gebhart/patrepeval huggingface dataset:
Phase I and pharmacokinetic study of 10-propargyl-10-deazaaminopterin, a new antifolate. (2000)

The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.
Performance of a conventional enzyme immunoassay for hepatitis C virus core antigen in the early phases of hepatitis C infection. (2001)

There are periods within the early phase of hepatitis C virus (HCV) infection in which the anti-HCV antibody test is unable to confirm HCV viremia. To reduce the risk of transmitting HCV through transfusions, we developed a simple and highly sensitive enzyme immunoassay (EIA) which detects the core antigen of HCV (HCVcAg). This assay employed a conventional colorimetric EIA system, and was based on a two-step sandwich assay, using a 96- well microplate. The reproducibility of the results was very high. When the cutoff values were set to 30 fmol of recombinant HCVcAg/L, as determined by the distribution of healthy subject sera (n=223), 99.6% of healthy subject sera and 100% of hepatitis B patient sera (n=50) were negative for HCVcAg. The clinical performance of this EIA was examined using 14 commercially available seroconversion panels. In every panel, HCVcAg could be detected at points preceding the seroconversion of anti-HCV antibodies. The points at which HCVcAg was detected were the same as those at which it was detected by an AMPLICOR HCV Monitor test. The EIA's window period for detecting the HCVcAg in all panels was on average 26 days shorter than that of the anti-HCV antibody test. In three panels where the first sample is negative for HCV RNA, the window period was shortened 50 days by this EIA for HCVcAg. There was a positive correlation between the concentration of HCVcAg and HCV RNA in anti-HCV antibody negative specimens. This assay was simpler to perform than assays based on gene amplification technology for the detection of HCV RNA, and the window period was shortened to that of the AMPLICOR HCV Monitor test. Thus, the EIA for HCVcAg would be useful in screening seroconverting donors and could reduce the residual risk of secondary HCV infections through transfusions.
Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator. (1998)

The low density lipoprotein receptor-related protein (LRP), a multi-functional endocytic receptor, mediates the cellular internalization of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator and their complexes with plasminogen activator inhibitor type 1 (PAI-1). LRP preferentially binds the complexed forms, exemplified by equilibrium dissociation constants (KD) that are at least an order of magnitude lower than those of the free components. To understand the molecular interactions, underlying the preference of the receptor for complexes rather than for the free components, we have performed a detailed analysis of the affinity and kinetics of the binding of PAI-1 and t-PA:PAI-1 complexes to the receptor, using surface plasmon resonance. To assess the involvement of the heparin-binding domain of PAI-1 for the interaction with LRP, we determined the equilibrium dissociation constants for the binding to LRP of a panel of PAI-1 mutants with single- and multiple amino-acid substitutions of the basic residues that constitute the heparin binding site of PAI-1 (K65, K69, R76, K80 and K88). The binding of these PAI-1 mutants was partially reduced with a 2 to 4 fold increase in KD values for single (K80, K88) and combined (K80, 88) substitution mutant proteins respectively. LRP binding of complexes, composed of t-PA with either wild type PAI-1 or any one of the single PAI-1 mutants indicated a major role of lysine 69 (K69) for the binding of t-PA:PAI-1 complexes to LRP (KD values of 6.1, 3.7. 75.4, 5.4, 12.5 and 8.1 nM for wild type, K65A, K69A, R76A, K80A and K88A complexes, respectively). Since the KD for the binding of free t-PA to LRP is 158 nM, we conclude that the PAI-1 moiety harbors the major determinant for t-PA:PAI-1 complex binding to LRP. The in vitro binding studies were extended by binding and clearance studies with COS-1 cells. Degradation of both 125I-t-PA:PAI-1 K69A and 125I-t-PA:PAI-1 K69A K80A K88A complexes after 2 h of incubation was reduced compared to the degradation of 125I-t-PA:PAI-1 complexes. We conclude that PAI-1 contains a cryptic binding site (lysine 69) for LRP, that is specifically expressed upon t-PA:PAI-1 complex formation.
Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response (2003)

Infection with the human microbial pathogen Helicobacter pylori is assumed to lead to invasive gastric cancer. We find that H. pylori activates the hepatocyte growth factor/scatter factor receptor c-Met, which is involved in invasive growth of tumor cells. The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response. CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2. The H. pylori-induced motogenic response is suppressed and blocked by the inhibition of PLCgamma and of MAPK, respectively. Thus, upon translocation, CagA modulates cellular functions by deregulating c-Met receptor signaling. The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.
Increased expression of collagenase-3 (MMP-13) and MT1-MMP in oesophageal cancer is related to cancer aggressiveness (2000)

These data suggest that production of collagenase-3 together with MT1-MMP is implicated in tumour aggressiveness and prognosis in human oesophageal carcinomas.
The BioCassava Plus Program: Biofortification of Cassava for Sub-Saharan Africa (2011)

More than 250 million Africans rely on the starchy root crop cassava (Manihot esculenta) as their staple source of calories. A typical cassava-based diet, however, provides less than 30% of the minimum daily requirement for protein and only 10%-20% of that for iron, zinc, and vitamin A. The BioCassava Plus (BC+) program has employed modern biotechnologies intended to improve the health of Africans through the development and delivery of genetically engineered cassava with increased nutrient (zinc, iron, protein, and vitamin A) levels. Additional traits addressed by BioCassava Plus include increased shelf life, reductions in toxic cyanogenic glycosides to safe levels, and resistance to viral disease. The program also provides incentives for the adoption of biofortified cassava. Proof of concept was achieved for each of the target traits. Results from field trials in Puerto Rico, the first confined field trials in Nigeria to use genetically engineered organisms, and ex ante impact analyses support the efficacy of using transgenic strategies for the biofortification of cassava.
Direct measurement of transmural laminar architecture in the anterolateral wall of the ovine left ventricle: new implications for wall thickening mechanics (2004)

Laminar, or sheet, architecture of the left ventricle (LV) is a structural basis for normal systolic and diastolic LV dynamics, but transmural sheet orientations remain incompletely characterized. We directly measured the transmural distribution of sheet angles in the ovine anterolateral LV wall. Ten Dorsett-hybrid sheep hearts were perfusion fixed in situ with 5% buffered glutaraldehyde at end diastole and stored in 10% formalin. Transmural blocks of myocardial tissue were excised, with the edges cut parallel to local circumferential, longitudinal, and radial axes, and sliced into 1-mm-thick sections parallel to the epicardial tangent plane from epicardium to endocardium. Mean fiber directions were determined in each section from five measurements of fiber angles. Each section was then cut transverse to the fiber direction, and five sheet angles (beta) were measured and averaged. Mean fiber angles progressed nearly linearly from -41 degrees (SD 11) at the epicardium to +42 degrees (SD 16) at the endocardium. Two families of sheets were identified at approximately +45 degrees (beta(+)) and -45 degrees (beta(-)). In the lateral region (n = 5), near the epicardium, sheets belonged to the beta(+) family; in the midwall, to the beta(-) family; and near the endocardium, to the beta(+) family. This pattern was reversed in the basal anterior region (n = 4). Sheets were uniformly beta(-) over the anterior papillary muscle (n = 2). These direct measurements of sheet angles reveal, for the first time, alternating transmural families of predominant sheet angles. This may have important implications in understanding wall mechanics in the normal and the failing heart.
Efficacy of Rheolytic Thrombectomy in Early Versus Late Myocardial Infarction (2006)

Rheolytic thrombectomy with the AngioJet catheter is more effective in terms of improvement in coronary blood flow as assessed by TFCs when used less than 12 hours after the onset of clinical symptoms suggestive of AMI.
In situx-ray-diffraction and -reflectivity studies of the Au(111)/electrolyte interface: Reconstruction and anion adsorption (1992)

In situ x-ray-scattering studies of the Au(111) electrode surface have been carried out in NaF, NaCl, LiCl, CsCl, KCl, and NaBr solutions using grazing-incident-angle diffraction and reflectivity techniques. The top layer of gold atoms undergoes a reversible phase transition between the (1\ifmmode\times\else\texttimes\fi{}1) bulk termination and a (p\ifmmode\times\else\texttimes\fi{} \ensuremath{\surd}3 ) uniaxial discommensuration (striped) phase on changing the electrode potential. Below the critical potential, in all solutions, p=23, which is identical to that obtained in vacuum. An ordered array of discommensuration kinks is not observed. Above the critical potential, 23p30. At sufficiently positive potentials, the surface forms an ideally terminated (111) surface. In the negative potential sweep, the reconstruction starts to reform at the critical potential. Analysis of the potential dependence of the scattered x-ray intensity with differing anions in NaF, NaCl, and NaBr solutions supports a unifying model that depends on the induced surface charge density. The transition to the (1\ifmmode\times\else\texttimes\fi{}1) phase is much faster than the formation of the reconstructed phase. Cycling the potential in the reconstructed region improves the reconstructed surface order. The adsorption of anions and ``surface water'' at the gold interface has been investigated using specular x-ray reflectivity.
UV-B-induced synthesis of photoprotective pigments and extracellular polysaccharides in the terrestrial cyanobacterium Nostoc commune (1997)

Liquid cultures of the terrestrial cyanobacterium Nostoc commune derived from field material were treated with artificial UV-B and UV-A irradiation. We studied the induction of various pigments which are though to provide protection against damaging UV-B irradiation. First, UV-B irradiation induced an increase in carotenoids, especially echinenone and myxoxanthophyll, but did not influence production of chlorophyll a. Second, an increase of an extracellular, water-soluble UV-A/B-absorbing mycosporine occurred, which was associated with extracellular glycan synthesis. Finally, synthesis of scytonemin, a lipid-soluble, extracellular pigment known to function as a UV-A sunscreen, was observed. After long-time exposure, the UV-B effect on carotenoid and scytonemin synthesis ceased whereas the mycosporine content remained constantly high. The UV-B sunscreen mycosporine is exclusively induced by UV-B (< 315 nm). The UV-A sunscreen scytonemin is induced only slightly by UV-B (< 315 nm), very strongly by near UV-A (350 to 400 nm), and not at all by far UV-A (320 to 350 nm). These results may indicate that the syntheses of these UV sunscreens are triggered by different UV photoreceptors.
Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism (2004)

Alzheimer's Disease (AD) is a devastating disease that affects millions of elderly persons. Despite years of intense investigations, genetic risk factors that affect the majority of AD cases have yet to be determined. Recent studies suggest that cholesterol metabolism has integral part in AD pathogenesis, suggesting that genes that regulate lipid metabolism may also play roles in AD. This review will first describe emerging evidence that links cholesterol to the mechanisms thought to underlie AD. Based on this rationale, candidate genes located in regions implicated in AD that have roles in lipid metabolism will then be discussed.
The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity (1998)

We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes. (1983)

There are two major R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) activation pathways to 5-fluorouracil, one that is mediated by microsomal cytochrome P-450 oxidation at C-5' of the tetrahydrofuran moiety and one that is mediated by soluble enzymes. This report demonstrates that the soluble enzyme pathway proceeds via enzymatic cleavage (possibly hydrolytic) of the N-1--C-2' bond to yield 5-fluorouracil and 4-hydroxybutanal, which is immediately further metabolized to gamma-butyrolactone or gamma-hydroxybutyric acid. The soluble activation pathway was present in liver, small intestine, and brain. Because of the limited distribution of cytochrome P-450 in body tissues and because of the lack of redistribution of 5-fluorouracil via the systemic circulation after ftorafur administration, we propose that the soluble enzyme pathway is at least in part responsible for organ toxicity and possibly antitumor effect. Distinction of the microsomal (C-5') and the soluble enzyme (C-2') activation pathways can be exploited in the design of more selective prodrug analogues.
Plasma and Cardiac Galectin-3 in Patients With Heart Failure Reflects Both Inflammation and Fibrosis (2017)

The present study suggests that myocardial Gal-3 can be considered as a possible marker for both cardiac inflammation and fibrosis, depending on the pathogenesis of heart failure. However, circulating concentrations of Gal-3 do not seem to reflect endomyocardial Gal-3 levels or cardiac fibrosis.
Principles of office anesthesia: part I. Infiltrative anesthesia. (2002)

The use of effective analgesia is vital for any office procedure in which pain may be inflicted. The ideal anesthetic achieves 100 percent analgesia in a short period of time, works on intact or nonintact skin without systemic side effects, and invokes neither pain nor toxicity. Because no single agent meets all of these criteria, the physician must choose from the available armamentarium based on the anesthetic properties that are most desired. Infiltrative anesthetics are frequently chosen because of their proven safety record, low cost, ease of storage, widespread availability, and rapid onset of action. Allergy to local injectable anesthetics is rare, and when it occurs it is often secondary to the preservative in multidose vials. Anesthesia can be prolonged with the addition of epinephrine or the use of longer-acting agents. Buffering the local anesthetic with bicarbonate, warming the solution, and injecting slowly can minimize the pain of anesthetic injection. Complications are rare but include central nervous system and cardiovascular toxicity, or extreme vasoconstriction in an end organ, if epinephrine is used.
Cutting Edge: A Monoclonal Antibody Specific for the Programmed Death-1 Homolog Prevents Graft-versus-Host Disease in Mouse Models (2011)

Upon interaction with B7 homolog 1, programmed death-1 (PD-1) transmits a critical coinhibitory signal to T cells to negatively regulate immune responses. By extensively searching the genomic database with the IgV region of PD-1, we identified a homolog and named it PD-1 homolog (PD-1H). PD-1H is broadly expressed on the cell surface of hematopoietic cells and could be further upregulated on CD4(+) and CD8(+) T cells following activation. We have generated an mAb against PD-1H, which strikingly prevents acute graft-versus-host disease in semi- and fully allogeneic murine models, leading to full chimerism following treatment. Graft-versus-host disease remains a primary hindrance to successful allogeneic hematopoietic cell transplantation therapy for the treatment of hematologic malignancy. Therefore, manipulation of PD-1H function may provide a new modality for controlling T cell responses to allogeneic tissues in transplant medicine.
Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase (1998)

The mechanism by which 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors increase endothelial nitric oxide synthase (eNOS) expression is unknown. To determine whether changes in isoprenoid synthesis affects eNOS expression, human endothelial cells were treated with the HMG-CoA reductase inhibitor, mevastatin (1-10 microM), in the presence of L-mevalonate (200 microM), geranylgeranylpyrophosphate (GGPP, 1-10 microM), farnesylpyrophosphate (FPP, 5-10 microM), or low density lipoprotein (LDL, 1 mg/ml). Mevastatin increased eNOS mRNA and protein levels by 305 +/- 15% and 180 +/- 11%, respectively. Co-treatment with L-mevalonate or GGPP, but not FPP or LDL, reversed mevastatin's effects. Because Rho GTPases undergo geranylgeranyl modification, we investigated whether Rho regulates eNOS expression. Immunoblot analyses and [35S]GTPgammaS-binding assays revealed that mevastatin inhibited Rho membrane translocation and GTP binding activity by 60 +/- 5% and 78 +/- 6%, both of which were reversed by co-treatment with GGPP but not FPP. Furthermore, inhibition of Rho by Clostridium botulinum C3 transferase (50 microg/ml) or by overexpression of a dominant-negative N19RhoA mutant increased eNOS expression. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 (200 ng/ml) decreased eNOS expression. These findings indicate that Rho negatively regulates eNOS expression and that HMG-CoA reductase inhibitors up-regulate eNOS expression by blocking Rho geranylgeranylation, which is necessary for its membrane-associated activity.
Identification of Five MAGE-A1 Epitopes Recognized by Cytolytic T Lymphocytes Obtained by In Vitro Stimulation with Dendritic Cells Transduced with MAGE-A1 (1999)

MAGE genes are expressed by many human tumors of different histological types but not by normal cells, except for male germline cells. The Ags encoded by MAGE genes and recognized by T cells are therefore strictly tumor-specific. Clinical trials involving therapeutic vaccination of cancer patients with MAGE antigenic peptides or proteins are in progress. To increase the range of patients eligible for therapy with peptides, it is important to identify additional MAGE epitopes recognized by CTL. Candidate peptides known to bind to a given HLA have been used to stimulate T lymphocytes in vitro. In some instances, CTL clones directed against these synthetic peptides have been obtained, but these clones often failed to recognize tumor cells expressing the relevant gene. Therefore, we designed a method to identify CTL epitopes that selects naturally processed peptides. Monocyte-derived dendritic cells infected with a recombinant canarypoxvirus (ALVAC) containing the entire MAGE-A1 gene were used to stimulate CD8+ T lymphocytes from the blood of individuals without cancer. Responder cell microcultures that specifically lysed autologous cells expressing MAGE-A1 were cloned using autologous stimulator cells either transduced with a retrovirus coding for MAGE-A1 or infected with recombinant Yersinia-MAGE-A1 bacteria. The CTL clones were tested for their ability to lyse autologous cells loaded with each of a set of overlapping MAGE-A1 peptides. This strategy led to the identification of five new MAGE-A1 epitopes recognized by CTL clones on HLA-A3, -A28, -B53, -Cw2, and -Cw3 molecules. All of these CTL clones recognized target cells expressing gene MAGE-A1.
Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin (1993)

The hepatocyte growth factor/scatter factor (HGF/SF) receptor consists of an alpha- and a beta-subunit, which are derived from a single-chain precursor by endoproteolytic processing. The precursor is not proteolytically processed in LoVo colon carcinoma cells. The uncleaved receptor immunopurified from the cells was cleaved in vitro by furin. Furthermore, the HGF/SF receptor was proteolytically processed in LoVo cells transfected with furin cDNA. These results indicate that furin is a processing endoprotease for the HGF/SF receptor. Tyrosine autophosphorylation of the uncleaved receptor was induced by HGF/SF, and the growth of the cells expressing the uncleaved receptor was stimulated by HGF/SF, indicating that the proteolytic processing of the receptor is not essential for the signal transduction of HGF/SF.