gebhart/patrepeval huggingface dataset:
Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. (1989)

According to classical models of drug-receptor interactions, competitive antagonists share with agonists the ability to bind to a common site on the receptor molecule. However, they are different from agonists, as they cannot trigger the "stimulus" that leads to biological responses--i.e., they lack intrinsic activity. For those receptors whose signals are transduced to effector systems by GTP-binding regulatory proteins (G proteins), a mechanistic equivalent of such a stimulus is an increased ability of agonist-bound receptor to accelerate nucleotide exchange and thus GTPase activity on the G-protein molecule. Here we show that for a member of this family of receptors (delta opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished. One type has no intrinsic activity, since it neither stimulates nor inhibits the GTPase activity of G proteins and its apparent affinity for the receptor is not altered by pertussis toxin-mediated uncoupling of receptor and G protein. The second type, however, can inhibit GTPase and thus exhibits negative intrinsic activity; its affinity for receptors is increased following uncoupling from G proteins. The existence of antagonists with negative intrinsic activity may be a general feature of several classes of neurotransmitters or hormone receptors and calls for a reevaluation of biological effects produced by competitive antagonists.
The c-Myc Transactivation Domain Is a Direct Modulator of Apoptotic versus Proliferative Signals (2000)

We have assayed the oncogenic, proliferative, and apoptotic activities of the frequent mutations that occur in the c-myc gene in Burkitt's lymphomas. Some alleles have a modest (50 to 60%) increase in transforming activity; however, the most frequent Burkitt's lymphoma allele (T58I) had an unexpected substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-myc knockout. There was discordance for some alleles between apoptotic and oncogenic activities, but only the T58A allele had elevated transforming activity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compared to wild-type Myc, yet this mutation has never been found in lymphomas, suggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochondria, suggesting a mechanism of action for this mutation. Phosphopeptide mapping provided a biochemical basis for the dramatically different biological activities of the transformation-defective T58I and transformation-enhanced T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insulin-like growth factor 1 was found to suppress phosphorylation of T58, suggesting that the c-Myc transactivation domain is a direct target of survival signals.
293 A novel CD3/BCMA bispecific antibody selectively kills plasma cells in bone marrow of healthy individuals with improved safety (2019)

<h3>Background</h3> Autoantibodies play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasma cells secrete these autoantibodies but are unfortunately refractory to conventional immunosuppressive treatments. B-cell Maturation Antigen (BCMA) is exclusively expressed on mature B cells and, for that reason, is considered a good target for plasma cell depletion. Here, we analyze a promising therapeutic in development for Multiple Myeloma (MM), that could be used for the treatment for SLE. The antiCD3*BCMA bispecific antibody TNB-383B is in clinical trials for the treatment of MM. <i>In vitro</i> experiment showed that TNB-383B added to human bone marrow samples <i>ex vivo</i> induced a dose dependent lysis of BCMA-expressing plasma cells. <h3>Methods</h3> Depletion of plasma cells by TNB-383B was tested using bone marrow samples extracted from bone retrieved of hip replacments. Human bone marrow mononuclear cells (n=10) were incubated with TNB-383B at increasing concentrations. The activity of TNB-383B was compared to a positive control antibody (PC), which has a BCMA-binding domain and an Fc region identical to TNB-383B, but binds to CD3 with stronger affinity. Bone marrow mononuclear cells were incubated for 18 hours with controls and TNB383B and samples were analyzed for plasma cell depletion (cells expressing CD19+, IgD-, IgM-, CD38++, CD27++) and T cell activation (CD69, CD107a, CD137, CD154). Cytokine production (IFN-, TNF, IL-2, IL-6, IL-12p70, IL-13, IL-4 and IL-10) was evaluated using multiplex. <h3>Results</h3> TNB-383B effectively depleted plasma cells in bone marrow samples of healthy individuals undergoing hip replacement; more than 80% of BCMA expressing plasma cells were depleted after an overnight incubation with TNB-383B or a positive control. Analysis activation markers showed that TNB-383B activated T cells as evidenced by the expression of activation markers (CD69, CD154 or CD137) but only minimal cytokine production was observed. <h3>Conclusions</h3> TNB-383B represents a novel immunotherapeutic with improved safety and efficacy for the treatment of pathogenic long-lived plasma cells. TNB-383B is in clinical trials for the treatment of Multiple Myeloma. TNB-383B could be an attractive treatment to prevent acute organ rejection in Panel Reactive Antibody (PRA) organ transplantation and autoimmune patients including Systemic Lupus Erythematosis. Teneobio anticipates to start testing TNB-383B in PRA patients by late 2019. <h3>Funding Source(s):</h3> Teneobio, Inc.
Gene expression of 5-lipoxygenase and LTA4 hydrolase in renal tissue of nephrotic syndrome patients (1999)

Leukotrienes (LT) of the 5-lipoxygenase pathway constitute a class of potent biological lipid mediators of inflammation implicated in the pathogenesis of different models of experimental glomerulonephritis. The key enzyme, 5-lipoxygenase (5-LO), catalyses oxygenation of arachidonic acid to generate the primary leukotriene LTA4. This LT, in turn, serves as a substrate for either LTA4 hydrolase, to form the potent chemoattractant LTB4, or LTC4 synthase, to produce the powerful vasoconstrictor LTC4. To investigate the potential role of LT in the pathogenesis of human glomerulonephritis with nephrotic syndrome, we examined the gene expression of 5-LO and LTA4 hydrolase in renal tissue of 21 adult patients with nephrotic syndrome and 11 controls. The patients consisted of 11 cases of membranous nephropathy (MN), seven focal and segmental glomerulosclerosis (FSGS), two non-IgA mesangial glomerulonephritis and one minimal change disease. Total RNA purified from renal tissue was reverse transcribed into cDNA and amplified with specific primers in a polymerase chain reaction (RT-PCR). Eight patients' renal tissue, four MN and four FSGS, co-expressed 5-LO and LTA4 hydrolase. In situ hybridization analysis revealed 5-LO expression and distribution limited to the interstitial cells surrounding the peritubular capillaries. Comparative clinical and immunohistological data showed that these eight patients had impaired renal function and interstitial changes that significantly correlated with 5-LO expression. These findings suggest that leukotrienes may play an important role in the pathogenesis of MN and FSGS. These results are also relevant to elucidating the pathophysiologic mechanisms which underlie progression to renal failure in these diseases.
Deformable lung registration between exhale and inhale CT scans using active cells in a combined gradient force approach (2010)

The results show that the proposed method can accurately register lungs with large deformations and can considerably reduce the processing time. The proposed deformable registration technique can be used for quantitative assessments of air trapping in obstructive lung disease and for tumor motion tracking during the planning of radiotherapy treatments.
Development of Replication-Defective Herpes Simplex Virus Vectors (2003)

A greater understanding of the molecular, biochemical, and genetic factors involved in the progression of a specific disease state has led to the development of genetic therapies using direct gene transfer to ameliorate the disease condition or correct a genetic defect in situ. Effective gene therapy approaches require delivery strategies and vehicles that 1) efficiently deliver the therapeutic gene(s) to a sufficient number of dividing or nondividing cells to achieve the desired therapeutic effect; 2) persist long term within the cell without disturbing host cell functions; and 3) can regulate the level and duration of therapeutic gene expression for diseases that may either require high-level transient transgene expression or continuous low-level synthesis of the therapeutic product. Numerous viral and nonviral vectors have been employed to treat a variety of genetic and acquired diseases. Each vector system has its own particular advantages and disadvantages that will suit it to a specific therapeutic application.
Early Response of Prostate Carcinoma Xenografts to Docetaxel Chemotherapy Monitored With Diffusion MRI (2002)

For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.
Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model (2010)

Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection.
Transport of organic contaminants in groundwater (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTransport of organic contaminants in groundwaterDouglas M. Mackay, Paul V. Roberts, and John A. CherryCite this: Environ. Sci. Technol. 1985, 19, 5, 384–392Publication Date (Print):May 1, 1985Publication History Published online1 May 2002Published inissue 1 May 1985https://pubs.acs.org/doi/10.1021/es00135a001https://doi.org/10.1021/es00135a001research-articleACS PublicationsRequest reuse permissionsArticle Views2056Altmetric-Citations210LEARN 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
Sialic Acid 9-O-Acetylation on Murine Erythroleukemia Cells Affects Complement Activation, Binding to I-type Lectins, and Tissue Homing (1996)

O-Acetylation of the 9-hydroxyl group of sialic acids has been suggested to modify various recognition phenomena involving these molecules, but direct proof has been lacking in most situations. In the accompanying paper (Shi, W.-X., Chammas, R., and Varki, A. (1996) J. Biol. Chem. 261, 31517-31525), we report that the extent of 9-O-acetylation of cell surface sialic acids on murine erythroleukemia (MEL) cells can be modified by various manipulations, including differentiation, nocodazole treatment, and 9-O-acetyl esterase treatment. We have used this system to explore the putative roles of 9-O-acetylation in modulating alternative pathway complement activation, I-type lectin binding, and tissue homing. MEL cells are shown to be sensitive to lysis in vitro by the alternative pathway of human complement. Induced differentiation of the MEL cells causes resistance to lysis, and this correlates directly with extent of decrease in 9-O-acetylation. A similar resistance to alternative pathway lysis can be obtained by selective enzymatic removal of 9-O-acetyl groups from sialic acids. Conversely, the increase in cell surface 9-O-acetylation caused by nocodazole treatment correlates with increased sensitivity to alternative pathway lysis. Thus, a 9-O-acetyl group added to the side chain of cell surface sialic acids may abrogate its normal function in restricting alternative pathway activation. Indeed, the binding of human complement factor H, a negative regulator of the alternative pathway, is shown to be blocked by O-acetylation of the sialic acids on MEL cells. MEL cells are also shown to have cell surface ligands for the I-type lectins sialoadhesin and CD22. Sialoadhesin (but not CD22) binding is selectively enhanced by differentiation-induced loss of cell surface 9-O-acetylation and by direct enzymatic removal of the ester groups. Thus, some sialoadhesin ligands are masked by 9-O-acetylation, presumably because the side chain is required for recognition. Since sialoadhesin is expressed on some macrophages in vivo, we reasoned that tissue homing of MEL cells might be affected by O-acetylation. Indeed, enzymatic removal of cell surface 9-O-acetyl groups alters the tissue distribution of intravenously injected cells. In particular, de-O-acetylation caused significant increase in homing to the liver and spleen. These data demonstrate that cell surface 9-O-acetylation can affect a variety of biological recognition phenomena and provide a system for further exploration of the specific molecular mechanisms involved.
An integrated voice and data radio access system (2003)

A method for a digital mobile radio communication system to incorporate data transmission into full-duplex digital voice transmission channels is presented. In this method a voice terminal sends a short packet to a base station prior to sending a voice signal. When the base station receives the short packet or detects a collision between the short packet and data packet, it inhibits data transmission. Finding a pause period of voice signal transmission, the base station broadcasts a message to enable the data transmission. The results of computer simulation with voice data from real telephone conversations show that through the present system the almost maximum performance of the slotted ALOHA system is reached. Applying the proposed method to a 12-channel, 32-kb/s voice coding TDMA system, one can get a data transmission channel with average capacity of 270 kb/s on the voice communication system.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Elective Induction of Labor (2007)

Director, Midwifery and Wellness Center, Aurora Sinai Medical Center/Milwaukee, Wis, Assistant Professor, University of Wisconsin School of Medicine and Public Health, Madison, Wis
<i>In vitro</i> Cytotoxic, Antibacterial and Antiviral Activities of Triterpenes from the Red Sea Sponge, <i>Siphonochalina siphonella</i> (2015)

Purpose: To study the phytochemical composition of Siphonochalina siphonella sponge from the western coast of the Red Sea and to evaluate the isolates for possible in vitro cytotoxic, antibacterial and antiviral activities.Methods: The compounds obtained were isolated and purified by different chromatographic means. Their structures were established by means of spectral analysis including 1D 1H and 13C and 2D correlation nuclear magnetic resonance (NMR) and high resolution mass spectroscopy (HR-MS). Crystal violet staining method (CVS) was used for the assessment of the cytotoxic activity against HepG-2 and MCF-7 human cell lines, while agar-well diffusion method was employed to measure antimicrobial activity against two Gram-positive and two Gram-negative bacteria. The antiviral activity was determined by the inhibition of cytopathic effect (CPE) in susceptible mammalian cells.Results: Four triterpenes, possessing two different skeletons, were isolated and identified as sipholenone A, sipholenol A, neviotine A and sipholenol L. All four compounds were significantly cytotoxic to MCF-7 and HepG-2 cancer cell lines (p &lt; 0.05) in a concentration-dependent manner with IC50 (the inhibitory concentration required to reduce cell survival by 50 %) in range 2.8 - 19.2 μg/mL. The highest antibacterial activity was observed for neviotine A (Compound 3) against Bacillis subtilis (17.2 ± 0.58). On the other hand, all the compounds showed moderate to weak anti-viral activity.Conclusion: The findings reveal the strong cytotoxic activity of all the isolated triterpenes from the Red Sea Sponge, S. siphonella. Sipholenone A (Compound 1) displayed significant cytotoxic activity towards MCF-7 and HepG-2 cancer cell lines with IC50 = 3.0 and 2.8 μM, respectively.Keywords: Red Sea Sponge, Siphonochalina siphonella, Triterpenes, Cancer cells, Cytotoxic, Antibacterial, Antiviral
Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). (1985)

Human B-cell differentiation factor (BCDF) was purified to homogeneity by sequential filtration and chromatography of culture supernatants from TCL-Na1 cells on an AcA34 gel column and then on a Mono P column with fast protein liquid chromatography and reversed-phase HPLC. A 5300-fold enrichment in specific activity of BCDF with about 25% recovery was attained. The homogeneity of purified BCDF was evidenced by the following: (i) the specific activity was 1.7 X 10(7) units/mg of protein, (ii) only two bands, Mr 19,000 and 21,000, were identified by NaDodSO4/PAGE under reduced as well as nonreduced conditions, and (iii) BCDF activity was recovered from the gel after NaDodSO4/PAGE in the fractions corresponding to protein bands of Mr 19,000 or 21,000. Purified BCDF induced Ig secretion in Epstein-Barr virus-transformed cell lines; as little as 3 pM gave 50% of the maximum reaction achieved by 30-80 pM BCDF. Purified BCDF induced Ig production in activated B cells without any effect on cell growth. Purified BCDF did not show any activity of interleukin 1 or 2, B-cell stimulatory factor (BSF)p-1, B-cell growth factor II (BCGF-II), or interferon. Since BCDF was isolated and characterized as described, we propose that the BCDF that induces the final differentiation of B cells into high-rate Ig-secreting cells be designated BSFp-2.
Energetics of Interaction between the G-protein Chaperone, MeaB, and B12-dependent Methylmalonyl-CoA Mutase (2006)

MeaB is an auxiliary protein that supports the function of the radical B(12)-dependent enzyme, methylmalonyl-CoA mutase, although its precise role is not understood. Mutations in the human homolog of MeaB, MMAA, lead to methylmalonic aciduria, an inborn error of metabolism that can be fatal. To obtain insights into the function of this recently discovered protein, we have characterized the entropic and enthalpic contributions to DeltaGdegree (assoc) for complexation of MeaB (in the presence and absence of nucleotides) with methylmalonyl-CoA mutase (in the presence and absence of cofactor). The dissociation constant for binding of methylmalonyl-CoA mutase and MeaB ranges from 34 +/- 4 to 524 +/- 66 nm, depending on the combination of nucleotide and mutase form. Holomutase binds MeaB 15-fold more tightly when the nonhydrolyzable GTP analog, GMPPNP, is bound versus GDP. In contrast, the apomutase binds MeaB with similar affinity in the presence of either nucleotide. Our studies reveal that a large structural rearrangement accompanies interaction between these proteins and buries between approximately 4000 and 8600A(2) of surface area, depending on the combination of ligands in the active sites of the two proteins. Furthermore, we demonstrate that MeaB binds GTP and GDP with similar affinity (K(d) of 7.3 +/- 1.9 and 6.2 +/- 0.7 microm, respectively at 20 degrees C) and has low intrinsic GTPase activity (approximately 0.04 min(-1) at 37 degrees C), which is stimulated approximately 100-fold by methylmalonyl-CoA mutase. These studies provide insights into the energetics of interaction between the radical enzyme methylmalonyl-CoA mutase and MeaB, which are discussed.
Solubility principles and practices for parenteral drug dosage form development. (1997)

Solubilization of poorly water soluble or water insoluble drugs for use in intravenously administered dosage forms is a very formidable task for the parenteral formulation scientist. We have briefly reviewed pertinent literature for parenteral drug solubilization and provided tabular information to assist parenteral formulation scientists in tackling and solving their solubility problems. However, until we can better understand and predict solubility behavior in interactive solvent systems, the why's and how's for parenteral drug solubilization using acceptable (safe and regulatory compliant) approaches will largely remain an empirical effort, leaving great opportunities for scientists to get more involved in this field.