wideband signals to overcome limitations of current conventional electronic frequency measurement approaches. Here, a novel microwave/millimeter-wave channelizer is presented based on a RF photonic front-end employing parametric wavelength multicasting and comb generation. This new technology enables a contiguous bank of channelized coherent I/Q IF signals covering extremely wide RF instantaneous bandwidth. High channel counts and wide RF instantaneous bandwidth are enabled by use of parametrically generated frequency-locked optical combs spanning >4 THz. Full field analysis capabilities of the coherent detection system are demonstrated by frequency domain analysis of 18 contiguous 1.2 GHz IF channels covering 15.5 GHz to 37.1 GHz input frequency range, and time and spectral domain analysis of a 75 GHz harmonically generated input signal. Sensitivity and dynamic range of the system are analyzed and discussed.
Salivary Gland NK Cells Are Phenotypically and Functionally Unique (2011)

Natural killer (NK) cells and CD8(+) T cells play vital roles in containing and eliminating systemic cytomegalovirus (CMV). However, CMV has a tropism for the salivary gland acinar epithelial cells and persists in this organ for several weeks after primary infection. Here we characterize a distinct NK cell population that resides in the salivary gland, uncommon to any described to date, expressing both mature and immature NK cell markers. Using RORγt reporter mice and nude mice, we also show that the salivary gland NK cells are not lymphoid tissue inducer NK-like cells and are not thymic derived. During the course of murine cytomegalovirus (MCMV) infection, we found that salivary gland NK cells detect the infection and acquire activation markers, but have limited capacity to produce IFN-γ and degranulate. Salivary gland NK cell effector functions are not regulated by iNKT or T(reg) cells, which are mostly absent in the salivary gland. Additionally, we demonstrate that peripheral NK cells are not recruited to this organ even after the systemic infection has been controlled. Altogether, these results indicate that viral persistence and latency in the salivary glands may be due in part to the presence of unfit NK cells and the lack of recruitment of peripheral NK cells.
Improving Erucic Acid Content in Rapeseed through Biotechnology: What Can the Arabidopsis FAE1 and the Yeast SLC1‐1 Genes Contribute?1,2 (2001)

The main goal of our research is to produce, by genetic manipulation, Brassica napus L. cultivars with higher amounts of 22:1 in their seed oil than in present Canadian high erucic acid rapeseed (HEAR) cultivars developed through traditional breeding, ideally with proportions of 22:1 approaching 80 mol% (828 g kg −1 ). To probe some rate‐limiting steps in the accumulation of triacylglycerols containing very long chain fatty acids (VLCFAs), particularly erucic acid (22:1), we have taken a transgenic approach, studying the effect of expressing two target genes in HEAR B. napus cv. Hero. To study the role of the elongase complex, involved in elongation of C 18 fatty acid moieties to produce VLCFAs, we expressed the Arabidopsis thaliana L., fatty acid elongase 1 ( FAE1 ) gene under the control of a seed‐specific promoter (napin), in Hero. This resulted in increased proportions of 22:1 in the seed oil, rising from 430 g kg −1 in non‐transformed controls to 480 to 530 g kg −1 22:1 in FAE1 transgenic Hero lines. The FAE1 lines exhibited higher elongase activity in vitro compared to control lines. These data suggest that the level of active condensing enzyme in the native elongase complex is somewhat rate limiting for synthesis of erucic acid and other VLCFAs in HEAR. In small scale field trials, the VLCFA and 22:1 content of FAE1 transgenic lines were superior to field‐grown control lines. We report that in field plot trials, the progeny of our best T 4 B. napus cv. Hero SLC1‐1 transgenic lines clearly out‐performed controls in terms of 22:1, oil content, and yield.
Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients (2009)

We have constructed and cross-platform validated a gene expression profile predictive for LR after BCT, which is characterized by genes involved in cell proliferation but not a surrogate for high histologic grade.
Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). (1993)

A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.
P1A Recombinant β-Lactamase Prevents Emergence of Antimicrobial Resistance in Gut Microflora of Healthy Subjects during Intravenous Administration of Ampicillin (2009)

Ipsat P1A is a recombinant beta-lactamase which degrades antibiotic residue in the gastrointestinal tract. In an open-label, single-center controlled trial, 36 healthy subjects were randomized to receive (i) ampicillin (1 g intravenously [i.v.] every 6 h [q6h]), (ii) oral P1A recombinant beta-lactamase (8.2 mg q6h), or (iii) ampicillin (1 g i.v. q6h) in combination with oral P1A recombinant beta-lactamase (8.2 mg q6h) for 5 days. Fecal samples were collected before treatment, during treatment (days 3 to 5), and at follow-up (day 12). The primary end points were (i) changes in gastrointestinal microflora (determined by temperature gradient gel electrophoresis [TGGE]) and (ii) emergence of bacterial resistance (determined by conventional microbiology and PCR of TEM beta-lactamase genes). Thirty-five subjects completed the study. The mean similarity percentages of TGGE profiles between baseline and each treatment day sample were significantly lower for the ampicillin group than for the group receiving ampicillin plus P1A recombinant beta-lactamase on days 3, 4, and 5 (P < 0.001). Compared with the ampicillin group, subjects receiving ampicillin plus P1A recombinant beta-lactamase had significantly fewer ampicillin-resistant coliforms on days 3, 4, and 5 and at follow-up (P < or = 0.001) and fewer TEM beta-lactamase genes on days 3, 4, and 5 (P < 0.02). P1A recombinant beta-lactamase was safe and well tolerated. In healthy subjects, P1A recombinant beta-lactamase prevents ampicillin-induced alterations in intestinal microflora, emergence of resistance, and the number of TEM genes.
The Effects of Unfractionated Heparin on Survival in Patients with Malignancy – A Systematic Review (1999)

Clinical and experimental studies have suggested that unfractionated heparin (UFH) effects malignancy progression. We reviewed all published clinical reports concerning the effects of UFH, as compared to no treatment on survival of cancer patients. Studies were classified on methodological strength and subdivided as to whether therapeutic or prophylactic dosages of UFH were used. Mortality rates after 3 years were extracted or calculated. One randomized study that evaluated the use of UFH in therapeutic dosages in patients with small cell lung carcinoma reported on an improved survival (odds ratio (OR) 0.64; 95% confidence interval (CI): 0.25 to 1.62). A detrimental effect was observed in 2 randomized studies which investigated the effects of intraportal UFH treatment in a prophylactic dose after surgery for gastrointestinal cancer (OR 1.66; 95% CI: 1.02 to 2.71). In contrast, level 2 studies in which either therapeutic or prophylactic dosages of UFH on mortality of patients with gastrointestinal cancer were evaluated, showed OR of 0.58 (95% CI; 0.11-3.13) and 0.65 (95% CI 0.51 to 0.84), respectively. We conclude that there is no convincing evidence of either positively or negatively effects of UFH on survival of patients with malignancy.
Pharmacotherapy of obesity in the near term (2003)

Purpose of review Description of the progress of pharmacotherapy for obesity. Recent findings Eating behavior is regulated by a highly complex and redundant homeostatic system set to ensure positive energy balance. Numerous agents of varying mechanisms have been studied for weight loss but few have progressed to clinical use. After a review of manuscripts on known mechanisms of and pharmacotherapy of obesity, these were summarized. Summary Existing therapies offer only modest weight loss as compared with placebo therapy. Some drugs, such as bupropion, topiramate, and zonisamide, which are used for other indications, have weight loss effects. Combinations of medications may induce greater weight loss than individual therapies. Although numerous agents are under investigation for the treatment of obesity, few, if any, novel agents are likely to be available in the near term.
Detailed Technical Analysis of Urine RNA-Based Tumor Diagnostics Reveals ETS2/Urokinase Plasminogen Activator to Be a Novel Marker for Bladder Cancer (2007)

The described methodology for RNA marker detection in urine appears to be clinically applicable. The ratio of ETS2 mRNA to uPA mRNA in urine is a potential marker for bladder cancer.
Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism (2008)

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.
Reduced Hippocampal Functional Connectivity in Alzheimer Disease (2007)

These findings suggest a functional disconnection between the hippocampus and other brain regions in patients with Alzheimer disease.
A Novel Mammalian Flavin-dependent Histone Demethylase (2009)

Methylation of Lys residues on histone proteins is a well known and extensively characterized epigenetic mark. The recent discovery of lysine-specific demethylase 1 (LSD1) demonstrated that lysine methylation can be dynamically controlled. Among the histone demethylases so far identified, LSD1 has the unique feature of functioning through a flavin-dependent amine oxidation reaction. Data base analysis reveals that mammalian genomes contain a gene (AOF1, for amine-oxidase flavin-containing domain 1) that is homologous to the LSD1-coding gene. Here, we demonstrate that the protein encoded by AOF1 represents a second mammalian flavin-dependent histone demethylase, named LSD2. The new demethylase is strictly specific for mono- and dimethylated Lys4 of histone H3, recognizes a long stretch of the H3 N-terminal tail, senses the presence of additional epigenetic marks on the histone substrate, and is covalently inhibited by tranylcypromine. As opposed to LSD1, LSD2 does not form a biochemically stable complex with the C-terminal domain of the corepressor protein CoREST. Furthermore, LSD2 contains a CW-type zinc finger motif with potential zinc-binding sites that are not present in LSD1. We conclude that mammalian LSD2 represents a new flavin-dependent H3-Lys4 demethylase that features substrate specificity properties highly similar to those of LSD1 but is very likely to be part of chromatin-remodeling complexes that are distinct from those involving LSD1.
Presence of Epstein-Barr virus in extranodal T-cell lymphomas: differences in relation to site (1994)

T-cell lymphomas with similar morphology but with different sites of origin have a different clinical behavior. The theoretical explanation for this finding originates from the hypothesis that non-Hodgkin's lymphomas (NHLs) are neoplastic equivalents of immunological reactions involving tissue-restricted lymphocytes. This hypothesis also implies that T-NHLs originating from different sites differ in their genesis, and thus may differ in oncogen expression, expression of adhesion molecules, or presence of certain DNA/RNA viral sequences. Therefore, we have investigated in T-cell lymphomas with similar morphology originating from different sites, ie, nose (n = 5; all pleomorphic small- or medium- and large-cell T-cell lymphomas [PTL]), skin (PTL, n = 6; anaplastic large-cell [ALCL], n = 11), gut (PTL, n = 8; ALCL, n = 4), and lung (PTL, n = 6), the presence of Epstein-Barr virus (EBV) at the DNA, RNA (EBER 1 and EBER 2), and protein level (LMP-1). A double- staining technique was used to detect EBER 1/2, LMP-1, and differentiation markers at the single-cell level. High numbers of EBER 1/2-positive tumor cells (&gt; 100 per medium power field [mpf]) were found in five of five nasal T-cell lymphomas, none of 17 primary cutaneous T-cell lymphomas, one of 12 gastrointestinal T-cell lymphomas (ALCL), and two of six pulmonary T-cell lymphomas. These lymphomas are therefore called EBV-associated lymphomas. In contrast to our earlier findings in lymph nodes, no extranodal lymphomas were found, with only a few EBV-positive tumor cells. Five gastrointestinal cases positive for EBV by polymerase chain reaction (PCR) showed that EBER 1/2 was only found in sporadic nonneoplastic, ie, reactive lymphocytes. Angiocentricity was present in 18 PTL and one ALCL, but not associated with the presence of EBV. These results indicate that the presence of EBV in extranodal T-cell lymphomas is site-restricted and argues for a different pathogenesis of T-cell lymphomas with similar morphology but originating from different sites. The presence of EBV in most tumor cells in these EBV-associated lymphomas suggests that when present, EBV might be important in the pathogenesis of these lymphomas.
Effect of Different Lipid Systems on Antioxidant Activity of Rosemary Constituents Carnosol and Carnosic Acid with and without α-Tocopherol (1996)

The effect of oxidizing lipid substrate on the antioxidant activity of carnosol and carnosic acid were evaluated in bulk and emulsified systems. In bulk methyl linoleate, carnosic acid was a better antioxidant than carnosol on the basis of conjugated diene hydroperoxide formation, and both were more active than α-tocopherol. However, in linoleic acid carnosol was more active than carnosic acid. In bulk corn oil triglycerides, α-tocopherol exhibited the most antioxidant activity followed by carnosic acid and carnosol. In all emulsified systems, α-tocopherol consistently exhibited more antioxidant activity than carnosol and carnosic acid. In mixtures, carnosol decreased and carnosic acid increased the oxidative stability of α-tocopherol in corn oil. During oxidation carnosic acid and carnosol are converted to unknown compounds which exhibit antioxidant activity. The type and polarity of the lipid system used as a model substrate significantly affect the antioxidant activity of carnosol and carnosic acid. Keywords: Antioxidants; a-tocopherol; carnosol; carnosic acid; methyl linoleate; linoleic acid; corn oil; oil; emulsion; synergism
Design of Ca2+‐independent Staphylococcus aureus sortase A mutants (2012)

Abstract The catalytic activity of Staphylococcus aureus sortase A (SaSrtA) is dependent on Ca 2+ , because binding of Ca 2+ to Glu residues distal to the active site stabilizes the substrate binding site. To obtain Ca 2+ ‐independent SaSrtA, we substituted two Glu residues in the Ca 2+ ‐binding pocket (Glu 105 and Glu 108 ). Although single mutations decreased SaSrtA activity, mutations of both Glu 105 and Glu 108 resulted in Ca 2+ ‐independent activity. Kinetic analysis suggested that the double mutations affect the substrate binding site, without affecting substrate specificity. This approach will allow us to develop SaSrtA variants suitable for various applications, including in vivo site‐specific protein modification and labeling. Biotechnol. Bioeng. 2012; 109: 2955–2961. © 2012 Wiley Periodicals, Inc.
Cloning and characterization of human protease-activated receptor 4 (1998)

Protease-activated receptors 1-3 (PAR1, PAR2, and PAR3) are members of a unique G protein-coupled receptor family. They are characterized by a tethered peptide ligand at the extracellular amino terminus that is generated by minor proteolysis. A partial cDNA sequence of a fourth member of this family (PAR4) was identified in an expressed sequence tag database, and the full-length cDNA clone has been isolated from a lymphoma Daudi cell cDNA library. The ORF codes for a seven transmembrane domain protein of 385 amino acids with 33% amino acid sequence identity with PAR1, PAR2, and PAR3. A putative protease cleavage site (Arg-47/Gly-48) was identified within the extracellular amino terminus. COS cells transiently transfected with PAR4 resulted in the formation of intracellular inositol triphosphate when treated with either thrombin or trypsin. A PAR4 mutant in which the Arg-47 was replaced with Ala did not respond to thrombin or trypsin. A hexapeptide (GYPGQV) representing the newly exposed tethered ligand from the amino terminus of PAR4 after proteolysis by thrombin activated COS cells transfected with either wild-type or the mutant PAR4. Northern blot showed that PAR4 mRNA was expressed in a number of human tissues, with high levels being present in lung, pancreas, thyroid, testis, and small intestine. By fluorescence in situ hybridization, the human PAR4 gene was mapped to chromosome 19p12.
In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein (2011)

All carbamazepine analogs or metabolites tested are Pgp substrates, except for carbamazepine. These data suggest that resistance to carbamazepine, oxcarbazepine, or eslicarbazepine acetate may be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates.