gebhart/patrepeval huggingface dataset:
Novel Aromatic/Heterocyclic Sulfonamides and Their Metal Complexes as Inhibitors of Carbonic Anhydraseisozymes I, II and IV (1997)

Reaction of five aromatic/heterocyclic sulfonamides containing free amino, groups with 5-nitro-alpha-2-toluenesultone and diethyl pyrocarbonate, respectively, afforded novel inhibitors of the zinc enzyme carbonic anhydrase (CA). Zn(II) complexes of the new sulfonamides were prepared. Excellent inhibition of three CA isozymes (CA I, II and IV respectively) were observed with some of the new sulfonamides, but especially with their Zn(II) complexes. Structure-activity correlations in this series of inhibitors are discussed.
Generation of Highly Selective Monoclonal Antibodies Inhibiting Tumorigenic Proteases (2015)

Overwhelming evidence has implicated that protease upregulation plays a critical role in cancer growth and tumorigenesis. Extracellular metalloproteinases (e.g. MMPs, MT-SPs) have been considered as therapeutic targets. However, prior attempts focusing on small compounds against metalloproteainses failed in clinical trials, indicating selectivity is the key for a successful protease inhibition. With a large contact surface by multiple complementarity determining regions (CDRs), antibodies are exquisitely specific thus considered as promising drugs. Unfortunately, at least two obstacles make the routine discovery of protease inhibiting antibodies considerably difficult: (1) low antigenicity of the proteolytic active sites, and (2) lack of a function-based selection method. To develop therapeutic antibodies that specifically inhibit metalloproteinases, this thesis aims to overcome aforementioned technical hurdles and establish general methodologies for the discovery of inhibitory antibodies. These research objectives were successfully achieved by: (1) Developing a function-based high-throughput inhibitory antibody screening method using a simple periplasmic preparation and a sensitive FRET assay without antibody purification. Using this method, inhibitory antibodies were rapidly distinguished from non-inhibitory clones with satisfactory Z-factors. (2) Developing a novel expression strategy for direct production of catalytic domain of MMP-14 in the E. coli periplasm without refolding or activation. Achieving co-expression of both MMP-14 and antibody fragment in the periplasm further facilitated screening of inhibitory antibodies without purification of MMP-14 or Fabs. (3) Constructing large synthetic human antibody libraries (&amp;gt;109 variants) carrying extended CDR-H3 (23 to 27 aa) and isolating a panel of highly potent and selective inhibitory antibodies from the constructed libraries. Particularly, 3A2 Fab was a competitive inhibitor exhibiting a binding affinity of 4.85 nM by SPR and an inhibition potency of 25 nM. (4) Converting a low potency peptide inhibitor (IC50=150 µM) into an antibody with an &amp;gt;103-fold improved inhibitory potency by grafting the inhibitory peptide into CDR-H3 of antibody scaffold and optimizing the sequences flanking peptide motif. The resulting 1F8 Fab exhibited an inhibition potency of IC50=120 nM against MMP-14. In conclusion, we believe these inhibitory antibody discovery approaches have great potentials to apply for proteases and important targets with biological significance.
Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. (2003)

The beta-catenin and APC genes are key components of the Wnt signaling pathway. Mutation of these genes results in increased levels of the beta-catenin protein, which is associated with enhanced cellular proliferation and the development of both colon polyps and colon cancer. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells so that it is now possible to specifically decrease the expression of cellular genes after transfection of annealed small interfering 21-mer RNAs. In the current study, we used small interfering RNA (siRNA) directed against beta-catenin to determine the effects of decreasing the high constitutive levels of this protein in colon cancer cell lines with mutations in either beta-catenin or APC. Our studies demonstrate that siRNA directed against beta-catenin markedly decreased beta-catenin-dependent gene expression and inhibited cellular proliferation as reflected in the reduced growth of these colon cancer cells both in soft agar and in nude mice. These results indicate that siRNA can target specific factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human cancer.
Principles of free radical biomedicine, Volume 2 (2011)

Introduction Non-enzymatic antioxidants Glutathione Vitamin C Vitamin E Nutritional antioxidants Antioxidant enzymes Superoxide dismutases SOD mimics Catalases Glutathione peroxidases Thioredoxins & glutaredoxins Peroxiredoxins Role & regulation of heme oxygenase in oxidative stress NF-kB transcription factor: Mechanism of redox regulation The Nrf2 (NFE2L2) transcription factor pathway Redox-modulated AP-1 signaling Subcellular Compartmentalization Oxidative stress in mitochondria Oxidative stress & lysosomes Oxidative stress & peroxisomes Oxidative stress & the endoplasmic reticulum Metabolism & Physiology Iron metabolism Copper metabolism Inflammation Mechanisms of oxygen sensing & hypoxia.
Idiotypic Mimicry of Biological Receptors (1986)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
A systematic SPR study of human plasma protein adsorption behavior on the controlled surface packing of self‐assembled poly(ethylene oxide) triblock copolymer surfaces (2009)

A well-controlled biocompatible nonfouling surface is significant for biomedical requirements, especially for the improvement of biocompatibility. We demonstrate the low or nonbiofouling surfaces by coating hydrophobic-hydrophilic triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) on the CH(3)-terminated self-assembled monolayer (SAM). Two types of copolymers are used to modify the surface, one with different PEO/PPO ratios ( approximately 20/80, 40/60, and 80/20, w/w) but the same PPO molecular weight ( approximately 2 k), the other with different copolymer MWs ( approximately 9, 11, and 15 k) but the same PEO/PPO ratio (80/20, w/w). In situ surface plasmon resonance (SPR) sensor is used to evaluate polymer adsorption on the SAMs and subsequent protein adsorption on the copolymer-treated surface. The effects of PEO-PPO-PEO molecular weight, PPO-to-PEO ratio, and ionic strength on protein adsorption from single protein solutions of fibrinogen, BSA, and complex mixed proteins are systematically investigated. A Pluronic F108 treated surface is highly resistant to nonspecific protein adsorption under the optimized conditions (MW of 15 k and PEO/PPO ratio of 80/20). This work demonstrates that the PEO-PPO-PEO polymer is able to achieve ultra low fouling surface via surface modification by controlling surface packing density of polymers (molecular weight, hydrophobic/hydrophilic ratio, and hydrophilic group coverage).
Mediators of non‐adrenergic non‐cholinergic inhibitory neurotransmission in porcine jejunum (2004)

The purpose of this study was to determine the non-adrenergic non-cholinergic inhibitory neurotransmitter in pig jejunum. Intracellular electrical activity was recorded from circular smooth muscle cells. Inhibitory junction potentials (IJPs) evoked by electrical field stimulation were inhibited by tetrodotoxin (1 micromol L(-1)), omega-conotoxin GVIA (0.1 micromol L(-1)) tetrodotoxin, apamin (1 micromol L(-1)), 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122; 10 micromol L(-1)) but not by N omega-nitro-l-arginine (l-NNA; 100 micromol L(-1)), haemoglobin (10 micromol L(-1)), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 micromol L(-1)) or 9-(tetrahydro-2-furyl)adenine (SQ-22536; 10 micromol L(-1)). S-nitroso-N-acetylpenicillamine (SNAP) hyperpolarized the membrane potential. This was inhibited by ODQ (3 micromol L(-1)) and charybdotoxin (0.1 micromol L(-1)). Adenosine-5-triphosphate (ATP; 100 micromol L(-1)) and 2-methylthio ATP (2-MeS-ATP; 100 micromol L(-1)) did not hyperpolarize the membrane potential and 6-N-N-diethyl-beta- gamma -dibromomethylene-d-adenosine-5'-triphosphate (ARL67156; 100 micromol L(-1)) did not modify IJPs. Carbon monoxide (CO; 10%) and tricarbonyl dichlororuthenium dimer ([Ru(CO3Cl2)]2; 100 micromol L(-1)) hyperpolarized the membrane potential however zinc, copper and tin protoporphyrin IX (100 micromol L(-1)) did not alter IJPs. Vasoactive intestinal peptide (VIP) hyperpolarized the membrane potential but 4-Cl-d-Phe6-Leu17-VIP (1 micromol L(-1)) did not modify IJPs. Pituitary adenylate cyclase activating peptide (PACAP)38 (0.5 micromol L(-1)) hyperpolarized the membrane potential. This was inhibited by apamin (1 micromol L(-1)) but not by tetrodotoxin (1 micromol L(-1)). Pituitary adenylate cyclase activating peptide6-38 (1 micromol L(-1)) inhibited IJPs. These data suggest that inhibitory neurotransmission in pig jejunum is mediated partly by PACAP.
Isolation and Characterization of Deletion Mutants of Herpes Simplex Virus Type 2 (Strain HG52) (1985)

We provide evidence that: (i) two variants lacking the XbaI site at map coordinate 0.7 have been selected following XbaI treatment of the DNA of herpes simplex virus type 2 strain HG52; (ii) one of these mutants had lost the 0.7 restriction site due to a deletion of approximately 150 base pairs and in the other the site loss was due to a similar sized sequence insertion; (iii) following XbaI treatment, four variants with deletions ranging in size from 1.5 kb (in both TRL and IRL) to 9 kb in IRL were isolated; (iv) substantial deletions in the long terminal repeat regions of HG52 are present with a frequency of 24% of genomes in the elite stock, a variant with a 3.75 kb deletion in IRL making up 10% and one with a 1.5 kb deletion in both IRL and TRL making up 14%; (v) two of the variants isolated after XbaI treatment of viral DNA were identical to the deletion prototype within the elite stock, suggesting that these variants were not generated as a result of XbaI treatment but pre-existed in the viral DNA pool; (vi) the deletion variants were stably maintained during routine stock propagation, were viable and could be propagated as cloned populations; (vii) the deletions did not have a marked deleterious effect on the one-step growth kinetics of the virus.
Enzymatic activity of glucose oxidase encapsulated in transparent glass by the sol-gel method (1992)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnzymatic activity of glucose oxidase encapsulated in transparent glass by the sol-gel methodStacey A. Yamanaka, Fumito Nishida, Lisa M. Ellerby, Clinton R. Nishida, Bruce Dunn, Joan S. Valentine, and Jeffrey I. ZinkCite this: Chem. Mater. 1992, 4, 3, 495–497Publication Date (Print):May 1, 1992Publication History Published online1 May 2002Published inissue 1 May 1992https://pubs.acs.org/doi/10.1021/cm00021a001https://doi.org/10.1021/cm00021a001research-articleACS PublicationsRequest reuse permissionsArticle Views995Altmetric-Citations175LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Growth Hormone-dependent Phosphorylation of Tyrosine 333 and/or 338 of the Growth Hormone Receptor (1995)

Many signaling pathways initiated by ligands that activate receptor tyrosine kinases have been shown to involve the binding of SH2 domain-containing proteins to specific phosphorylated tyrosines in the receptor. Although the receptor for growth hormone (GH) does not contain intrinsic tyrosine kinase activity, GH has recently been shown to promote the association of its receptor with JAK2 tyrosine kinase, to activate JAK2, and to promote the tyrosyl phosphorylation of both GH receptor (GHR) and JAK2. In this work, we examined whether tyrosines 333 and/or 338 in GHR are phosphorylated by JAK2 in response to GH. Tyrosines 333 and 338 in rat full-length (GHR1-638) and truncated (GHR1-454) receptor were replaced with phenylalanines and the mutated GHRs expressed in Chinese hamster ovary cells. These substitutions caused a loss of GH-dependent tyrosyl phosphorylation of truncated receptor and a reduction of GH-dependent phosphorylation of the full-length receptor. Consistent with Tyr333 and/or Tyr338 serving as substrates of JAK2, these substitutions resulted in a loss of tyrosyl phosphorylation of truncated receptor in an in vitro kinase assay using substantially purified GH.GHR.JAK2 complexes. The Tyr to Phe substitutions did not substantially alter GH-dependent JAK2 association with GHR or tyrosyl phosphorylation of JAK2. These results suggest that Tyr333 and/or Tyr338 in GHR are phosphorylated in response to GH and may therefore serve as binding sites for SH2 domain-containing proteins in GH signal transduction pathways.
Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis (2008)

Imatinib is a receptor tyrosine kinase inhibitor that blocks the activity of c-Abl, c-Kit, and PDGF receptors. We tested the protective effects of imatinib in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and associated membranoproliferative glomerulonephritis (MPGN), in which some glomerular manifestations likely result from PDGF receptor activation. Surprising, administration of imatinib beginning at weaning suppressed production of cryoglobulin, attenuating both the renal injury and systemic features of cryoglobulinemia. Flow cytometry suggested that inhibition of B cell development in the bone marrow likely caused the reduction in cryoglobulin production. In addition, administration of imatinib to thymic stromal lymphopoietin transgenic mice with established MPGN also diminished cryoglobulin production and reversed the renal and systemic lesions. These data suggest that treatment with imatinib may be a novel therapeutic approach for cryoglobulinemia and MPGN in humans.
Activation of mouse macrophages for tumor cell killing. I. Quantitative analysis of interactions between lymphokine and lipopolysaccharide. (1981)

Lymphokine-rich supernatants from concanavalin A-stimulated spleen cell cultures failed to activate mouse peritoneal macrophages for tumor cell killing, providing that the assay system was free of detectable (less than 0.125 ng/ml) endotoxin. Instead, increasing amounts of lymphokine progressively increased the sensitivity of macrophages to activation by purified bacterial lipopolysaccharide (LPS). Conversely, the effect of minute amounts of lymphokine could be detected in the presence of relatively high (though nonactivating) concentrations of LPS. The latter observation was exploited to develop a highly sensitive, quantitative assay for lymphokine. In this assay, serially diluted supernatants were tested on macrophage monolayers in the presence of a constant concentration (3 ng/ml) of LPS. Under these conditions, the lymphokine dose-response curve was sigmoidal and therefore suitable for conversion to a linear plot using the logarithmic transformation of the von Krogh equation. Activity could be expressed quantitatively and reproducibly in terms of units of activity. By facilitating purification the assay should contribute to the development of a more precise biochemical understanding of the role of lymphokine in macrophage activation for tumor cell killing.
Current Clinical Trials of the Anti-VEGF Monoclonal Antibody Bevacizumab (2001)

Given the well-established role of angiogenesis (or new blood vessel formation) in tumor growth and metastasis, antiangiogenic therapy, a concept first proposed by Dr. Judah Folkman,[1] has become increasingly recognized as a promising
Selective targeting of tumoral vasculature: Comparison of different formats of an antibody (L19) to the ED‐B domain of fibronectin (2002)

Abstract We recently demonstrated that a human recombinant scFv, L19, reacting with the ED‐B domain of fibronectin, a marker of angiogenesis, selectively targets tumoral vasculature in vivo. Using the variable regions of L19, we constructed and expressed a human “small immunoprotein” (SIP) and a complete human IgG1 and performed biodistribution studies in tumor‐bearing mice to compare the blood clearance rate, in vivo stability and performance in tumor targeting of the 3 L19 formats [dimeric scFv (scFv) 2 , SIP and IgG1]. The accumulation of the different antibody formats in the tumors studied was a consequence of the clearance rate and in vivo stability of the molecules. Using the SIP, the %ID/g in tumors was 2–5 times higher than that of the (scFv) 2 , reaching a maximum 4–6 hr after injection. By contrast, the accumulation of IgG1 in tumors constantly rose during the experiments. However, due to its slow clearance, the tumor‐blood ratio of the %ID/g after 144 hr was only about 3 compared to a ratio of 10 for the (scFv) 2 and 70 for the SIP after the same period of time. The different in vivo behavior of these 3 completely human L19 formats could be exploited for different diagnostic and/or therapeutic purposes, depending on clinical needs and disease. Furthermore, the fact that ED‐B is 100% homologous in human and mouse, which ensures that L19 reacts equally well with the human and the murine antigen, should expedite the transfer of these reagents to clinical trials. © 2002 Wiley‐Liss, Inc.
Metabolic design: How to engineer a living cell to desired metabolite concentrations and fluxes (1998)

A biotechnological aim of genetic engineering is to increase the intracellular concentration or secretion of valuable compounds, while making the other concentrations and fluxes optimal for viability and productivity. Efforts to accomplish this based on over-expression of the enzyme, catalyzing the so-called "rate-limiting step," have not been successful. Here we develop a method to determine the enzyme concentrations that are required to achieve such an aim. This method is called Metabolic Design Analysis and is based on the perturbation method and the modular ("top-down") approach-formalisms that were first developed for the analysis of biochemical regulation such as, Metabolic Control Analysis. Contrary to earlier methods, the desired alterations of cellular metabolism need not be small or confined to a single metabolite or flux. The limits to the alterations of fluxes and metabolite concentrations are identified. To employ Metabolic Design Analysis, only limited kinetic information concerning the pathway enzymes is needed.
In vitro susceptibility to a new antimalarial organometallic analogue, ferroquine, of Plasmodium falciparum isolates from the Haut-Ogooue region of Gabon (2003)

Ferroquine may be useful as an alternative drug for treating chloroquine-resistant malaria.
β1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome (2001)

Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS.
Long Peritoneal Lavage Decreases Pancreatic Sepsis in Acute Pancreatitis (1990)

Late infection of devitalized pancreatic and peripancreatic tissue has become the major cause of morbidity in severe acute pancreatitis. Previous experience found that peritoneal lavage for periods of 48 to 96 hours may reduce early systemic complications but did not decrease late pancreatic sepsis. A fortunate observation led to the present study of the influence of a longer period of lavage on late sepsis. Twenty-nine patients receiving primary nonoperative treatment for severe acute pancreatitis (three or more positive prognostic signs) were randomly assigned to short peritoneal lavage (SPL) for 2 days (15 patients) or to long peritoneal lavage (LPL) for 7 days (14 patients). Positive prognostic signs averaged 5 in both groups but the frequency of five or more signs was higher in LPL (71%) than in SPL (47%). Eleven patients in each group had early computed tomographic (CT) scans. Peripancreatic fluid collections were shown more commonly in LPL (82%) than in SPL (54%) patients. Longer lavage dramatically reduced the frequency of both pancreatic sepsis (22% LPL versus 40% SPL) and death from sepsis (0% LPL versus 20% SPL). Among patients with fluid collections on early CT scan, LPL led to a more marked reduction in both pancreatic sepsis (33% LPL versus 83% SPL) and death from sepsis (0% LPL versus 33% SPL). The differences were even more striking among 17 patients with five or more positive prognostic signs. In this group the incidence of pancreatic sepsis was 30% LPL versus 57% SPL and of death from sepsis 0% (LPL) versus 43% (SPL) (p = 0.05). In these patients, overall mortality was also reduced (20% LPL versus 43% SPL). When 20 patients treated by LPL were compared with 91 other patients with three or more positive prognostic signs who were treated without lavage or by lavage for periods of 2 to 4 days, the frequency of death from pancreatic sepsis was reduced from 13% to 5%. In those with five or more signs, the incidence of sepsis was reduced from 40% to 27% (p = 0.03) and of death for sepsis from 30% to 7% (p = 0.08). These findings indicate that lavage of the peritoneal cavity for 7 days may significantly reduce both the frequency and mortality rate of pancreatic sepsis in severe acute pancreatitis.