gebhart/patrepeval huggingface dataset:
The Medicinal Chemistry of Nonsteroidal Antiestrogens: A Review (1994)

Abstract: The inhibition of estrogen is a particularly useful strategy for the treatment of hormone-dependent breast tumors in postmenopausal females and possibly in premenopausal women and as a chemosuppressive in women at high risk of developing breast cancer. Nonsteroidal antiestrogens which exhibit potent antitumor effects represent a major advance in the management of breast cancer. Considerable effort by many research groups has been devoted to the search for novel pure nonsteroidal antiestrogens with the hope of finding antitumor agents that would be useful in estrogen receptor (ER) positive or estrogen receptor (ER) negative disease. The reasoning behind the search for pure antiestrogens is based on the recognition that antiestrogens generally possess the partial estrogenic activity and a complete blockade of estrogen action cannot be achieved by agents like tamoxifen. Novel pure antiestrogens should be more effective than partial agonist in reducing the mitogenic action of estrogen on the growth of breast tumors and complete ablation of hormonal-dependent tumor growth is very desirable since it could provide a more rapid and longer-lasting remission. In addition, pure antiestrogens could be more effective in patients who experience a relapse during tamoxifen therapy, serving as a second-line treatment, and have the potential of demonstrating greater efficacy in first-line treatment of advanced breast cancer. This review covers the chemistry of the experimental and potentially useful nonsteroidal antiestrogens and the only agent, tamoxifen, used in the therapy of breast cancer with special emphasis on structure-activity relationships. Special attention was paid to the structural classes [1,2-bis(hydroxyphenyl)ethane; 2-phenylindoles; indolo[2,1-a] isoquinolines; 2-phenylbenzo[b] thiophenes; dibenzo[a,g]quinolizinones; triarylpropenones (TAPs); 3,4-dihydro-1-naphthalenyl­ methanones; 3-aroyl-2-arylbenzo[b]thiophenes; 2,3-diaryi-2H-1-benzopyrans; triphenyl­ ethylenes (TPEs); dichlorodiarylcyclopropanes (DDACs) and the 1,1-dichloro-2,2,3-triarylcyclo­ propanes (DTACs)] whose agents demonstrated particular activity in the in vitro receptor binding affinity assay and the in vivo uterotrophic and antiuterotrophic assays. Where possible, the in vitro antiproliferative properties of these agents in cell culture assays also were discussed.
Expression in Multigene Families. Analysis of Chloroplast and Mitochondrial Proteases (2004)

The proteolytic machinery of chloroplasts and mitochondria in Arabidopsis consists primarily of three families of ATP-dependent proteases, Clp, Lon, and FtsH, and one family of ATP-independent proteases, DegP. However, the functional significance of the multiplicity of their genes is not clear. To test whether expression of specific isomers could be differently affected by growth conditions, we analyzed transcript abundance following short-term exposure to different environmental stimuli, using 70-mer oligonucleotide arrays. This analysis revealed variability in the response to high light and different temperatures within members of each family. Thirty out of the 41 tested genes were up-regulated in response to high light, including both chloroplast and mitochondrial isozymes, whereas only six and five genes responded to either high or low temperature, respectively. The extent of response was variable, ranging from 2- to 20-fold increase in the steady-state levels. Absolute transcript levels of the tested genes, compiled from one-channel arrays, were also variable. In general, transcripts encoding mitochondrial isozymes were accumulated to a lower level than chloroplastic ones. Within the FtsH family, transcript abundance of most genes correlated with the severity of mutant phenotypes in the relevant genes. This correlation was also evident at the protein level. Analysis of FtsH isozymes revealed that FtsH2 was the most abundant species, followed by FtsH5 and 8, with FtsH1 being accumulated to only 10% of FtsH2 level. These results suggest that, unlike previous expectations, the relative importance of different chloroplast protease isozymes, evidenced by mutant phenotypes at least in the FtsH family, is determined by their abundance, and not necessarily by different specific functions or specialized expression under certain conditions.
Cell death: Apoptosis versus necrosis (Review) (2002)

Cell death and the subsequent post-mortem changes, called necrosis, are integral parts of normal development and maturation cycle. Despite the importance of this process, the mechanisms underlying cell death are still poorly understood. In the recent literature, cell death is said to occur by two alternative, opposite modes: apoptosis, a programmed, managed form of cell death, and necrosis, an unordered and accidental form of cellular dying. The incorrect consequence is the overlapping of: a) the process whereby cells die, cell death; and b) the changes that the cells and tissues undergo after the cells die. Only the latter process can be referred to as necrosis and represents a <no return> process in cell life. In this review, we discuss the excellent basic research developed in this field during last decades and problems that remain to be resolved in defining both experimentally and mechanicistically the events that lead to and characterize cell death.
The degradation of serum amyloid A protein by activated polymorphonuclear leucocytes: participation of granulocytic elastase. (1982)

To determine the role of inflammation in amyloidogenesis, we have studied the degradation of human serum amyloid A (SAA) protein by purified preparations of human blood polymorphonuclear leucocytes (PMN) and monocytes. When both PMN and monocytes were incubated in SAA-containing medium, the concentration of SAA as measured by a competitive anti-AA radioimmunoassay decreased over time. The rate of decrease of SAA was similar for both monocytes and PMN and there were no differences between four patients with amyloidosis and three normal controls. Resting PMN from normal volunteers were able to degrade SAA to smaller acid-soluble peptides within 16 hr while zymosan-activated PMN produced significant degradation within 1 hr (31%–50%). The supernatants from zymosan-treated PMN also caused marked SAA degradation within 1 hr.

The following enzyme inhibitors were able to prevent degradation of SAA by PMN supernatants; phenylmethylsulphonyl fluoride, a serine esterase inhibitor; α1 anti-trypsin and soybean trypsin inhibitor; and acetyl-ala-ala-pro-val-chloromethyl ketone, an elastase inhibitor. The ability of a neutral lysosomal enzyme to degrade SAA was further confirmed by showing that purified PMN elastase significantly degraded 125I-SAA.

We conclude that PMN contain one or more lysosomal enzymes capable of degrading SAA, an apoprotein of HDL3 serum lipoproteins. Alteration in SAA proteolysis by activated PMN may contribute to the deposition of amyloid fibrils in the tissues of patients with chronic inflammatory disease.
High-Level Gene Transfer to Cord Blood Progenitors Using Gibbon Ape Leukemia Virus Pseudotype Retroviral Vectors and an Improved Clinically Applicable Protocol (1998)

The best methods for transducing hematopoietic progenitor cells usually involve either direct co-cultivation with virus-producing cells or human stromal supportive cells. However, these methods cannot be safely or easily applied to clinical use. Therefore, we aimed at improving retrovirus-mediated gene transfer into hematopoietic progenitors derived from cord blood CD34+ cells using viral supernatant to levels achieved at least with direct co-cultivation and under conditions that are suitable for clinical applications. In a first set of experiments, CD34+ cells were infected with supernatant containing amphotropic retroviral particles carrying the nls-lacZ reporter gene and the effects of centrifugation, cell adhesion to fibronectin, and Polybrene on the transduction of both clonogenic progenitors (CFC) and long-term culture initiating cells (LTC-IC) were studied. Transduction efficiency was evaluated on the percentage and total number of progenitors expressing the beta-galactosidase activity. Results show that a 48-hr infection of CD34+ cells with viral supernatant combining centrifugation at 1000 x g for 3 hr followed by adhesion to fibronectin allows transduction levels for both CFC and LTC-IC to be reached that are as good as using direct co-cultivation. In a second set of experiments, CD34+ cells were infected using this optimized protocol with pseudotyped retroviral particles carrying the gibbon ape leukemia virus (GALV) envelope protein. Under these conditions, between 50 and 100% of CFC and LTC-IC were transduced. Thus, we have developed a protocol capable of highly transducing cord blood progenitors under conditions suitable for a therapeutical use.
A user study on visualizing directed edges in graphs (2009)

Graphs are often visualized using node-link representations: vertices are depicted as dots, edges are depicted as (poly)lines connecting two vertices. A directed edge running from vertex A to B is generally visualized using an arrow representation: a (poly)line with a triangular arrowhead at vertex B. Although this representation is intuitive, it is not guaranteed that a user is able to determine edge direction as quickly and unambiguously as possible; alternative representations that exhibit less occlusion and visual clutter might be better suited. To investigate this, we developed five additional directed-edge representations using combinations of shape and color. We performed a user study in which subjects performed different tasks on a collection of graphs using these representations and combinations thereof to investigate which representation is best in terms of speed and accuracy. We present our initial hypotheses, the outcome of the user studies, and recommendations regarding directed-edge visualization.
Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease (2002)

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid beta-peptide (Abeta) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Abeta. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Abeta toxicity as the result of reduced repair of Abeta-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of Abeta were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by Abeta.
Rectifier modulators with frequency-selective terminations, with particular reference to the effect of even-order modulation products (1960)

Solutions are obtained for the modulation-product currents in series- and shunt-type rectifier modulators by separating out an equation for each possible modulation-product frequency and by assuming (a) square-wave switching of non-reactive rectifiers, and (b) signal-path terminating impedances which are a pure but not necessarily constant resistance—or zero or infinite—at each modulation-product frequency involved. The conditions under which there are no even-order modulation-product currents are determined, and the influence of such currents when they do exist is examined. Experimental results confirm the theory. It is shown that all the working and conclusions apply exactly to the ring modulator, provided that terminations required for odd-order modulation-product frequencies are applied in the output loop and those required for even-order frequencies are applied in the input.
Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogeneous (1991)

We previously demonstrated that the human anti-Haemophilus influenzae type b polysaccharide (Hib-PS) VL repertoire is dominated by a product of the V kappa II gene, A2, and that V kappa II-A2 anti-Hib-PS antibodies have little or no somatic mutation in VL. To further study this VL repertoire, we studied non-A2 anti-Hib-PS antibodies that were identified either serologically or by amino-terminal amino acid sequence analysis. Of 15 non-A2 anti-Hib-PS antibodies from 12 vaccinated adults, we found four V lambda, five V kappa I, one non-A2 V kappa II, four V kappa III, and one V kappa IV antibodies. As expected, all but two of these subjects also produced V kappa II-A2 antibodies. Interestingly, one of these subjects lacks the A2 gene in the germ line. However, both subjects who did not produce detectable V kappa II antibody did produce normal amounts of total anti-Hib-PS antibody after vaccination. Candidate V kappa genes for the non-A2 antibodies were identified by comparison of up to 60 VL amino acid residues, including CDR1 and CDR2, with all sequenced V kappa genes. V kappa I antibodies appear to be products of three newly sequenced V kappa I genes, O8, O18, and L11, that are reported here. The O8 and O18 genes encode identical amino acid sequences. The non-A2 V kappa II antibody is a likely product of the A1 or A17 genes, the V kappa III antibodies are likely products of the A27 gene, and the V kappa IV antibody is a product of the single V kappa IV gene, B3. Unlike V kappa II-A2 antibodies, the V kappa I, V kappa III, and V kappa IV antibodies differed by one to five CDR residues from the germ line product of the candidate genes, suggesting the presence of somatic mutations. Thus, anti-Hib-PS antibodies can be divided into two types, the most frequently observed A2 antibodies with little or no somatic mutation and non-A2 antibodies that likely contain somatic mutations.
Prevalence and risk factor analysis of GBV‐C/HGV infection in prostitutes (1997)

GB virus-C (GBV-C) and Hepatitis G virus (HGV) are variants of a recently cloned virus transmitted parenterally. It is unclear if sexual contact also transmits this virus. In this study, we detected serum GBV-C/HGV RNA in 140 prostitutes by reverse transcription polymerase chain reaction (RT-PCR) using different primers. Thirty (21%) were found with GBV-C RNA by nested PCR although only 22 (73%) had HGV RNA by single round RT-PCR. Both assays had a nearly perfect agreement (kappa value, 0.812). The prevalence of GBV-C RNA in prostitutes was significantly higher than the control group (30/140 vs. 2/40, P < 0.02). Multivariate analysis revealed that a frequency of paid sex more than 120 times per month was the only factor significantly associated with positive GBV-C RNA in prostitutes (P < 0.003). In summary, prostitutes are a high risk group and reservoir of GBV-C/HGV infection due to high frequency of paid-sex. J. Med. Virol. 52:83–85, 1997. © 1997 Wiley-Liss, Inc.
Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy (2014)

Advances in the design of chimeric antigen receptors (CARs) have improved the antitumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. We proposed that CAR expression in Vα24-invariant natural killer T (NKT) cells can build on the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKT cells were engineered to express a CAR against the GD2 ganglioside (CAR.GD2), which is highly expressed by neuroblastoma (NB). We compared CAR.GD2 constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB costimulatory endodomains. CAR.GD2 expression rendered NKT cells highly cytotoxic against NB cells without affecting their CD1d-dependent reactivity. We observed a striking T helper 1-like polarization of NKT cells by 4-1BB-containing CARs. Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKT cells. These CAR.GD2 NKT cells effectively localized to the tumor site had potent antitumor activity, and repeat injections significantly improved the long-term survival of mice with metastatic NB. Unlike T cells, CAR.GD2 NKT cells did not induce graft-versus-host disease. These results establish the potential of NKT cells to serve as a safe and effective platform for CAR-directed cancer immunotherapy.
Infrared horizon sensor modeling for attitude determination and control: Analysis and mission experience (1985)

The work performed by the Attitude Determination and Control Section at the National Aeronautics and Space Administration/Goddard Space Flight Center in analyzing and evaluating the performance of infrared horizon sensors is presented. The results of studies performed during the 1960s are reviewed; several models for generating the Earth's infrared radiance profiles are presented; and the Horizon Radiance Modeling Utility, the software used to model the horizon sensor optics and electronics processing to computer radiance-dependent attitude errors, is briefly discussed. Also provided is mission experience from 12 spaceflight missions spanning the period from 1973 to 1984 and using a variety of horizon sensing hardware. Recommendations are presented for future directions for the infrared horizon sensing technology.
Similar sequence specificity of mitoxantrone and VM-26 stimulation of in vitro DNA cleavage by mammalian DNA topoisomerase II (1993)

The molecular mechanism of topoisomerase II trapping by antitumor drugs probably involves the formation of a ternary complex DNA-drug-topoisomerase II. Recent studies support the view that a drug molecule might be placed at the DNA cleavage site interacting with the two flanking base pairs and amino acid residues of the enzyme. In this work, the DNA sequence-dependent action of mitoxantrone on topoisomerase II DNA cleavage was investigated in SV40 DNA fragments and short oligonucleotides, in comparison to VM-26, 4-demethoxydaunorubicin, and mAMSA. Mitoxantrone and VM-26 had a much lower degree of selectivity than 4-demethoxydaunorubicin and mAMSA in stimulating DNA cleavage. DNA cleavage at sites that were always stimulated also by VM-26. In contrast, mitoxantrone and 4-demethoxydaunorubicin shared only 7% of cleavage sites, and about 70% of the 4-demethoxydaunorubicin-stimulated sites were also stimulated by VM-26. Unlike what is generally seen with anthracyclines, the structurally related drug, mitoxantrone, stimulated cleavage also at DNA sites observed without drugs. Local base preferences at the cleavage site as determined by statistical analysis showed that mitoxantrone preferentially cleaved the DNA at sites with a cytosine or a thymine at position-1. However, strong DNA cleavage stimulation by mitoxantrone was favored by specific base pairs at the next positions flanking the cleaved bond (positions -2 and +2) and at positions +8 and +9. Effects of base mutations on drug stimulation of DNA cleavage in short DNA oligonucleotides independently showed that a pyrimidine at position -1 is required for mitoxantrone action.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of a Structural Determinant in Thrombin-Protease Nexin 1 Complexes That Mediates Clearance by the Low Density Lipoprotein Receptor-related Protein (1999)

We recently identified a synthetic peptide, Pro47-Ile58, derived from the mature protease nexin 1 (PN1) sequence, that inhibited the low density lipoprotein receptor-related protein (LRP)-mediated internalization of thrombin-PN1 (Th-PN1) complexes. Presently, we have analyzed this sequence in Th-PN1 complex catabolism using two independent approaches: 1) An antibody was generated against Pro47-Ile58, which inhibited complex degradation by 70% but had no effect on the binding of the complexes to cell surface heparins. This places the structural determinant in PN1 mediating complex internalization by the LRP outside of the heparin-binding site. 2) Site-directed genetic variants of PN1 with a single Ala substitution at His48, or two Ala substitutions, one at His48 and another at Asp49, were expressed in Sf9 insect cells. The catabolic rate of complexes formed between Th and the singly substituted and doubly substituted variants was lowered to 50 and 15%, respectively, when compared with the catabolic rate of native Th-PN1 complexes. This is the first analysis of a structural determinant in a serine protease inhibitor (SERPIN) required for LRP-mediated internalization and in part may explain the cryptic nature of this site in the unreacted serine protease inhibitor.
Attachment and growth of mammalian cells on microcarriers with different ion exchange capacities (1987)

In the design of microcarriers for animal cell growth, the exchange capacity has been considered a critical factor. However, charge densities of microcarriers under culture conditions are not the same as the exchange capacities. Furthermore, the charge density requirement for optimum attachment is not necessarily the same as that required for optimum growth. We demonstrate that charge is not the sole factor affecting the attachment and growth of animal cells on microcarriers. We also show that supplemental serum in the growth medium has a negative effect on cell attachment to microcarriers.
Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study (2009)

The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.
Losartan in the Therapy of Heart Failure Patients (2001)

The effects of losartan on myocardial remodeling and neurohumoral status were studied in 240 patients with congestive heart failure. The patients were randomized into 3 groups of 80 subjects. Each group continued to receive conventional therapy including the angiotensin-converting enzyme inhibitor enalapril. Group 1 was also given a placebo, groups 2 and 3 had losartan in doses of 25 mg and 50 mg daily, respectively. The course of treatment was 48 weeks. Cardiac function was assessed by B-mode and Doppler echocardiography. Plasma neurohormone levels were determined by radioimmunoassay. Losartan in a dose of 50 mg daily gave the best improvement in cardiac function and the most marked reduction in plasma levels of renin, angiotensin II, aldosterone, atrial natriuretic peptide, endothelin-1, and norepinephrine levels than the lower dose of losartan or placebo. The fall in cortisol and serotonin levels was similar in each group. These data demonstrate the dose-dependent effects of losartan and clarify its role in the treatment of congestive heart failure.