gebhart/patrepeval huggingface dataset:
Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation. (1996)

Interaction of thrombopoietin (TPO) with its receptor, c-Mpl, triggers cell growth and differentiation responses controlling primitive haemopoietic cell production and megakaryocytopoiesis. To examine the important receptor domains and signal transduction pathways involved in these cellular responses, c-Mpl cytoplasmic domain truncation and tyrosine substitution mutants were generated. In the myelomonocytic leukaemia cell lines WEHI3B-D+ and M1, ectopic expression of the wild-type c-Mpl receptor induced TPO-dependent cellular differentiation characterized by increased cell migration through agar and acquisition of the morphology and molecular markers of macrophages. Consistent with the concept that proliferative and differentiation signals emanate from distinct receptor domains, the C-terminal 33 amino acids of c-Mpl were dispensable for a proliferative response in Ba/F3 cells but proved critical for WEHI3B-D+ and M1 differentiation. Finer mapping revealed that substitution of Tyr599 by phenylalanine within this c-Mpl domain was sufficient to abolish the normal differentiation response. Moreover, in contrast to the normal c-Mpl receptor, this same mplY599F mutant was also incapable of stimulating TPO-dependent Shc phosphorylation, the association of Shc with Grb2 or c-Mpl and of inducing c-fos expression. Thus activation of components of the Ras signalling cascade, initiated by interaction of Shc with c-Mpl Tyr599, may play a decisive role in specific differentiation signals emanating from the c-Mpl receptor.
Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study (1995)

<h3>Background:</h3> Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an elevated risk of peptic ulcer and upper gastrointestinal hemorrhage, but published reports have lacked information on rates of outpatient disease, have concentrated on the elderly, and have not provided comparisons of rates for specific types of NSAIDs. <h3>Methods:</h3> We compared incidence rates of peptic ulcer and upper gastrointestinal hemorrhage in 68 028 people younger than 65 years who used diclofenac sodium, naproxen, piroxicam, or sulindac, and who were members of a network of health maintenance organizations. We reviewed automated insurance claims data and medical records to ascertain cases and included conditions treated on an outpatient basis. <h3>Results:</h3> Medical claims data were adequate for crude identification of potential cases, but review of medical records led to rejection of 63% of these, representing either no abnormality or diseases other than peptic ulcer or upper gastrointestinal hemorrhage. Of the total 112 cases, 64 (57%) were treated as outpatients. The crude incidence rate per 1000 person-years in users of any current, recent, or past NSAID was 2.2 and in distant-past users of NSAIDs was 0.75. For diclofenac, naproxen, piroxicam, and sulindac, we found a consistent pattern of decreasing NSAID effects from current to recent to past exposure. The risk of peptic ulcer or upper gastrointestinal hemorrhage was 1.6 cases per 1000 people using NSAIDs. <h3>Conclusions:</h3> Combining use of automated claims records with review of medical records promotes efficiency while maintaining specificity of case ascertainment. This study, with 57% of cases treated as outpatients, had results consistent with other published reports that were based on hospitalized patients. Within the limits of statistical error, the incidence rates of peptic ulcer and upper gastrointestinal hemorrhage appeared to be similar for the various NSAIDs studied. (Arch Intern Med. 1995;155:1371-1377)
Hairless and Wnt Signaling: Allies in Epithelial Stem Cell Differentiation (2006)

Nuclear receptors and Wnt signaling are both important regulators of developmental and physiological processes. Recent work linking these pathways in epithelial stem cell differentiation has come from studies analyzing the in vivo function of the nuclear receptor corepressor, Hairless (HR). The HR protein has long been suspected to regulate a stem cell-mediated process, hair cycling, as mutations in the Hr gene cause hair loss in both mice and men. The discovery that the HR protein is a nuclear receptor corepressor indicated that HR function in hair cycling is by regulating gene expression. A recent study revealed that HR represses expression of Wise, an inhibitor of Wnt signaling, leading to a model in which HR controls the timing of Wnt signaling required for hair cycling. Here we review these data, and provide new data showing that HR corepressor activity is essential for its in vivo function, and identify an additional putative Wnt inhibitor regulated by HR. This work complements previous studies demonstrating the role of Wnt signaling in epithelial stem cell differentiation.
Clinical and Metabolic Efficacy of Glutamine-supplemented Parenteral Nutrition after Bone Marrow Transplantation (1992)

Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.
[Results of serological reactions in patients with presumptive diagnosis of toxoplasmosis]. (1993)

Even though Toxoplasma gondii is an ubiquitous parasite that can effect most of human structures and organs, not all clinical manifestations suggestive of being produced by it are caused by this protozoon. For these reasons sera samples of patients suspected of having toxoplasmosis are sent to the laboratory for detecting specific antibodies which would facilitate the differential diagnosis. Thus, 716 sera from suspected patients, mainly from the Metropolitan Region of Chile, were sent to the Parasitology Laboratory of Chile University in order to carry out in them, specific serological tests for toxoplasmosis: indirect hemagglutination test (IHAT), Sabin Feldman reaction (SFT) and complement fixation test (CFT). Were considered positive: IHAT and/or SFT with titers > or = 1:16 and CFT with titer > or = 1:5. The pathologies for demanding these serological tests were obstetrical problems 210 (29.3%), congenital problems 193 (27.0%), ophthalmopathies 81 (11.3%), adenopathies 77 (10.8%), AIDS 67 (9.4%), myocardiopathies 46 (6.4%) and miscellaneous 42 (5.9%). The positivity found in these sera was higher in ophthalmopathies (61.7%), followed by obstetrical problems, miscellaneous problems, myocardiopathies and AIDS (50.7-52.4%), less frequent was the positivity in adenopathies (35.1%) and congenital problems (23.1%). In general, the 43.7% of positivity for toxoplasmosis found in these patients is higher than the 37.0% found in the general population. High titers of IHAT and SFT plus positive CFT was found in 13-fold higher proportion than in the general population.
Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep. (1994)

We previously reported on the successful engraftment and long-term multilineage expression (erythroid, myeloid, lymphoid) of human fetal liver hematopoietic stem cells in sheep after transplantation in utero. That the engraftment of long-term repopulating pluripotent stem cells occurred in these animals was shown here by the fact that transplantation of human CD45+ cells isolated from bone marrow of these chimeric animals into preimmune fetal sheep resulted in engraftment and expression of human cells. Marrow cells were obtained from three chimeric sheep at 3.2-3.6 yr after transplant. The relative percentage of human CD45+ cells present in these marrows was 3.3 +/- 0.32%. A total of 29 x 10(6) CD45+ cells were isolated by panning, pooled, and transplanted into six preimmune sheep fetuses (4.8 x 10(6) cells/fetus). All six recipients were born alive. Hematopoietic progenitors exhibiting human karyotype were detected in marrows of two lambs soon after birth. Cells expressing human CD45 antigen were also detected in blood and marrow of both lambs. Human cell expression has been multilineage and has persisted for > 1 yr. These results demonstrate that the expression of human cells in this large animal model resulted from engraftment of long-term repopulating pluripotent human stem cells.
Current and emerging investigational medical therapies for the treatment of overactive bladder (2006)

Overactive bladder (OAB) is a chronic distressing condition characterised by urinary urgency with or without urge incontinence, usually with frequency (voiding at least eight times daily) and nocturia. It affects millions of people worldwide independent of age, sex and race. The prevalence increases with age and is relatively higher in women compared with men. The treatment of OAB is aimed at reducing the debilitating symptoms so as to improve the overall quality of life for patients. Anticholinergic agents targeting the muscarinic receptors in the bladder represent the mainstay of pharmacotherapy for the treatment of OAB. Besides their status as the current standard of care, use of antimuscarinic drugs is limited by certain side effects, particularly dry mouth and constipation; therefore, various attempts have been made to improve the organ selectivity of these drugs to overcome the side effects. These include the development of new antimuscarinic agents with structural modifications and the use of innovative drug delivery methods. The advancement in the drug delivery systems extends to the long-term therapeutic efficacy with improved tolerability and patient compliance; however, future prospective therapies are aimed at novel targets with novel mechanisms of action, including beta3-adrenoceptor agonists, K+ channel openers, 5-HT modulators and botulinum toxin, which are currently under different stages of clinical development. Among other investigational therapies, neurokinin receptor antagonists, alpha-adrenoceptor antagonists, nerve growth factor inhibitors, gene therapy and stem cell-based therapies are of considerable interest. The future for the development of new modalities for the treatment of OAB looks promising.
Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element (2003)

Hematopoiesis is a complex process involving hematopoietic stem cell (HSC) self-renewal and lineage commitment decisions that must continue throughout life. Establishing a reproducible technique that allows for the long-term ex vivo expansion of human HSCs and maintains self-renewal and multipotential differentiation will allow us to better understand these processes, and we report the ability of the leukemia-associated AML1-ETO fusion protein to establish such a system. AML1-ETO-transduced human CD34+ hematopoietic cells routinely proliferate in liquid culture for more than 7 months, remain cytokine dependent for survival and proliferation, and demonstrate self-renewal of immature cells that retain both lymphoid and myeloid potential in vitro. These cells continue to express the CD34 cell surface marker and have ongoing telomerase activity with maintenance of telomere ends, however they do not cause leukemia in nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice. Identification of the signaling pathways that are modulated by AML1-ETO and lead to the self-renewal of immature human progenitor cells may assist in identifying compounds that can efficiently expand human stem and progenitor cells ex vivo.
Activation of human B cells. Comparison of the signal transduced by IL-4 to four different competence signals. (1989)

The effects of the cytokine IL-4 on resting and activated human B cells were compared with the effects of known "competence" signals able to drive resting B cells into the cell cycle, including anti-Ig, PMA, anti-CD20, and a recently described competence signal, anti-Bgp95. In proliferation assays, IL-4 was costimulatory with anti-Ig and anti-Bgp95 but not with anti-CD20 or PMA. IL-4 alone triggered increases in expression of class II DR/DQ and CD40, but it did not trigger increases in intracellular free calcium [Ca2+]i in resting B cells or induce resting B cells to leave G0 and enter the G1 phase of the cell cycle. Although IL-4 has some characteristics of competence signals, it was most effective if added to B cells up to 12 h after anti-Ig or anti-Bgp95 rather than before, and thus, in this respect, works more like a progression signal. Like IL-4, all four competence signals for B cells triggered increases in class II and CD40, but only IL-4 consistently induced increases in CD23 surface levels. IL-4 was costimulatory only with anti-Ig and anti-Bgp95, each of which can trigger increases in [Ca2+]i and new protein synthesis of the proto-oncogene c-myc, and can increase attachment of protein kinase C to the plasma membrane. IL-4 was not costimulatory with signals that 1) did not affect [Ca2+]i yet induced c-myc protein synthesis (anti-CD20), 2) only stimulated the translocation of protein kinase C (PMA), or 3) only stimulated increases in [Ca2+]i (calcium ionophore). These results suggest that resting human B cells require at least two intracytoplasmic signals before IL-4 can effectively promote B cell proliferation.
P4‐236: Modulation of synaptic function by extracellular tau enriched in oligomers (2009)

The classical hallmarks of Alzheimer's disease (AD) are inter-neuronal plaques consisting of precipitates or aggregates of amyloid beta protein (Aβ) and intra-neuronal neurofibrillary tangles (NFTs) consisting of tau protein. Although plaques and tangles have so far been the primary focus as drug discovery targets, recently there is an emerging interest in studying the role of soluble oligomers of amyloid beta and tau protein as therapeutic targets for AD. Soluble oligomers of Aβ have been demonstrated to inhibit synaptic function. Picomolar concentration of Amyloid-β has been shown to modulate synaptic plasticity in mice. Over-expression of soluble tau caused neuron loss and memory impairment in mouse models for tauopathies, whereas NFTs were not associated with these phenotypes. Levels of extracellular tau increase in cerebrospinal fluid in AD, and extracellular tau has been shown to be toxic to cultured neurons suggesting a contributing pathological role in AD. The model of long-term potentiation (LTP) was used to evaluate the effects of tau isoforms on synaptic function targeting the hippocampus, an area of the brain fundamentally important in memory acquisition. LTP at the connection between Shaeffer collateral and CA1 pyramidal neurons in hippocampal slices of 3-5 month-old WT mice was evaluated. Hippocampal slices were perfused with a solution containing tau protein for 20 min before inducing LTP through tetanic stimulation of the Schaeffer collateral pathway. Potentiation in vehicle-treated slices was used as control. We have previously demonstrated that 200 nM extracellular Tau inhibited LTP in hippocampal slices of 3-5 month-old WT mice. Preparations of tau with four microtubule binding domains (4R Tau) enriched in oligomer content, were used in the LTP studies. Here, we studied the lowest concentration of tau necessary to show inhibitory effect on LTP in 3-5 month old WT mice hippocampal slices. In addition, we also studied the effect of Tau352 (3R Tau) at the same necessary concentration at which the 4R Tau inhibits LTP. This work extends our observation that extracellular 4R tau inhibits LTP by determining the lowest concentrations of 3R and 4R tau that inhibit LTP.
Glypican‐3 is overexpressed in human hepatocellular carcinoma (2003)

To identify candidate genes that could be used as diagnostic and therapeutic targets for hepatocellular carcinoma (HCC), we searched for the genes that are overexpressed in HCC by combining representational difference analysis and microarray. Genes such as glypican-3 (GPC3), insulin-like growth factor 2, long-chain fatty-acid-coenzyme A ligase 4, farnesyl diphosphate synthase were frequently identified in our screening. Northern blot analysis with these four genes confirmed their overexpression in HCC. Among them we found that GPC3 transcript is upregulated in six out of seven cases of HCC. Immunoblot and immunohistochemical staining using polyclonal anti-GPC3 antibodies further confirmed that GPC3 protein is indeed increased in HCC tumor samples. We also found that GPC3 is secreted into culture media from cell lines derived from HCC. We conclude that GPC3 is a good molecular marker for HCC.
Melanoma patient antibody responses to melanoma tumor-associated antigens defined by murine monoclonal antibodies. (1989)

Sera from melanoma patients undergoing immunization with three distinct immunogens were evaluated for development of IgG antibody specific for the melanoma tumor-associated antigens (TAAs) GD3 and 250-kd glycoprotein (high molecular weight; HMW). Of 99 patients receiving either irradiated allogeneic melanoma cells admixed with bacillus Calmette-Guérin, vaccinia viral oncolysate melanoma cell membranes, or cholesterol hemisuccinate-modified melanoma cells, 12 were determined to have responded against GD3 and 17 against the HMW TAA. This reactivity was measured using both direct binding to purified TAA and specific inhibition of binding of murine monoclonal antibodies R24 and Me-1-14 for GD3 and HMW TAA, respectively. Preimmune sera from these patients did not react with these TAAs, nor did preimmune sera or follow-up sera from melanoma patients electing not to receive immunotherapy. These results suggest that melanoma patients can be immunized against these TAAs as presented on the melanoma cell membrane in an immunotherapy setting and that immunization using purified TAAs might likewise be feasible.
N-Aryl N‘-Hydroxyguanidines, A New Class of NO-Donors after Selective Oxidation by Nitric Oxide Synthases:  Structure−Activity Relationship (2001)

The formation of nitric oxide (NO) was followed during the oxidation of 37 N-hydroxyguanidines or related derivatives, including 18 new N-aryl N'-hydroxyguanidines, by recombinant inducible nitric oxide synthase (NOS II). Several N-aryl N'-hydroxyguanidines bearing a relatively small, electron-donating para subtituent, such as H, F, Cl, CH(3), OH, OCH(3), and NH(2), led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, N(omega)-hydroxy-L-arginine (NOHA). The characteristics of these reactions were very similar to those previously reported for the oxidation of NOHA by NOS:(i) the strict requirement of NOS containing (6R)-5,6,7,8-tetrahydro-L-biopterin, reduced nicotinamide adenine dinucleotide phosphate, and O(2) for the oxidation to occur, (ii) the formation of NO and the corresponding urea in a 1:1 molar ratio, and (iii) a strong inhibitory effect of the classical NOS inhibitors such as N(omega)-nitro-L-arginine and S-ethyl-iso-thiourea. Structure-activity relationship studies showed that two structural factors are crucial for NO formation from compounds containing a C(triple bond)NOH function. The first one is the presence of a monosubstituted N-hydroxyguanidine function, since disubstituted N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes failed to produce NO. The second one is the presence of a N-phenyl ring bearing a relatively small, not electron-withdrawing para substituent that could favorably interact with a hydrophobic cavity close to the NOS catalytic site. The k(cat) value for NOS II-catalyzed oxidation of N-para-fluorophenyl N'-hydroxyguanidine was 80% of that found for NOHA, and its k(cat)/K(m) value was only 9-fold lower than that of NOHA. Interestingly, the K(m) value found for NOS II-catalyzed oxidation of N-(3-thienyl) N'-hydroxyguanidine was 25 microM, almost identical to that of NOHA. Recombinant NOS I and NOS III also oxidize several N-aryl N'-hydroxyguanidines with the formation of NO, with a clearly different substrate specificity. The best substrates of the studied series for NOS I and NOS III were N-(para-hydroxyphenyl) and N-(meta-aminophenyl) N'-hydroxyguanidine, respectively. Among the studied compounds, the para-chlorophenyl and para-methylphenyl derivatives were selective substrates of NOS II. These results open the way toward a new class of selective NO donors after in situ oxidation by each NOS family.
A Panel of Kallikrein Marker Predicts Prostate Cancer in a Large, Population-Based Cohort Followed for 15 Years without Screening (2011)

Use of the panel to determine referral to biopsy could substantially reduce the number of unnecessary prostate biopsies.
A dicarba analog of β‐atrial natriuretic peptide (β‐ANP) inhibits guanosine 3′,5′‐cyclic monophosphate production induced by α‐ANP in cultured rat vascular smooth muscle cells (1989)

The synthesis and biological properties are described of [Asu7,23']-beta-ANP-(7-28) (Asu, L-alpha-aminosuberic acid), a dicarba analog of beta-atrial natriuretic peptide (beta-ANP, an antiparallel dimer of human alpha-ANP with the chains linked by 7-23' and 7'-23 disulfide bonds). This Asu-analog (referred to as analog III) displaced 125I-alpha-ANP specifically bound to cultured rat vascular smooth muscle cells (VSMC) with an apparent Ki of 2.1 x 10(-8) M, but did not stimulate formation of intracellular cGMP at 10(-8) -10(-5) M. Analog III inhibited the alpha-ANP-stimulated cGMP production in VSMC competitively with a pA2 value of 7.45 and behaved as an antagonist of alpha-ANP in rat aorta smooth muscle relaxation. In addition, beta-ANP was also shown to inhibit the alpha-ANP-induced cGMP production in a dose-dependent manner. The mechanism of action of beta-ANP is also discussed.
MRBench: A Benchmark for MapReduce Framework (2008)

MapReduce is Google's programming model for easy development of scalable parallel applications which process huge quantity of data on many clusters. Due to its conveniency and efficiency, MapReduce is used in various applications (e.g., Web search services and online analytical processing). However, there are only few good benchmarks to evaluate MapReduce implementations by realistic testsets. In this paper, we present MRBench that is a benchmark for evaluating MapReduce systems. MRBench focuses on processing business oriented queries and concurrent data modifications. To this end, we build MRBench to deal with large volumes of relational data and execute highly complex queries. By MRBench, users can evaluate the performance of MapReduce systems while varying environmental parameters such as data size and the number of (map/reduce) tasks. Our extensive experimental results show that MRBench is a useful tool to benchmark the capability of answering critical business questions.
Circulating tumor cells as a biomarker of response to treatment in patient derived xenograft mouse models of pancreatic adenocarcinoma (2013)

Torphy, Robert J. BS; Tignanelli, Christopher J. BS, MD; Moffitt, Richard A. BS, PhD; Soper, Steven A. BA, BS, PhD; Yeh, Jen Jen MD, FACS Author Information