gebhart/patrepeval huggingface dataset:
Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation (2007)

Abstract Rationale Nitric oxide–independent agonists of soluble guanylate cyclase (sGC) have been developed. Objectives We tested whether inhalation of novel dry-powder microparticle formulations containing sGC stimulators (BAY 41-2272, BAY 41-8543) or an sGC activator (BAY 58-2667) would produce selective pulmonary vasodilation in lambs with acute pulmonary hypertension. We also evaluated the combined administration of BAY 41-8543 microparticles and inhaled nitric oxide (iNO). Finally, we examined whether inhaling BAY 58-2667 microparticles would produce pulmonary vasodilation when the response to iNO is impaired. Methods In awake, spontaneously breathing lambs instrumented with vascular catheters and a tracheostomy tube, U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mm Hg. Measurements and Main Results Inhalation of microparticles composed of either BAY 41-2272, BAY 41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine, albumin, lactose) produced dose-dependent pulmonary vasodilation and increased transpulmonary cGMP release without significant effect on mean arterial pressure. Inhalation of microparticles containing BAY 41-8543 or BAY 58-2667 increased systemic arterial oxygenation. The magnitude and duration of pulmonary vasodilation induced by iNO were augmented after inhaling BAY 41-8543 microparticles. Intravenous administration of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the prosthetic heme group of sGC, markedly reduced the pulmonary vasodilator effect of iNO. In contrast, pulmonary vasodilation and transpulmonary cGMP release induced by inhaling BAY 58-2667 microparticles were greatly enhanced after treatment with ODQ. Conclusions Inhalation of microparticles containing agonists of sGC may provide an effective novel treatment for patients with pulmonary hypertension, particularly when responsiveness to iNO is impaired by oxidation of sGC.
Initial study on in vivo conductivity mapping of breast cancer using MRI (2014)

This study shows that conductivity mapping of breast cancers is feasible using a noninvasive in vivo MREPT technique combined with a coil combination process. The method may provide a tool in the MR diagnosis of breast cancer.
Abstract P6-15-16: LIV-1 Antibody-Drug Conjugate: A Novel Therapeutic Agent for Breast Cancer (2010)

Abstract LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. LIV-1, as a downstream target of STAT3, promotes the epithelial to mesenchymal transition that is important in the malignant progression to metastasis. Consistent with its role in cancer, we determined by immunohistochemical (IHC) analysis that LIV-1 is expressed in 86% (n=22) of estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites), and in 65% (n=20) of ER-/PR-/Her2- (triple-negative) breast cancers. In healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). We generated an antibody-drug conjugate (ADC) consisting of a humanized anti-LIV-1 mAb conjugated to the antitubulin agent monomethyl auristatin E (MMAE), via a plasma stable, enzyme-cleavable linker (vc). The humanized LIV-1 mAb bound with high affinity to both human and cynomolgous LIV-1 (2-4 nM). In vitro, anti-LIV-1-vcMMAE showed specific cytotoxic activity against a MCF-7 cell line with an IC50= 78 ng/ml. In vivo studies also demonstrated antitumor activity of anti-LIV-1-vcMMAE in preclinical xenograft models, including MCF-7 breast cancer cell line, with significant delay of tumor growth compared to control groups. The broad expression of LIV-1 in both hormonally-treated and triple-negative tumors and the limited expression in vital organs make LIV-1 an excellent target for an ADC. These findings support the further development of anti-LIV-1-vcMMAE as a promising therapeutic agent for the treatment of ER+ and triple-negative breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-16.
Film Thickness Dependence of Protein Adsorption from Blood Serum and Plasma onto Poly(sulfobetaine)-Grafted Surfaces (2008)

In this work, we investigate protein adsorption from single protein solutions and complex media such as 100% blood serum and plasma onto poly(sulfobetaine methacrylate) (polySBMA)-grafted surfaces via atom transfer radical polymerization (ATRP) at varying film thicknesses. It is interesting to observe that protein adsorption exhibits a minimum at a medium film thickness. Results show that the surface with 62 nm polySBMA brushes presents the best nonfouling character in 100% blood serum and plasma although all of these surfaces are highly resistant to nonspecific protein adsorption from single fibrinogen and lysozyme solutions. Surface resistance to 100% blood serum or plasma is necessary for many applications from blood-contacting devices to drug delivery. This work provides a new in vitro evaluation standard for the application of biomaterials in vivo.
Characterization of human uroguanylin: a member of the guanylin peptide family (1994)

Guanylin, a peptide homologue of the bacterial heat-stable enterotoxins (ST), is an endogenous activator of guanylate cyclase C (GC-C). We have initiated a search for other members of the guanylin peptide family and in the current study describe a "guanylin-like peptide" from human urine. Bioactivity was monitored by determining the effect of urine extracts on T84 cell guanosine 3',5'-cyclic monophosphate (cGMP) levels. Purification yielded two bioactive peaks of peptides that, when sequenced by NH2-terminal analysis, possessed 15 and 16 amino acids. The sequence of the smaller peptide represented an NH2-terminal truncation of the larger peptide. We have termed the larger peptide human uroguanylin; it has the following amino acid sequence: NDDCELCVNVACTGCL. Human uroguanylin shares amino acid sequence homology with guanylin and ST. Synthetic uroguanylin increased cGMP levels in T84 cells, competed with 125I-labeled ST for receptors, and stimulated Cl- secretion as reflected by an increased short-circuit current. Thus we report the isolation from human urine of a unique peptide, uroguanylin, that behaves in a manner similar to guanylin and appears to be a new member of this peptide family.
Plasma biomarkers predictive for disease control duration in the phase I study of E7080, a multitarget kinase inhibitor (2009)

e14524 Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. In the phase I study for advanced solid tumors, E7080 was repeated every 3 weeks (twice daily by 2 wks-on/ 1 wk-off). The toxicities were manageable and the preliminary antitumor activity including one partial response was observed at doses up to MTD [ASCO 2008; abstract 3527]. This study was conducted to evaluate whether the change of plasma biomarkers in the E7080 phase I study could predict the antitumor activity or the disease control duration. Methods: The treatment duration was determined as a period from the first dosing to treatment failure. Plasma angiogenic proteins and circulating endothelial cells (CEC)/ progenitor cells (CEP) were measured in blood samples collected on Days 1 (pre-dose), 8 and 15 of Cycles 1 and 2. CEC and CEP population with (+) or (-) c-kit expression were analyzed by FACS. Correlation was determined by Spearman's rank correlation coefficient (r) and test for non-correlation (p). Results: 19 (76%) out of 25 evaluable patients had PR/SD including 6 (24%) patients with the treatment duration of ≥180 days. VEGF increase and sVEGFR1 and -R2 decreases in plasma were seen with the increased dose of E7080. But these changes had no correlations with disease control. E7080 decreased c-kit(+) CEC and CEP, but not c-kit(-) population. Importantly, patients showing the decrease of c-kit(+) CEC in Cycle 1 had received E7080 treatment for significantly longer duration (r=-0.468, p=0.018). The decrease of c- kit(+) CEC diminished during treatment-off for final 7 days in Cycle 1 and repeatedly decreased in Cycle 2 treatment. The decrease of c- kit(+) ratio in CEP correlated with the increase of plasma SCF (r=-0.457, p=0.021) and SDF1 (r=-0.466, p=0.018), but not with VEGF or thrombopoietin. Conclusions: The change of c-kit(+) CEC correlated with the disease control duration in the phase I study of E7080. SCF and SDF1 may play a role in c-kit(+) CEP accumulation. C-kit(+)-selective changes of CEC could be a candidate biomarker to predict the disease control duration in anti-angiogenic therapy of E7080. [Table: see text]
Histidine 265 Is Important for Covalent Catalysis by Vaccinia Topoisomerase and Is Conserved in All Eukaryotic Type I Enzymes (1997)

Vaccinia topoisomerase catalyzes DNA cleavage and rejoining via transesterification to pentapyrimidine recognition site 5'-(C/T)CCTT downward arrow in duplex DNA. The proposed reaction mechanism involves general-base catalysis of the attack by active site nucleophile Tyr-274 on the scissile phosphodiester and general-acid catalysis of the expulsion of the 5'-deoxyribose oxygen on the leaving DNA strand. The pKa values suggest histidine and cysteine side chains as candidates for the roles of proton acceptor and donor, respectively. To test this, we replaced each of the eight histidines and two cysteines of the vaccinia topoisomerase with alanine. Single mutants C100A and C211A and a double mutant C100A-C211A were fully active in DNA relaxation, indicating that a cysteine is not the general acid. Only one histidine mutation, H265A, affected enzyme activity. The rates of DNA relaxation, single-turnover strand cleavage, and single-turnover religation by H265A were 2 orders of magnitude lower than the wild-type rates. Yet the H265A mutation did not alter the dependence of the cleavage rate on pH, indicating that His-265 is not the general base. Replacing His-265 with glutamine or asparagine slowed DNA relaxation and single-turnover cleavage to about one-third of the wild-type rate. All three mutations, H265A, H265N, and H265Q, skewed the cleavage-religation equilibrium in favor of the covalently bound state. His-265 is strictly conserved in every member of the eukaryotic type I topoisomerase family.
Structure and function of the mycobacterial transcription initiation complex with the essential regulator RbpA (2017)

RbpA and CarD are essential transcription regulators in mycobacteria. Mechanistic analyses of promoter open complex (RPo) formation establish that RbpA and CarD cooperatively stimulate formation of an intermediate (RP2) leading to RPo; formation of RP2 is likely a bottleneck step at the majority of mycobacterial promoters. Once RPo forms, CarD also disfavors its isomerization back to RP2. We determined a 2.76 Å-resolution crystal structure of a mycobacterial transcription initiation complex (TIC) with RbpA as well as a CarD/RbpA/TIC model. Both CarD and RbpA bind near the upstream edge of the −10 element where they likely facilitate DNA bending and impede transcription bubble collapse. In vivo studies demonstrate the essential role of RbpA, show the effects of RbpA truncations on transcription and cell physiology, and indicate additional functions for RbpA not evident in vitro. This work provides a framework to understand the control of mycobacterial transcription by RbpA and CarD.
A risk index for 12-month suicide attempts in the National Comorbidity Survey Replication (NCS-R) (2006)

A short, preliminary risk index based on retrospectively reported responses to fully structured questions is strongly correlated with 12-month suicide attempts among ideators, with a high concentration of attempts among high-risk ideators.
Extracellular matrix regulates expression of the TGF-beta 1 gene. (1993)

Transforming growth factor-beta (TGF-beta) is a potent regulator of cell proliferation and modulates the interactions of cells with their extracellular matrix (ECM), in part by inducing the synthesis of various ECM proteins. Three different isoforms of TGF-beta are synthesized in a defined pattern in specific cell populations in vivo. In the specific case of TGF-beta 1, this well-defined and limited expression stands in sharp contrast to its synthesis by virtually all cells in culture. Using mammary epithelial cells as a model system, we evaluated the substratum dependence of the expression of TGF-beta 1. The level of TGF-beta 1 expression is high in cells on plastic, but is strongly downregulated when cells are cultured on a reconstituted basement membrane matrix. In contrast, TGF-beta 2 mRNA levels in cells on either substratum remain unchanged. Using the chloramphenicol acetyl transferase gene as reporter gene under the control of the TGF-beta 1 promoter, we show that transcription from this promoter is suppressed when the cells are in contact with either endogenously synthesized or exogenously administered basement membrane. TGF-beta 1 promoter activity is strongly induced by the absence of basement membrane, i.e., by direct contact of the cells with plastic. This modulation of transcription from the TGF-beta 1 promoter occurs in the absence of lactogenic hormones which allow full differentiation. Our results thus indicate that basement membrane is an important regulator of TGF-beta 1 synthesis, and explain why most cells in culture on plastic express TGF-beta 1 in contrast with the more restricted TGF-beta 1 synthesis in vivo. We propose that there is a feedback loop whereby TGF-beta 1-induced synthesis of basement membrane components is repressed once a functional basement membrane is present. Finally, these results together with our current knowledge of regulation of TGF-beta 1 and TGF-beta 2 synthesis, suggest that, in vivo, TGF-beta 1 may play a major role in regulating the ECM synthesis and the cell-ECM interactions, whereas TGF-beta 2 may be more important in morphogenetic processes.
Recommendations for the Clinical Evaluation of Agents for Treatment of Osteoporosis: Consensus of an Expert Panel Representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF) (2007)

The panel concluded that placebo-controlled trials with fracture endpoints are appropriate and, with informed consent, are ethical for registration of new compounds. Trials may be 18-24 mo in duration for efficacy, assuming longer duration to 5 yr for safety and demonstration of sustained fracture reduction. Once fracture efficacy has been established for a particular agent, intermediate endpoints (e.g., BMD and bone turnover markers) may be used as outcomes for new indications other than corticosteroid-induced osteoporosis.
ChemInform Abstract: Heterocyclic Systems Containing a Bridgehead Nitrogen Atom. Part 54. Synthesis of Thiazolo(3,2‐a)benzimidazol‐3‐(2H)‐ones. (1987)

Abstract The desired compounds (VII) and (VIII) are synthesized as described in the scheme.
Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives (2016)

We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C–H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine.
Aging of Microstructural Compartments in Human Compact Bone (2003)

Composition of microstructural compartments in compact bone of aging male subjects was assessed using Raman microscopy. Secondary mineralization of unremodeled fragments persisted for two decades. Replacement of these tissue fragments with secondary osteons kept mean composition constant over age, but at a fully mineralized limit. Slowing of remodeling may increase fracture susceptibility through an increase in proportion of highly mineralized tissue. In this study, the aging process in the microstructural compartments of human femoral cortical bone was investigated and related to changes in the overall tissue composition within the age range of 17-73 years. Raman microprobe analysis was used to assess the mineral content, mineral crystallinity, and carbonate substitution in fragments of primary lamellar bone that survived remodeling for decades. Tissue composition of the secondary osteonal population was investigated to determine the composition of turned over tissue volume. Finally, Raman spectral analysis of homogenized tissue was performed to evaluate the effects of unremodeled and newly formed tissue on the overall tissue composition. The chemical composition of the primary lamellar bone exhibited two chronological stages. Organic matrix became more mineralized and the crystallinity of the mineral improved during the first stage, which lasted for two decades. The mineral content and the mineral crystallinity did not vary during the second stage. The results for the primary lamellar bone demonstrated that physiological mineralization, as evidenced by crystal growth and maturation, is a continuous process that may persist as long as two decades, and the growth and maturation process stops after the organic matrix becomes "fully mineralized." The average mineral content and the average mineral crystallinity of the homogenized tissue did not change with age. It was also observed that the mineral content of the homogenized tissue was consistently greater than the osteons and similar to the "fully mineralized" stage of primary bone. The results of this study demonstrated that unremodeled compartments of bone grow older through maturation and growth of mineral crystals in a protracted fashion. However, the secondary osteonal remodeling impedes this aging process and maintains the mean tissue age fairly constant over decades. Therefore, slowing of remodeling may lead to brittle bone tissue through accumulation of fully mineralized tissue fragments.
High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation (2008)

In lymphatic tissues, chronic lymphocytic leukemia (CLL) cells are interspersed with CD68(+) nurselike cells (NLCs), T cells, and other stromal cells that constitute the leukemia microenvironment. However, the mechanism regulating colocalization of CLL and these accessory cells are largely unknown. To dissect the molecular cross talk between CLL and NLCs, we profiled the gene expression of CD19-purified CLL cells before and after coculture with NLCs. NLC coculture induced high-level expression of B-cell maturation antigen and 2 chemoattractants (CCL3, CCL4) by CLL cells. CCL3/CCL4 induction in NLC cocultures correlated with ZAP-70 expression by CLL cells. High CCL3/CCL4 protein levels were found in CLL cocultures with NLCs, and CCL3/CCL4 induction was abrogated by R406, a Syk inhibitor, suggesting that NLCs induce these chemokines via B-cell receptor (BCR) activation. BCR triggering also caused robust CCL3/CCL4 protein secretion by CLL cells. High CCL3 and CCL4 plasma levels in CLL patients suggest that this pathway plays a role in vivo. These studies reveal a novel mechanism of cross talk between CLL cells and their microenvironment, namely, the secretion of 2 T-cell chemokines in response to NLC coculture and BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells and thereby actively create a supportive microenvironment.
Evaluating security requirements in a general-purpose processor by combining assertion checkers with code coverage (2012)

The problem of malicious inclusions in hardware is an emerging threat, and detecting them is a difficult challenge. In this research, we enhance an existing method for creating assertion-based dynamic checkers, and demonstrate how behavioral security requirements can be derived from a processor's architectural specification, then converted into security checkers that are part of the processor's design. The novel contributions of this research are: - We demonstrate the method using a set of assertions, derived from the architectural specification, on a full-scale open-source general-purpose processor design, called OpenRISC. Previous work used only a single assertion on a toy processor design. - We demonstrate the use of our checker-generator tool, called psl2hdl, which was created for this research. - We illustrate how the method can be used in concert with code coverage techniques, to either detect malicious inclusions or greatly narrow the search for malicious inclusions that use rare-event triggers.
Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-β1 in normal human lung fibroblasts (NHLF) (2010)

Our study suggests that some regulatory properties of BMP-7 may be tissue or cell type specific and unveil a potential regulatory role for BMP-4 in the regulation of lung fibroblast function.
Dyadic Green’s functions and guided surface waves for a surface conductivity model of graphene (2008)

An exact solution is obtained for the electromagnetic field due to an electric current in the presence of a surface conductivity model of graphene. The graphene is represented by an infinitesimally thin, local, and isotropic two-sided conductivity surface. The field is obtained in terms of dyadic Green’s functions represented as Sommerfeld integrals. The solution of plane wave reflection and transmission is presented, and surface wave propagation along graphene is studied via the poles of the Sommerfeld integrals. For isolated graphene characterized by complex surface conductivity σ=σ′+jσ″, a proper transverse-electric surface wave exists if and only if σ″&amp;gt;0 (associated with interband conductivity), and a proper transverse-magnetic surface wave exists for σ″&amp;lt;0 (associated with intraband conductivity). By tuning the chemical potential at infrared frequencies, the sign of σ″ can be varied, allowing for some control over surface wave properties.