gebhart/patrepeval huggingface dataset:
Stromal Cell-Derived Factor-1-CXC Chemokine Receptor 4 Interactions Play a Central Role in CD4+ T Cell Accumulation in Rheumatoid Arthritis Synovium (2000)

Rheumatoid arthritis (RA) is characterized by the accumulation of CD4(+) memory T cells in the inflamed synovium. To address the mechanism, we analyzed chemokine receptor expression and found that the frequency of CXC chemokine receptor (CXCR)4 expressing synovial tissue CD4(+) memory T cells was significantly elevated. CXCR4 expression could be enhanced by IL-15, whereas stromal cell-derived factor (SDF)-1, the ligand of CXCR4, was expressed in the RA synovium and could be increased by CD40 stimulation. SDF-1 stimulated migration of rheumatoid synovial T cells and also inhibited activation-induced apoptosis of T cells. These results indicate that SDF-1-CXCR4 interactions play important roles in CD4(+) memory T cell accumulation in the RA synovium, and emphasize the role of stromal cells in regulating rheumatoid inflammation.
Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia (2017)

Case presentationsCase 1A 3-year-old boy presented with a leukocyte count of 5.9 3 10 9 /L and was found to have near-haploid B-lineage acute lymphoblastic leukemia (ALL) with a 27, X, 1Y, 113, 118, 121 karyotype.He was enrolled in the St. Jude Children's Research Hospital Total Therapy XV study.After 19 days of remission induction therapy with 1 high dose of methotrexate, 14 days of prednisone, 2 doses of vincristine and daunorubicin, and 6 doses of Escherichia coli-derived asparaginase, flow cytometry examination of his bone marrow revealed the presence of minimal residual disease (MRD) amounting to 3 leukemic cells per 10 000 mononucleated cells (0.03%).Upon completion of the remaining remission induction therapy consisting of 1 dose of cyclophosphamide, 14 days of mercaptopurine, and 8 onceper-day doses of cytarabine, he attained a morphologic remission on day 46, with undetectable (,0.01%)MRD by flow cytometry and polymerase chain reaction.Because of the near-haploid ALL karyotype and negative day 46 MRD, he was assigned to receive intensive chemotherapy for 3 years.MRD remained undetectable throughout treatment.He has remained in continuous complete remission for 11.6 years. Case 2A 9-year-old boy presented with a 3-month history of progressive pallor and upper respiratory tract infection.He had no hepatosplenomegaly or mediastinal mass.An abnormal blood count with hemoglobin 3.4 g/dL, leukocytes 4.2 3 10 9 /L with 15% neutrophils, 52% lymphocytes, 33% blasts, and platelets 123 3 10 9 /L prompted a bone marrow examination which disclosed 96% replacement with leukemic lymphoblasts.By flow cytometry, the blasts expressed CD45, surface CD3, CD2, CD7, T-cell receptor g/d, CD11b, and CD13, with a subset of cells positive for CD56, a cell profile indicative of T-cell ALL.He was enrolled on the Total Therapy XV study and began remission induction therapy with high-dose methotrexate followed by prednisone once per day, vincristine once per week, daunorubicin once per week, and E coli-derived asparaginase 3 times per week.On day19 of treatment, 62.9% of bone marrow mononucleated cells were leukemic lymphoblasts by flow cytometry (31% of all cells were blasts by morphology).Three additional doses of asparaginase were given, and the remaining remission induction therapy consisted of cyclophosphamide, mercaptopurine, and cytarabine.On day 46, he attained morphologic remission (with 3% lymphoblasts), but MRD by flow cytometry was 5.82%.After consolidation treatment with 4 courses of high-dose methotrexate plus mercaptopurine as well as 1 course of re-intensification therapy with dexamethasone, etoposide, high-dose cytarabine, and asparaginase, MRD decreased to 0.18%.He attained MRD-negative status (,0.01%) after a second course of re-intensification treatment and subsequently underwent a matched-related allogeneic hematopoietic stem cell transplantation.He has remained in continuous complete remission for 11.9 years.
Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC (2013)

Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.
Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity (2013)

The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug-induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs.
Parallel changes in large-scale software development (2001)

An essential characteristic of large-scale software development is parallel development by teams of developers. How this parallel development is structured and supported has a profound effect on both the quality and timeliness of the product. We conduct an observational case study in which we collect and analyze the change and configuration management history of a legacy system to delineate the boundaries of, and to understand the nature of, the problems encountered in parallel development. The results of our studies are (1) that the degree of parallelism is very highhigher than considered by tool builders; (2) there are multiple levels of parallelism, and the data for some important aspects are uniform and consistent for all levels; (3) the tails of the distributions are long, indicating the tail, rather than the mean, must receive serious attention in providing solutions for these problems; and (4) there is a significant correlation between the degree of parallel work on a given component and the number of quality problems it has. Thus, the results of this study are important both for tool builders and for process and project engineers.
Growth factors in preimplantation mammalian embryos. (1993)

It has been hypothesized for some time that secretions of the oviduct and uterus are involved in stimulating cell proliferation in preimplantation mammalian embryos and promotion of early differentiation events that lead to successful implantation. At least some of the regulatory factors present within uterine secretions are growth factors that can act along a paracrine pathway by binding to specific receptors on embryonic cells. A list of polypeptide growth factors present in uterine tissues and fluids has been previously published by Brigstock et al. (1989) and along with those reported in this review, includes EGF, TGF-alpha, insulin, IGF-I, IGF-II, IGF-BPs, acidic and basic FGF, and CSF-1. The early embryo itself produces a number of growth factors and receptors. A summary of those covered in this review, including temporal aspects of their expression, is contained in Table 2.1. Most of the data are from studies on mouse embryos but where, possible, we have also included reports for other mammalian embryos. Taken together with the factors present in oviduct and uterine secretions, it is clear that preimplantation embryos reside in an environmental milieu in which they are exposed to growth factors of many kinds and that regulatory pathways at the autocrine, juxtacrine, and paracrine levels may all be operating. From a functional point of view, many of the factors we have reviewed have been shown to be able to enhance development when added to medium for culture of preimplantation embryos. The exact circuit or pathway and mechanism through which they exert their effects remain, for the most part, to be elucidated. None the less, a number of general features regarding growth factor function during preimplantation development have emerged. There appears to be a redundancy of gene products within several growth factor families, all of which can stimulate cell proliferative or metabolic events when added exogenously to preimplantation embryos in culture. Perhaps, then, in addition to functions of growth factors acting singly on their specific receptors, combinations of factors are important for induction of a specific developmental response. We have included many examples of synergistic actions of growth factors during preimplantation development in the previous sections. It is also possible that the result of combinations of factors may involve a process of interference whereby exposure of embryonic cells to one growth factor may compromise its ability to bind and respond to another.(ABSTRACT TRUNCATED AT 400 WORDS)
Quality-adjusted time without symptoms or toxicity (Q-TWiST) of nanoliposomal irinotecan (nal-IRI; MM-398) plus 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma (mPAC) patients (pts) previously treated with gemcitabine-based therapy. (2016)

e15732 Background: nal-IRI is a nanoliposomal formulation of irinotecan. In the primary analysis of the pivotal NAPOLI-1 Phase-3 trial, nal-IRI+5-FU/LV significantly improved median overall survival (OS, primary endpoint; 6.1 vs 4.2 months, HR = 0.67, P = 0.012) and progression-free survival (PFS; 3.1 vs 1.5 months, HR = 0.56, P = 0.0001) vs 5-FU/LV alone in mPAC pts previously treated with gemcitabine-based therapy. This analysis evaluates between-treatment differences in quality-adjusted survival using a Q-TWiST approach. Methods: Total survival in NAPOLI-1 intent-to-treat cohort over 12 months was partitioned into time with adverse event grade ≥ 3 toxicity (TOX), time in relapse after disease progression (REL), and time without symptoms or adverse event grade ≥ 3 toxicity (TWiST). Mean Q-TWiST was calculated by multiplying time spent in each health state by its respective utility. In the base-case, the utility for TOX (uTOX), REL (uREL) and TWIST (uTWiST) were set to 0.5, 0.5 and 1.0. Nonparametric bootstrapped 95% CIs were derived. The relative Q-TWiST gain of nal-IRI+5-FU/LV vs mean OS for 5-FU/LV was calculated. Threshold analyses varied uTOX and uTWiST between 0.0 and 1.0. Scenario analysis was conducted using per-protocol (PP) population. Results: Nal-IRI+5-FU/LV (n = 117) vs 5-FU/LV (n = 119) pts had significantly more time in TWiST (mean 3.4 vs 2.4 months) and TOX (1.0 vs 0.3 month) but similar time in REL (2.5 vs 2.7 months). In the base-case, nal-IRI+5-FU/LV pts had a 1.3 months (95% CI: 0.4–2.1; 5.1 vs 3.9) greater Q-TWiST (range threshold analyses: 0.9–1.6 months), with a relative Q-TWiST gain of 24% (range threshold analyses: 17%-31%). In the PP population, Q-TWiST was also significantly superior in MM-398+5-FU/LV pts (Q-TWiST gain = 1.8 months; 95% CI: 0.7–3.0). Conclusions: Within NAPOLI-1, combination of nal-IRI+5-FU/LV resulted in statistically significant and clinically important gains in quality-adjusted survival vs 5-FU/LV alone, confirming the clinical outcome benefit of nal-IRI+5-FU/LV in mPAC. Clinical trial information: NCT01494506.
Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor α (2000)

Phytanic acid and pristanic acid are branched-chain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Here we show that both phytanic acid and pristanic acid activate the peroxisome proliferator-activated receptor alpha (PPARalpha) in a concentration-dependent manner. Activation is observed via the ligand-binding domain of PPARalpha as well as via a PPAR response element (PPRE). Via the PPRE significant induction is found with both phytanic acid and pristanic acid at concentrations of 3 and 1 microM, respectively. The trans-activation of PPARdelta and PPARgamma by these two ligands is negligible. Besides PPARalpha, phytanic acid also trans-activates all three retinoic X receptor subtypes in a concentration-dependent manner. In primary human fibroblasts, deficient in phytanic acid alpha-oxidation, trans-activation through PPARalpha by phytanic acid is observed. This clearly demonstrates that phytanic acid itself, and not only its metabolite, pristanic acid, is a true physiological ligand for PPARalpha. Because induction of PPARalpha occurs at ligand concentrations comparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands for PPARalpha. These results demonstrate that both pristanic acid and phytanic acid are naturally occurring ligands for PPARalpha, which are present at physiological concentrations.
Surface Reaction of Alkynes and Alkenes with H-Si(111):  A Density Functional Theory Study (2004)

Recent experiments on the addition of alkene and alkyne molecules to H-terminated silicon surfaces have provided evidence for a surface chain reaction initiated at isolated Si dangling bonds and involving an intermediate carbon radical state, which, after abstraction of a hydrogen atom from a neighboring Si-H unit, transforms into a stable adsorbed species plus a new Si dangling bond. Using periodic density functional theory (DFT) calculations, together with an efficient method for determining reaction pathways, we have studied the initial steps of this chain reaction for a few different terminal alkynes and alkenes interacting with an isolated Si dangling bond on an otherwise H-saturated Si(111) surface. Calculated minimum energy pathways (MEPs) indicate that the chain mechanism is viable in the case of C(2)H(2), whereas for C(2)H(4) the stabilization of the intermediate state is so small and the barrier for H-abstraction so (relatively) large that the molecule is more likely to desorb than to form a stable adsorbed species. For phenylacetylene and styrene, stabilization of the intermediate state and decrease of the H-abstraction barrier take place. While a stable adsorbed species exists in both cases, the overall heat of adsorption is larger for the alkyne molecules.
Depression in Family Members Caring for a Relative With Alzheimer's Disease (1988)

The reformulated learned helplessness model of depression was tested in a study of families caring for relatives with Alzheimer's disease who did not participate in family support groups or have access to respite care. Family members who identified themselves as major caregivers, ie, those providing daily assistance to the patient, received a clinical psychiatric interview, the Beck Self-Report Depression Scale, and a modified Hammen and deMayo Attributional Style Questionnaire. The results showed that 55% of major caregivers, primarily spouses, living with an older relative with dementia experienced clinical depression. Depressed caregivers were more likely to perceive a lack of control over their situation than those who were not depressed. Contrary to the reformulated learned helplessness hypothesis, they did not perceive their situation to be the result of internal, stable, and global attributions. The results suggest the need to study depression in ecologically stressful natural settings and to develop effective clinical intervention strategies.
Las golosinas en la alimentación infantil: Análisis antropológico nutricional (2004)

The increasing consumption of junk food and snacks in Chile in recent years and its association with marketing strategies and prevalent diseases, is reviewed. In the context of world economy, junk food is a global phenomenon. The availability of junk food and snacks at low prices and marketing has triggered an evolution of consumption of foods that require neither the structure nor the preparation of a formal meal. Many studies have suggested that the increase in snack consumption is associated with an increase in obesity, tooth decay and other chronic diseases among children and adolescents. The hypothesis suggests a link between the pattern of snack consumption and an increase increase in the energy density of food consumed, a decrease in satiety, passive over consumption, and an increase in obesity. Between 1977 and 1996, the contribution: of snacks to daily energy intake among children between 2 and 5 years increased by 30% in the United States. In each age group in Chile the frequency of non-transmissible chronic diseases is increasing due primarily to a westernized diet that is high in fat, cholesterol, sodium, and sugar and a sedentary lifestyle. Education about junk food consumption and healthy eating habits in the family, starling since childbirth and public policies about healthy lifestyles should be strengthened.
Evaluation in vitro and in vivo of cationic liposome-expression construct complexes for cystic fibrosis gene therapy. (1995)

We have tested the cationic liposome N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethyl-ammoniummethylsul phate, (DOTAP), for gene delivery in vitro and in vivo with a view to clinical use in gene therapy for cystic fibrosis. Delivery of lacZ cDNA-DOTAP complexes via aerosol showed promoter-dependent differences in the pattern and longevity of expression. Repeated administration was well tolerated. The potential for the transfer of foreign genes into reproductive tissue was investigated by intravenous injection of DNA-DOTAP into female mice. Foreign DNA was undetectable in the ovaries by Southern blot analysis at 1 and 7 days after injection. Our results suggest that DOTAP merits testing in cystic fibrosis patients for delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the respiratory tract and that substitution of the cytomegalovirus (CMV) promoter for the simian virus (SV) promoter may improve on the transitory response reported previously.
Prediction of the Coding Sequences of Unidentified Human Genes. XVII. The Complete Sequences of 100 New cDNA Clones from Brain Which Code for Large Proteins in vitro (2000)

To provide information regarding the coding sequences of unidentified human genes, we have conducted a sequencing project of human cDNAs which encode large proteins. We herein present the entire sequences of 100 cDNA clones of unknown human genes, named KIAA1444 to KIAA1543, from two sets of size-fractionated human adult and fetal brain cDNA libraries. The average sizes of the inserts and corresponding open reading frames of cDNA clones analyzed here were 4.4 kb and 2.6 kb (856 amino acid residues), respectively. Database searches of the predicted amino acid sequences classified 53 predicted gene products into the following five functional categories: cell signaling/communication, nucleic acid management, cell structure/motility, protein management and metabolism. It was also revealed that homologues for 32 KIAA gene products were detected in the databases, which were similar in sequence through almost their entire regions. Additionally, the chromosomal loci of the genes were determined by using human-rodent hybrid panels unless their chromosomal loci were already assigned in the public databases. The expression levels of the genes were monitored in spinal cord, fetal brain and fetal liver, as well as in 10 human tissues and 8 brain regions, by reverse transcription-coupled polymerase chain reaction, products of which were quantified by enzyme-linked immunosorbent assay.
Comparative Protein Structure Modeling of Genes and Genomes (2000)

Comparative modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. The number of protein sequences that can be modeled and the accuracy of the predictions are increasing steadily because of the growth in the number of known protein structures and because of the improvements in the modeling software. Further advances are necessary in recognizing weak sequence-structure similarities, aligning sequences with structures, modeling of rigid body shifts, distortions, loops and side chains, as well as detecting errors in a model. Despite these problems, it is currently possible to model with useful accuracy significant parts of approximately one third of all known protein sequences. The use of individual comparative models in biology is already rewarding and increasingly widespread. A major new challenge for comparative modeling is the integration of it with the torrents of data from genome sequencing projects as well as from functional and structural genomics. In particular, there is a need to develop an automated, rapid, robust, sensitive, and accurate comparative modeling pipeline applicable to whole genomes. Such large-scale modeling is likely to encourage new kinds of applications for the many resulting models, based on their large number and completeness at the level of the family, organism, or functional network.
Electrophoresis of cells and the biological relevance of surface charge (2002)

Recent developments in electrophoresis of cells are reviewed. Problems and progress in automation and miniaturization of analytical electrophoresis instruments as well as in the interpretation of experimentally determined electrophoretic mobility (EPM) data are summarized: In recent times, the EPM determination techniques not only became more reliable and faster, but also more knowledge could be gained about the cell surface electrical properties, the structure of the glycocalyx as well as its influence on the cell peripheral regions and microenvironment by applying cell electrophoresis. In addition, ways are shown to solve discrepancies between physical requirements of a preparative cell electrophoresis procedure and the quantities of ions, which have to be dissolved in cell suspension media. As the modern machines allow the purification of untagged cells suspended in more cell friendly and physiological media, they are likely to be valuable tools in several useful practical applications in clinical transplantation, gene therapy and treatment of disease states.