gebhart/patrepeval huggingface dataset:
Antibody fragments (2010)

The antibody molecule is modular and separate domains can be extracted through biochemical or genetic means. It is clear from review of the literature that a wave of novel, antigen-specific molecular forms may soon enter clinical evaluation. This report examines the developmental histories of therapeutics derived from antigen-specific fragments of antibodies produced by recombinant processes. Three general types of fragments were observed, antigen-binding fragments (Fab), single chain variable fragments (scFv) and "third generation" (3G), each representing a successive wave of antibody fragment technology. In parallel, drug developers have explored multi-specificity and conjugation with exogenous functional moieties in all three fragment types. Despite high hopes and an active pipeline, enthusiasm for differentiating performance of fragments should, perhaps, be tempered as there are yet few data that suggest these molecules have distinct clinical properties due only to their size.
Regulation of biosynthesis of nitric oxide. (1994)

Nitric oxide synthases (NOSs)' (L-arginine, NADPH:oxygen oxidoreductases (nitric oxide forming); EC 1.14.13.39) are unique among eukaryotic enzymes in being dimeric, calmodulin-dependent or calmodulin-containing cytochrome P450-like hemoproteins that combine reductase and oxygenase catalytic domains in one monomer, bear both FAD and FMN, and carry out a 5-electron oxidation of a non-aromatic amino acid (L-arginine) with the aid of tetrahydrobiopterin (1).Eukaryotes as phylogenetically ancient and diverse as Limulus polyphemus (2) and Rhodnius prolixus (3) make NO, and species as distantly related as Drosophila' and man (&lo) have yielded NOS cDNAs.Biosynthesis of nitric oxide (NO) appears to be within the repertoire of most mammalian cell types ( l l ) , provided they are appropriately stimulated.NO has been known for the past 6 years to mediate aspects of macrophage cytotoxicity, regulate blood pressure, and participate in neurotransmission (11,12), yet a steady stream of reports continues to enlarge NO'S sphere of action.For example, endogenous NO can contribute to destruction of the host's joints (13, 14) and kidneys ( 14) or to its survival from viral infection (15).Accordingly, regulation of NO biosynthesis has attracted intensive study and is the subject of this review.Other recent surveys deal with the enzymology of NOSs (1, 16) and their physiologic roles (11,12). RecapResearch through 1992 described two constitutive, calmodulindependent NOSs (cNOSs).One is apparently restricted to endothelium.The other is found in central and peripheral neurons, neuroblastomas (7), human but not rat skeletal muscle (6), p cells of pancreatic islets, and epithelial cells of bronchioli, uterus, and stomach (17).The cNOSs lie dormant until and so long as a rise in intracellular Ca2+ sustains the binding of calmodulin, leading to NO release over several minutes (18).An inducible NOS is expressed in many cell types after challenge with immunologic or inflammatory stimuli (11) and thereupon generates large amounts of NO over periods as long as 5 days (19).Tonic activation of this isoform may reflect its ability to bind calmodulin even at the trace levels of Ca2+ found in resting cells (20).This isoform was termed iNOS to signify its independence of elevated Ca2+ and exogenous calmodulin (21).These elements of the picture remain in place.Now, however, the canvas is crowded with new details. How Many NOSs?The human endothelial cNOS gene, residing at 7q35-7q36, comprises 26 exons that span 21 kb (22,23).The 28-exon neural cNOS gene on human chromsome 12q24.2extends over 100 kb (7).3 Hu-
Electromagnetic Fields and Health Outcomes (2001)

Over the past two decades, there has been increasing interest in the biological effects and possible health outcomes of weak, low-frequency electric and magnetic fields. Epidemiological studies on magnetic fields and cancer, reproduction and neurobehavioural reactions have been presented. More recently, neurological, degenerative and heart diseases have also been reported to be related to such electromagnetic fields. Furthermore, the increased use of mobile phones worldwide has focussed interest on the possible effects of radiofrequency fields of higher frequencies. In this paper, a summary is given on electromagnetic fields and health outcomes and what policy is appropriate--"no restriction to exposure", "prudent avoidance" or "expensive interventions"? The results of research studies have not been unambiguous; studies indicating these fields as being a health hazard have been published and so were studies indicating no risk at all. In "positive" studies, different types of effects have been reported despite the use of the same study design, e.g., in epidemiological cancer studies. There are uncertainties as to exposure characteristics, e.g., magnetic field frequency and exposure intermittence, and not much is known about possible confounding or effect-modifying factors. The few animal cancer studies reported have not given much help in risk assessment; and in spite of a large number of experimental cell studies, no plausible and understandable mechanisms have been presented by which a carcinogenic effect could be explained. Exposure to electromagnetic fields occurs everywhere: in the home, at work, in school, etc. Wherever there are electric wires, electric motors and electronic equipment, electromagnetic fields are created. This is one of the reasons why exposure assessment is difficult. For epidemiologists, the problems is not on the effect side as registers of diseases exist in many countries today. The problem is that epidemiologists do not know the relevant exposure characteristics to be used in their studies. In international guidelines, limits for restrictions of field exposure are several orders of magnitude above what can be measured from overhead power lines and found in "electrical" occupations. These guidelines emphasize that the state of scientific knowledge today does not warrant limiting exposure levels for the public and the work force, and that further data are required to confirm whether health hazards are present. In some countries, however, the "principle of caution" or "prudent avoidance" has been adopted; meaning the low-cost avoidance of unnecessary exposure as long as there is scientific uncertainty about its health effects.
The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei (1996)

The in-vitro activities of four anticancer alkyllysophospholipids, ET-18-OCH3 (edelfosine), hexadecylphosphocholine (miltefosine), ilmofosine and SRI 62-834, were determined with ED50 values for Leishmania donovani and Trypanosoma cruzi amastigotes between 0.2 and 5.0 microM and for Trypanosoma brucei trypomastigotes between 7.0 and 50.8 microM. In BALB/c mice miltefosine and ilmofosine were the most active compounds with ED50 values of 2.9 and 14.5 mg/kg x 5 doses against L. donovani and a suppressive effect on T. cruzi infections at 30 mg/kg x 5 doses.
Induction of Angiogenesis by a Fragment of Human Tyrosyl-tRNA Synthetase (2002)

The first step of protein synthesis is catalyzed by aminoacyl-tRNA synthetases. In addition, certain mammalian tRNA synthetases link protein synthesis to cytokine signaling pathways. In particular, human tyrosyl-tRNA synthetase (TyrRS) can be split by proteolysis into two fragments having distinct cytokine activities. One of the TyrRS fragments (mini TyrRS) contains features identical to those in CXC chemokines (like interleukin-8) that also act as angiogenic factors. Here mini TyrRS (but not full-length TyrRS) is shown to stimulate chemotaxis of endothelial cells in vitro and stimulate angiogenesis in each of two in vivo animal models. The angiogenic activity of mini TyrRS can be opposed by anti-angiogenic chemokines like IP-10. Thus, a biological fragment of human tyrosyl-tRNA synthetase links protein synthesis to regulation of angiogenesis.
Platelet ADP receptors contribute to the initiation of intravascular coagulation (2003)

While the adenosine 5'-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagen-adhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y12 and P2Y1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectron-microscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y1-deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus.
A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer (2003)

The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.
In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. (1996)

To investigate the in vivo angiogenic activity of placenta growth factor (PIGF) and its heterodimers with vascular endothelial growth factor (VEGF), the induction of neovascularization of these factors in the mouse cornea was studied. VEGF165 is sufficiently potent to stimulate new capillary growth from the limbal vessels. PIGF129/VEGF165 heterodimers also induce corneal neovascularization with a maximal vessel length similar to VEGF165, but with a marked decrease of vessel density. In contrast, PIGF129 has little or no effect in this in vivo angiogenesis assay. The expression of VEGF mRNA and protein is drastically up-regulated by hypoxia in choriocarcinoma cells, whereas expression of PIGF is not affected by the low concentration of oxygen. Up-regulation of VEGF production results in increased formation of PIGF/VEGF heterodimers in these tumor cells. Thus, hypoxia indirectly up-regulates expression levels of PIGF/VEGF heterodimers and modulates VEGF activity when these factors are co-expressed.
2-Methoxyestradiol blocks estrogen-induced rat pituitary tumor growth and tumor angiogenesis: possible role of vascular endothelial growth factor. (2000)

Natural and synthetic estrogens have been associated with several types of human and animal cancers including prolactin-secreting pituitary tumors in Fischer 344 rats. These prolactin-secreting tumors are highly angiogenic and their growth is angiogenic dependent. In the present study we have utilized this model to evaluate the effect of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite that is a potent inhibitor of endothelial cell proliferation in vitro, on estrogen-induced pituitary tumor growth and angiogenesis. Adult female rats were implanted (subcutaneously) with a silastic capsule containing estradiol-17beta (E2). After seven days of constant E2 exposure animals were injected (sc) daily with 25 mg/kg of 2-ME and killed either three or 8 days later. Changes in pituitary weight and proliferating cell nuclear antigen (PCNA) labeling index indicated growth while degree of angiogenesis was determined immunohistochemically using factor VIII related antigen. The results indicate that 2-ME inhibited estrogen-induced lactotroph growth by 32% and tumor angiogenesis by 89%. Furthermore, vascular endothelial growth factor (VEGF) expression, evaluated by immunohistochemical analysis, was down-regulated concomitant with tumor angiogenic suppression. These studies suggest that 2-ME may have therapeutic potential for hormone-induced cancer and that its angiostatic activity may be modulated through down-regulation of VEGF expression.
Differential Ca2+ signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells (2004)

Thrombin and related protease-activated receptors 1, 2, 3, and 4 (PAR1-4) play a multifunctional role in many types of cells including endothelial cells. Here, using RT-PCR and immunofluorescence staining, we showed for the first time that PAR1-4 are expressed on primary human brain microvascular endothelial cells (HBMEC). Digital fluorescence microscopy and fura 2 were used to monitor intracellular Ca2+ concentration ([Ca2+]i) changes in response to thrombin and PAR1-activating peptide (PAR1-AP) SFFLRN. Both thrombin and PAR1-AP induced a dose-dependent [Ca2+]i rise that was inhibited by pretreatment of HBMEC with the phospholipase C inhibitor U-73122 and the sarco(endo)plasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Thrombin induced transient [Ca2+]i increase, whereas PAR1-AP exhibited sustained [Ca2+]i rise. The PAR1-AP-induced sustained [Ca2+]i rise was significantly reduced in the absence of extracellular calcium or in the presence of an inhibitor of store-operated calcium channels, SKF-96365. Restoration of extracellular Ca2+ to the cells that were initially activated by PAR1-AP in the absence of extracellular Ca2+ resulted in significant [Ca2+]i rise; however, this effect was not observed after thrombin stimulation. Pretreatment of the cells with a low thrombin concentration (0.1 nM) prevented [Ca2+]i rise in response to high thrombin concentration (10 nM), but pretreatment with PAR1-AP did not prevent subsequent [Ca2+]i rise to high PAR1-AP concentration. Additionally, treatment with thrombin decreased transendothelial electrical resistance in HBMEC, whereas PAR1-AP was without significant effect. These findings suggest that, in contrast to thrombin, stimulation of PAR1 by untethered peptide SFFLRN results in stimulation of store-operated Ca2+ influx without significantly affecting brain endothelial barrier functions.
Glucose‐sensitive afferent nerve fibres in the hepatic branch of the vagus nerve in the guinea‐pig. (1982)

1. Afferent discharges were recorded from nerve filaments dissected from the hepatic branch of the vagus nerve in the guinea-pig in situ. 2. A significant decrease in the discharge rate was observed following the administration of D-glucose into the portal vein but not after the administration of D-mannose, D-fructose, D-galactose, L-glucose, D-xylose or D-arabinose. 3. The mean discharge rate of these fibres was inversely related to the concentration of glucose in the portal blood. 4. These results suggest the existence of D-glucose 'sensors' in the liver which monitor the glucose concentration of portal blood.
Planar Antennas for Wireless Communications (2003)

Preface. Introduction and Overview. PIFAs for Internal Mobile Phone Antennas. Very-Low-Profile Monopoles for Internal Mobile Phone Antennas. Base Station Antennas for Cellular Communication Systems. Antennas for WLAN Applications. Dielectric Resonator Antennas for Wireless Communications. Integration of Antennas for Different Operating Bands. Appendix: Summary of Acronyms. Index.
Evidence for decreasing quality of semen during past 50 years (1993)

Objective-To investigate whether semen quality has changed during the past 50 years.
Iterative generation of motion-compensated side information for distributed video coding (2005)

Distributed video coding (DVC) is a coding paradigm that gives the decoder the task to exploit the source statistics to achieve efficient compression. Current approaches to DVC rely on motion-compensated interpolation to generate at the decoder an estimation of the frame being decoded. This paper presents an iterative motion-compensated interpolation technique that takes advantage of all available information about the frame being estimated, not only the previous and posterior frames as is common practice. Simulation results show that the addition of this estimation technique to an existing DVC codec produces a 0.15 dB improvement in the PSNR of the rate-distortion plots.
Hhat Is a Palmitoylacyltransferase with Specificity for N-Palmitoylation of Sonic Hedgehog (2008)

Palmitoylation of Sonic Hedgehog (Shh) is critical for effective long- and short-range signaling. Genetic screens uncovered a potential palmitoylacyltransferase (PAT) for Shh, Hhat, but the molecular mechanism of Shh palmitoylation remains unclear. Here, we have developed and exploited an in vitro Shh palmitoylation assay to purify Hhat to homogeneity. We provide direct biochemical evidence that Hhat is a PAT with specificity for attaching palmitate via amide linkage to the N-terminal cysteine of Shh. Other palmitoylated proteins (e.g. PSD95 and Wnt) are not substrates for Hhat, and Porcupine, a putative Wnt PAT, does not palmitoylate Shh. Neither autocleavage nor cholesterol modification is required for Shh palmitoylation. Both the Shh precursor and mature protein are N-palmitoylated by Hhat, and the reaction occurs during passage through the secretory pathway. This study establishes Hhat as a bona fide Shh PAT and serves as a model for understanding how secreted morphogens are modified by distinct PATs.
Ferulate Cross-Links Limit the Enzymatic Degradation of Synthetically Lignified Primary Walls of Maize (1998)

Ferulate cross-linking of arabinoxylans to lignin may restrict the enzymatic degradation of structural polysaccharides, limiting the utilization of graminaceous crops and crop residues as feedstuffs and as feedstocks for fuel and chemical production. Maize walls from nonlignified cell suspensions with ca. 5.1 or 17.6 mg g-1 of ferulates were synthetically lignified with coniferyl alcohol and H2O2 to form dehydrogenation polymer−cell wall complexes with ca. 4.8 or 15.8 mg g-1 of ferulates incorporated into lignin. Ferulate concentrations in cell walls were reduced from normal levels by growing cell suspensions with 2-aminoindan-2-phosphonic acid or by methylating wall ferulates with diazomethane prior to complex formation. A 70% reduction in ferulate−lignin cross-linking increased carbohydrate solubilization by 24−46% after 6 h and by 0−25% after 72 h of hydrolysis with two fungal enzyme mixtures. Reduced cross-linking enhanced the hydrolysis of xylans and, to a lesser degree, cellulose from walls. The results presented indicate that reduced feruloylation of arabinoxylans will significantly improve the hydrolysis of lignified grass walls. Keywords: Gramineae; Zea mays; cell wall; ferulic acid; diferulic acids; lignin; cross-linking; cellulase; degradability
99m Tc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer (2013)

Because traditional endpoints in oncology trials are not always applicable for metastatic prostate cancer, better ways of fol-lowing response to treatment are needed. Prostate-specific membraneantigen (PSMA) isa transmembraneproteinexpressed innormalhumanprostate epitheliumand isupregulated inprostate cancer. (S)-2-(3-((S)-1-carboxy-5-((4-123I-iodobenzyl)amino)pen-tyl)ureido)pentanedioic acid, 123I-MIP-1072, targets PSMA and was evaluated formonitoring the growth of PSMA-positive LNCaP cells in vitro and as xenografts after paclitaxel therapy.Methods: LNCaP and 22Rv1 cells were treated with paclitaxel (0– 100 nM) for 48 h, after which binding of 123I-MIP-1072 was examined. Cell numberwas determined byMTS assay, and PSMA expression was analyzed by Western blotting. LNCaP xenograft– bearingmicewere treatedwithpaclitaxel (6.25mg/kg) for3.5cycles of 5 d on and 2 d off. Tissue distribution of 123I-MIP-1072 was determined on days 2 and 23 from the start of paclitaxel treatment. Results: Paclitaxel (10–100 nM) inhibited LNCaP and 22Rv1 cell growthafter 48h, andbindingof 123I-MIP-1072wasproportional to cell number. Western blot analysis verified there was no pacli-taxel-dependent change in PSMA expression. Treatment of LNCaP xenografts with paclitaxel resulted in a decrease in tumor volume (221%), compared with an increase in the untreated xenografts (1205%) by day 23. Tumor uptake of 123I-MIP-1072 was proportional to changes in tumor mass: decreased by pacli-taxel treatment and increased in untreated mice. Conclusion: Treatment of LNCaP cells or xenograft tumors with paclitaxel resulted in growth inhibition, which was detected with 123I-MIP-1072. The high specificity of 123I-MIP-1072 for prostate cancer may allowmonitoring of tumor progression in patients before, dur-ing, and after chemotherapy. KeyWords:molecular imaging; oncology; radiopharmaceuticals; prostate cancer; prostate-specific membrane antigen
l-Arginine influences the structure and function of arginase mRNA in Aspergillus nidulans (2007)

Expression of the arginase structural gene (agaA) in Aspergillus nidulans is subject to complex transcriptional and post-transcriptional regulation. Arginase mRNA has a long 5'-UTR sequence. Analysis of this sequence in silico revealed its putative complex secondary structure, the presence of arginine-binding motifs (arginine aptamers) and a short intron with two potential 3' splicing sites. In this report we present evidence that L-arginine (i) binds directly to the arginase 5'-UTR; (ii) invokes drastic changes in the secondary structure of the 5'-UTR, unlike several other L-amino acids and D-arginine; and (iii) forces the selection of one of two 3' splice sites of an intron present in the 5'-UTR. We postulate that expression of the eukaryotic structural gene coding for arginase in A. nidulans is regulated at the level of mRNA stability, depending on riboswitch-mediated alternative splicing of the 5'-UTR intron.
MicroRNA alterations in head and neck squamous cell carcinoma (2008)

MicroRNAs (mirs) are small noncoding RNA molecules (~22 nucleotides) that regulate posttranscriptional gene expression. Currently, there has not been a comprehensive study of their role in primary head and neck squamous cell carcinoma (HNSCC). To determine the role of mirs in HNSCC, we screened for altered microRNA expression in HNSCC primary tissue and cell lines. We then further tested the functional impact of alterations of specific mirs. An initial screening of 4 primary HNSCC, 4 normal mucosal controls and 4 HNSCC cell lines was analyzed for mature microRNA expression by microarray. Significance was determined using significance analysis of microarrays (SAM). Nine microRNAs were found by SAM to be upregulated or downregulated in tumor tissue including mir-21, let-7, 18, 29c, 142-3p, 155, 146b (overexpressed) and 494 (underexpressed). Mir-21 was validated by qRT-PCR. Functional validation by growth assays was performed, further validating mir-21. Transfection of mir-21 into JHU-011 and JHU-012 cell lines showed a 39% increase in cell growth at 72 hr relative to controls (p < 0.05). Transfection of the inhibitor into JHU-O12 cell lines showed a 92% decrease in cell growth relative to controls at 72 hr (p < 0.05). In addition, flow cytometry analysis of JHU-012 cells 48 hr after mir-21 inhibitor transfection showed a statistically significant increase in cytochrome c release and increased apoptosis. These differentially expressed microRNAs may be of interest as potential novel oncogenes and tumor suppressor genes in HNSCC. Mir-21 is a putative oncogenic microRNA in head and neck cancer.