gebhart/patrepeval huggingface dataset:
Medicinal Inorganic Chemistry Approaches to Passivation and Removal of Aberrant Metal Ions in Disease (2009)

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTMedicinal Inorganic Chemistry Approaches to Passivation and Removal of Aberrant Metal Ions in DiseaseLauren E. Scott and Chris Orvig*View Author Information Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, Canada* To whom correspondence should be addressed. Mailing address: University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. Phone: (604) 822-4449. Fax: (604) 822-2847. E-mail: [email protected]Cite this: Chem. Rev. 2009, 109, 10, 4885–4910Publication Date (Web):July 28, 2009Publication History Received15 January 2009Published online28 July 2009Published inissue 14 October 2009https://pubs.acs.org/doi/10.1021/cr9000176https://doi.org/10.1021/cr9000176review-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views6754Altmetric-Citations275LEARN 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 SUBJECTS:Ions,Iron,Mechanisms of action,Metals,Therapeutics Get e-Alerts
Identification of proteins that interact with NF‐YA (1999)

We used the yeast two-hybrid system to show that the serum response factor (SRF) and zinc-fingers and homeobox 1 (ZHXI) proteins interact with the A subunit of nuclear factor-Y (NF-YA). GST pulldown assays revealed that both proteins interact specifically with NF-YA in vitro. Amino acids located between 272 and 564, a region that contains two homeodomains, are required for the interaction of ZHX1 with NF-YA. Two different domains of NF-YA, a glutamine-rich region and a serine/threonine-rich region, are necessary for the interactions with ZHX1 and SRF, respectively.
Modulation of murine lymphocyte and macrophage proliferation by parenteral zinc. (1983)

The effects of a single i.p. injection of zinc (0.7, 1.3, 4.0 or 12.0 mg/kg), 24 h prior to sacrifice, on lymphocyte blastogenesis as well as lymphocyte and macrophage progenitor cell proliferation were examined using cells from adult BALB/c mice. Splenic lymphocyte blastogenesis in response to T cell mitogens decreased for mice receiving the highest zinc dosage while responses to B cell mitogens were initially depressed, subsequently increased, and finally declined sharply as the LD50 was approached. Splenic B cell colony formation decreased linearly in relation to zinc dosage with a 50% suppression of colony formation observed at approximately 8.0 mg/kg. In contrast, bone marrow granulocyte-macrophage colonies were enhanced at higher dosages (greater than or equal to 2.5 mg/kg) of zinc. These results indicate that zinc exposure at dosages less than the LD50 can influence lymphocyte blastogenesis and clonal expansion of both B cell and macrophage progenitors.
Ligand-induced Ubiquitination of the Epidermal Growth Factor Receptor Involves the Interaction of the c-Cbl RING Finger and UbcH7 (1999)

c-Cbl plays a negative regulatory role in tyrosine kinase signaling by an as yet undefined mechanism. We demonstrate here, using the yeast two-hybrid system and an in vitro binding assay, that the c-Cbl RING finger domain interacts with UbcH7, a ubiquitin-conjugating enzyme (E2). UbcH7 interacted with the wild-type c-Cbl RING finger domain but not with a RING finger domain that lacks the amino acids that are deleted in 70Z-Cbl, an oncogenic mutant of c-Cbl. The in vitro interaction was enhanced by sequences on both the N- and C-terminal sides of the RING finger. In vivo and in vitro experiments revealed that c-Cbl and UbcH7 synergistically promote the ligand-induced ubiquitination of the epidermal growth factor receptor (EGFR). In contrast, 70Z-Cbl markedly reduced the ligand-induced, UbcH7-mediated ubiquitination of the EGFR. MG132, a proteasome inhibitor, significantly prolonged the ligand-induced phosphorylation of both the EGFR and c-Cbl. Thus, c-Cbl plays an essential role in the ligand-induced ubiquitination of the EGFR by a mechanism that involves an interaction of the RING finger domain with UbcH7. This mechanism participates in the down-regulation of tyrosine kinase receptors and loss of this function, as occurs in the naturally occurring 70Z-Cbl isoform, probably contributes to oncogenic transformation.
Atrial Na,K-ATPase Increase and Potassium Dysregulation Accentuate the Risk of Postoperative Atrial Fibrillation (2009)

The present study supports the increasing evidence of dysregulation of the potassium homeostasis as an important factor in the development of cardiac arrhythmias. High atrial Na,K-ATPase and sudden plasma potassium concentration increase may contribute to precipitate atrial fibrillation.
Mapping of murine IgE epitopes involved in IgE‐Fcε receptor interactions (1989)

The generation of anti-IgE monoclonal antibodies has permitted the identification of various serological epitopes on the IgE molecule. The relationship of the sites on IgE recognized by such antibodies to the Fc epsilon receptor (Fc epsilon R) interaction site has been determined using cross-inhibition studies. However, interpretation of this type of experiment is limited by problems of steric hindrance. Thus, to accomplish precise mapping on the IgE molecule of the Fc epsilon R interaction site and the binding sites of various anti-IgE mAb, we employed site-directed mutagenesis of the IgE heavy chain gene. To this end we have constructed and expressed a recombinant murine constant epsilon heavy chain (C epsilon) gene bearing a (4-hydroxy-3-nitrophenyl)acetic acid (NP)-binding VH region. Several site-specific mutants in the C epsilon 3 and C epsilon 4 domains of this recombinant C epsilon gene were prepared and expressed by transfection into the light chain-producing J558L myeloma cell line. The resulting IgE antibodies were tested for binding to mast cells and to various anti-IgE mAb. The mutants produced include a proline to histidine point mutant at amino acid residue 404 in the C epsilon 3 domain, a mutant with a truncated C epsilon 4 domain, a mutant with a 45 amino acid deletion in the carboxy end of C epsilon 3, and a chimeric human C epsilon in which the human C epsilon 3 was replaced by the homologous mouse C epsilon 3 domain. These mutants have permitted the localization, to the C epsilon 3 domain, of the epitopes recognized by the 84.1C and 95.3 anti-IgE mAb. The 84.1C mAb recognizes a site on IgE which is identical or very close to the Fc epsilon R binding site, and 95.3 recognizes a site on IgE which is related, but not identical to the Fc epsilon R binding site. The antigenic determinant recognized by the 51.3 mAb, which is inefficient at blocking the IgE-Fc epsilon R interaction, has been mapped to the C epsilon 4 domain. When tested for binding to the Fc epsilon R on RBL-2H3 cells, the point mutant bound to the Fc epsilon R with twofold reduced affinity, while the C epsilon 3 deletion mutant and the mutant truncated in C epsilon 4 lost all receptor binding activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Insulin-regulated sorting of glucose transporters in 3T3-L1 adipocytes (1992)

Two glucose transporters (GLUT-4 and GLUT-1) move from within the cell to the plasma membrane (PM) when 3T3-L1 adipocytes are stimulated with insulin. To study the sorting of these two molecules, vesicles containing GLUT-4 and GLUT-1 were immunoadsorbed from basal and insulin-treated cells. Two different vesicle populations were isolated as follows: 1) a compartment that contained the majority of intracellular GLUT-4 and GLUT-1 and 2) a subpopulation of vesicles containing 43% of the intracellular GLUT-4 that was highly insulin regulatable and that contained relatively low levels of GLUT-1. After incubation at 19 degrees C, basal glucose transport was slightly increased, whereas insulin-dependent transport was blocked. Consistent with these observations, cell surface GLUT-1 levels were increased in the basal state, whereas insulin-dependent translocation of GLUT-4 to the PM was blocked at 19 degrees C. However, insulin-dependent sorting of GLUT-4 within the intracellular compartment was still evident at 19 degrees C. These data indicate that GLUT-1 and GLUT-4 are heterogeneously distributed throughout the same intracellular compartment in 3T3-L1 adipocytes. Furthermore, we have uncoupled two distinct steps in the insulin-dependent movement of GLUT-4 to the cell surface. These include movement of GLUT-4 out of its storage compartment and accumulation of GLUT-4 at the cell surface. Only the former step occurs in cells preincubated at 19 degrees C.
Unconventional Splicing of HAC1/ERN4 mRNA Required for the Unfolded Protein Response (1998)

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates an intracellular signaling pathway from the ER to the nucleus, termed the unfolded protein response. We and others recently identified transcription factor Hac1p/Ern4p responsible for the response in Saccharomyces cerevisiae and found that Hac1p expression is controlled by the regulated splicing of HAC1 mRNA. Walter and co-workers (Sidrauski, C., Cox, J. S., and Walter, P. (1996) Cell, 87, 405-413) further showed that the splicing requires tRNA ligase but not spliceosome. In this report, we carried out mutational analysis of HAC1 mRNA and revealed several unique features of the splicing. First, a mutation or deletion of the branchpoint-like sequence present in HAC1 intron did not affect the splicing. Second, cleavage of the splice sites was sequence-specific and thus completely blocked by some point mutations introduced at the 5' or 3' splice site. Third, cleavage of the 5' and 3' splice sites could occur independently as judged by the nature of splicing intermediates accumulated. Fourth, swapping the nucleotide sequences of the 5' and 3' splice sites inhibited the ligation but not the cleavage step. We conclude that signaling from the ER activates putative endonucleases that can carry out sequence-specific cleavage of the splice sites in a random order.
Grip Control Using Biomimetic Tactile Sensing Systems (2009)

We present a proof-of-concept for controlling the grasp of an anthropomorphic mechatronic prosthetic hand by using a biomimetic tactile sensor, Bayesian inference, and simple algorithms for estimation and control. The sensor takes advantage of its compliant mechanics to provide a triaxial force sensing end-effector for grasp control. By calculating normal and shear forces at the fingertip, the prosthetic hand is able to maintain perturbed objects within the force cone to prevent slip. A Kalman filter is used as a noise-robust method to calculate tangential forces. Biologically inspired algorithms and heuristics are presented that can be implemented online to support rapid, reflexive adjustments of grip.
Identification and preliminary characterization of a lectinlike protein from Capnocytophaga gingivalis (emended) (1986)

A polypeptide believed to be the monomeric form of the lectin responsible for the coaggregation of Capnocytophaga gingivalis (emended) and Actinomyces israelii has been identified. Denaturing polyacrylamide gel electrophoresis and immunoblot analyses were used to distinguish the protein from other proteins in the outer membrane of C. gingivalis. The subunit of the putative lectin has a pI of 8.6 and a molecular weight of 155,000.
Quantitative analysis of the agonist and antagonist actions of some ATP analogues at P2X‐purinoceptors in the rabbit ear artery (1993)

1. The agonist and antagonist effects of a series of beta, gamma-methylene dihalo- and 2-methylthio-substituted analogues of ATP at P2x-purinoceptors have been analysed on the rabbit isolated ear artery preparation. Cumulative and sequential dosing experimental protocols were employed in the construction of agonist concentration-effect curves in order to address the possible influence of acute receptor desensitization on subsequent analyses. 2. Using the cumulative curve design the following results were obtained: D-AMP-PCBr2P, 2-methylthio-D-AMP-PCCl2P, L-AMP-PCF2P, L-AMP-PCCl2P and LAMP-PCBr2P each behaved as partial agonists. D-AMP-CPP was used as a reference full agonist and these analogues were analysed by the comparative method of Barlow et al. (1967), to provide estimates of affinity and efficacy. 2-Methylthio-L-AMP-PCBr2P was virtually silent as an agonist and was analysed as a competitive antagonist by Schild analysis. 3. Two agonists, L-AMP-PCCl2P and L-AMP-PCBr2P, were analysed by the sequential curve design, and the antagonist effects of one of the agonists, L-AMP-PCBr2P were also analysed using this protocol. The resulting estimates of affinity and efficacy, while similar to those obtained with the cumulative design, indicated that acute desensitization may affect curve definition and estimation of these quantities. 4. The following structure-activity trends emerged: D-analogues tended to have higher efficacy but lower affinity than L-analogues; efficacy varied markedly and inversely with the atomic weight of the halogen while affinity was only minimally affected; 2-methylthio- substitution also reduced efficacy with minimal effect on affinity. 5. The results of this analysis are discussed in terms of the utility of affinity and efficacy information in the classification of purinoceptors and the design of chemical probes for them.
Danazol in autoimmune haemolytic anaemia (1993)

Ten adult patients with warm antibody haemolytic anaemia at initial presentation and seven other patients with either refractory AIHA (two patients) or who relapsed after an initial response to prednisone (five patients) were treated with both Danazol and prednisone. 80% of the first group, but also 60% of the second group displayed long-lasting responses (mean follow up 21 months). Minimal side-effects occurred. Finally, addition of Danazol at presentation in warm AIHA may decrease the duration of prednisone therapy and markedly reduce the necessity of second-line splenectomy which is usually required in many patients.
Using capacitive cross-coupling technique in RF low noise amplifiers and down-conversion mixer design (2000)

We report an approach to improve the noise performance of RF low noise amplifiers (LNAs) and down-conversion mixers. The technique we described here is based on capacitive cross-coupling across the two sides of a differential input stage. A LNA and mixer have been implemented in 0.5µ CMOS process to demonstrate the viability of this technique. The measurements show that the LNA achieves 3.0dB noise figure and 12.2 dB voltage gain (optimized for the maximum power transfer), and the mixer has 5.2dB DSB noise figure and 13.2 dB voltage conversion gain. Both LNA and mixer operate at 2.7V voltage supply and consume 27mW and 8.1mW power, respectively.
THE PROSTACYCLIN-THROMBOXANE A2 BALANCE: PATHOPHYSIOLOGICAL AND THERAPEUTIC IMPLICATIONS (1983)

Journal Article THE PROSTACYCLIN-THROMBOXANE A 2 BALANCE: PATHOPHYSIOLOGICAL AND THERAPEUTIC IMPLICATIONS Get access S BUNTING, PhD, S BUNTING, PhD Wellcome Research Laboratories BeckenhamKent Search for other works by this author on: Oxford Academic PubMed Google Scholar S MONCADA, PhD, S MONCADA, PhD Wellcome Research Laboratories BeckenhamKent Search for other works by this author on: Oxford Academic PubMed Google Scholar J R VANE, DSc FRS J R VANE, DSc FRS Wellcome Research Laboratories BeckenhamKent Search for other works by this author on: Oxford Academic PubMed Google Scholar British Medical Bulletin, Volume 39, Issue 3, 1983, Pages 271–276, https://doi.org/10.1093/oxfordjournals.bmb.a071832 Published: 01 September 1983
Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): Results from a phase II randomized discontinuation trial (RDT). (2012)

535 Background: Dysregulation of MET and VEGF signaling has been implicated in breast cancer development and progression, including tumor invasion and dissemination. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types, including MBC. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized discontinuation phase was progression-free survival (PFS). Results: Enrollment to this cohort is complete (n = 45); all pts are unblinded. Baseline characteristics: median age 56; invasive ductal 86%, invasive lobular 7%; ER+ 93%, HER2+ 18%, triple- 5%; visceral disease 91%; bone metastases 73%; median prior lines of therapy 3 (range 1-8), including 71% with prior anthracyclines. Median follow-up was 2.9 mos (range 0.1 -16). 21 pts (47%) completed Lead-in stage with only 9 randomized to continue cabo (n = 5) or placebo (n = 4). Median PFS from Study Day 1 was 4.1 mos. At wk 12, objective response rate was 14% and disease control rate 48%. Tumor regression was observed in 25/39 pts (64%) with ≥1 post-baseline tumor assessment. 4/10 pts evaluable by bone scan had partial resolution of bone lesions. Of 12 pts receiving narcotics for bone pain, 5 pts reported improved pain and 2 pts had decreased narcotics use, per investigator. 4/14 evaluable pts (29%) with bone metastases experienced ≥50% decline in serum NTx. Most common Grade 3/4 AEs were palmar-plantar erythrodyesthesia (13%) and fatigue (11%). One related Grade 5 AE of respiratory compromise was reported during the Lead-in stage. Conclusions: Cabo demonstrated a 14% rate of objective tumor regression in heavily pretreated MBC pts. Observed effects on bone scan and pain are consistent with those seen in other malignancies. The safety profile of cabo was comparable to that seen with other VEGFR TKIs.
cDNA Cloning of Polypeptide Chain Elongation Factor 1&alpha; from Medaka <i>Oryzias latipes</i> (1999)

Polypeptide chain elongation factor 1α (EF1α) was cloned from a liver cDNA library of medaka Orizias latipes. The analysis of the clone containing 1.6kbp DNA revealed that the entire open reading frame of EFla was 1383 bp long. Deduced amino acid sequence of medaka EFlα showed high similarity (more than 87% identity) with those of other vertebrates. Medaka EFlα had one amino acid deletion at the position of 447 amino acid of other EF1αs and unique 17 replacement against those of other vertebrates. Northern hybridization analysis revealed that this EF1α was expressed in all tissues tested.
Inotropes in the management of acute heart failure (2008)

Impaired cardiac contractility is a fundamental component of the heart failure syndrome, initiating the cycle of vasoconstriction, neurohormonal and inflammatory activation, and adverse ventricular remodeling that leads to heart failure progression. Based on this core paradigm, drugs that increase cardiac contractility (positive inotropes) are theoretically appealing as a heart failure therapy, and such agents have been extensively investigated in both acute and chronic heart failure. Although these agents clearly improve cardiac output, their use in heart failure has consistently been associated with increased myocardial oxygen demand, cardiac arrhythmias, and mortality in a variety of clinical settings. Based on these data, the routine use of inotropes as heart failure therapy is not indicated in either the acute or chronic setting. Inotropes may be a necessary evil in a subset of acute heart failure patients, such as those with acute heart failure decompensation in the setting of clinically evident hypoperfusion or shock, or as a bridge to more definitive treatment, such as revascularization or cardiac transplantation. Currently available inotropes, such as dobutamine and milrinone, act (directly or indirectly) by increasing cyclic adenylate monophosphate and therefore intracellular calcium flux. Whether newer inotropes with differing mechanisms of action will realize the potential clinical benefits of inotropic therapy without the risk remains a subject of ongoing investigation.
Design, Synthesis, and Pharmacological Evaluation of Second-Generation Tetrahydroisoquinoline-Based CXCR4 Antagonists with Favorable ADME Properties (2018)

CXCR4 is a G-protein-coupled receptor that interacts with its cognate ligand, CXCL12, to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small-molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal-chemistry efforts toward the redesign of TIQ15 as a result of high mouse-microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability. Guided by the in vitro ADME data of TIQ15, structural modifications were executed to provide compound 12a, which demonstrated a reduced potential for first-pass metabolism while maintaining CXCR4 potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist possessing good intestinal permeability and low risk of CYP-mediated drug-drug interactions.