gebhart/patrepeval huggingface dataset:
Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: Results of a phase II study (2006)

4082 Background: Pasireotide is a novel multiligand somatostatin analogue that exhibits high binding affinity to 4 of 5 somatostatin receptor subtypes: sst 1,2,3 and sst 5 . Compared with octreotide, pasireotide has 30, 5 and 40 times greater affinity for sst 1,3 and sst 5 receptors respectively and a comparable affinity for sst 2 . Methods: This was a Phase II, open-label, multicenter study in patients with metastatic carcinoid tumors whose symptoms (diarrhea and flushing) were inadequately controlled by octreotide LAR. Patients had histopathologically confirmed disease, elevated 5-HIAA and/or CgA levels and at least one measurable lesion (excluding bone). Patients initially received pasireotide 300 μg sc bid and escalated to a maximum dose of 1200 μg sc bid every 3 days until clinical response was achieved. Partial response (PR) was defined as a mean of &lt;4 bowel movements (BM)/day with no more than 6 BM on any given day, and a mean of &lt;2 flushing episodes/day for 15 consecutive days on a fixed dose of pasireotide. Complete response (CR) was defined as a mean of ≤3 BM/day, with no more than 3 BM on any given day, and no flushing episodes. Results: Safety data are reported from 45 patients as of September 2005; 44 patients (mean age 61 years) qualified for efficacy assessment. Carcinoid tumors were predominantly of midgut origin. Preliminary efficacy data in controlling symptoms of carcinoid syndrome showed PR in 9 patients (20%) at 600–1200 μg sc bid doses and CR in 2 patients (5%) at the 600 and 900 μg sc bid doses. Objective tumor response in 11 patients showed 9 with stable disease and 2 with progressive disease at 6 months. Adverse events (AEs) were primarily gastrointestinal (GI): abdominal pain (31%) and nausea (27%). Weight loss (22%) and fatigue (22%) were also reported. Most AEs were mild or moderate. Glucose-related AEs (predominantly CTC grade 1–2) were observed in 24% of patients. Most discontinuations were due to GI AEs (n = 6) or lack of therapeutic response. Conclusions: Pasireotide 600–1200 μg sc bid was effective in controlling symptoms of diarrhea and flushing in 25% of patients with metastatic carcinoid tumors inadequately controlled by octreotide LAR. The safety profile of pasireotide is similar to octreotide LAR. [Table: see text]
Immunopharmacologic Modulation of Experimental Allergic Encephalomyelitis: Low‐Dose Cyclosporin‐A Treatment Causes Disease Relapse and Increased Systemic T and B Cell‐Mediated Myelin‐Directed Autoimmunity (1993)

Therapies with immunosuppressive drugs in autoimmune experimental diseases often down-regulate disease but sometimes may lead to paradoxical disease exacerbation. To elucidate possible mechanisms behind such phenomena the effects were studied of mitoxantrone (Mx) and cyclosporin A (CsA) given at high and low doses on clinical course, and on autoreactive T- and B-cell responses in actively induced experimental allergic encephalomyelitis (EAE) in Lewis rats. Treatment with Mx and high dose CsA abrogated EAE and decreased dramatically the measured immune responses compared to vehicle-treated control EAE rats. Low-dose CsA treatment caused a disease relapse 20-30 days post immunization (p.i.). This relapse was accompanied by increased numbers of cells spontaneously producing IFN-gamma in the CNS and regional lymph nodes. Furthermore, anti-myelin and anti-MBP secreting cells were increased as were numbers of primed T cells that produced IFN-gamma in response to myelin antigens. It was concluded that these aspects of the myelin autoreactive immune response correlated well with clinical disease and are useful in evaluating immunotherapeutic intervention. Low-dose CsA treatment may interfere with systemic down-regulatory mechanisms acting on both T- and B-cell myelin-directed autoimmunity.
Constrained Route Distribution for Border Gateway Protocol/MultiProtocol Label Switching (BGP/MPLS) Internet Protocol (IP) Virtual Private Networks (VPNs) (2006)

This document defines Multi-Protocol BGP (MP-BGP) procedures that
allow BGP speakers to exchange Route Target reachability information.
This information can be used to build a route distribution graph in
order to limit the propagation of Virtual Private Network (VPN)
Network Layer Reachability Information (NLRI) between different
autonomous systems or distinct clusters of the same autonomous system.
This document updates RFC 4364. [STANDARDS-TRACK]
Measurements vs. Bits: Compressed Sensing meets Information Theory (2006)

Abstract — Compressed sensing is a new framework for acquiring sparse signals based on the revelation that a small number of linear projections (measurements) of the signal contain enough information for its reconstruction. The foundation of Compressed sensing is built on the availability of noise-free measurements. However, measurement noise is unavoidable in analog systems and must be accounted for. We demonstrate that measurement noise is the crucial factor that dictates the number of measurements needed for reconstruction. To establish this result, we evaluate the information contained in the measurements by viewing the measurement system as an information theoretic channel. Combining the capacity of this channel with the ratedistortion function of the sparse signal, we lower bound the rate-distortion performance of a compressed sensing system. Our approach concisely captures the effect of measurement noise on the performance limits of signal reconstruction, thus enabling to benchmark the performance of specific reconstruction algorithms. I.
Highly Enantioselective, Catalytic Conjugate Addition of Cyanide to α,β-Unsaturated Imides (2003)

(Salen)Al-Cl complex 1a catalyzes the asymmetric conjugate addition of hydrogen cyanide to alpha,beta-unsaturated imides in high yields and enantioselectivities. The cyanide adducts can readily be converted into a variety of useful chiral building blocks, including alpha-substituted-beta-amino acids and beta-substituted-gamma-aminobutyric acids. Mechanistic data obtained thus far point to a cooperative bimetallic mechanism for nucleophile and electrophile activation.
Purine 8-cyclonucleosides (1969)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPurine 8-cyclonucleosidesMorio IkeharaCite this: Acc. Chem. Res. 1969, 2, 2, 47–53Publication Date (Print):February 1, 1969Publication History Published online1 May 2002Published inissue 1 February 1969https://pubs.acs.org/doi/10.1021/ar50014a003https://doi.org/10.1021/ar50014a003research-articleACS PublicationsRequest reuse permissionsArticle Views208Altmetric-Citations56LEARN 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
The Profile of Soluble Amyloid β Protein in Cultured Cell Media (1996)

To study the metabolism of amyloid beta protein (Abeta) in Alzheimer's disease, we have developed a new approach for analyzing the profile of soluble Abeta and its variants. In the present method, Abeta and its variants are immuno-isolated with Abeta-specific monoclonal antibodies. The identities of the Abeta variants are determined by measuring their molecular masses using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The levels of Abeta variants are determined by their relative peak intensities in mass spectrometric measurements by comparison with internal standards of known identities and concentrations. We used this method to examine the Abeta species in conditioned media of mouse neuroblastoma cells transfected with cDNAs encoding wild type or mutant human amyloid precursor protein. In addition to human Abeta-(1-40) and Abeta-(1-42), more than 40 different human Abeta variants were identified. Endogenous murine Abeta and its variants were also identified by this approach. The present approach is a new and sensitive method to characterize the profile of soluble Abeta in conditioned media and biological fluids. Furthermore, it allows direct measurement of each individual peptide in a peptide mixture and provides comprehensive information on the identity and concentration of Abeta and Abeta variants.
Hormone- and substrate-regulated intracellular degradation of cytochrome P450 (2E1) involving MgATP-activated rapid proteolysis in the endoplasmic reticulum membranes. (1992)

We have examined differences in post-translational regulation between rat liver ethanol-inducible cytochrome P450 2E1 (CYP2E1) and phenobarbital-inducible CYP2B1 using hepatocyte cultures and subcellular fractions, prepared from starved and acetone-treated rats. The intracellular degradation of CYP2E1 was rapid (approximate t1/2 = 9 h) and increased by glucagon treatment of the cells in an isozyme-specific manner, whereas CYP2B1 degradation in the same cells, was slower (t1/2 = 21 h). The glucagon effect on CYP2E1 degradation was abolished by either cycloheximide treatment of cells, indicating the involvement of protein components with rapid turnover, or by lowering of the culture temperature to 23 degrees C. The rapid phase of CYP2E1 degradation was not influenced by inhibitors of the autophagosomal/lysosomal pathway. In vitro experiments with isolated liver microsomes revealed the presence of a Mg(2+)-ATP-activated proteolytic system active on CYP2E1, previously modified by phosphorylation on Ser-129 or denatured by reactive metabolites formed from carbon tetrachloride. Imidazole, a CYP2E1 substrate, specifically inhibited the rapid intracellular degradation of CYP2E1 and also prevented phosphorylation and subsequent proteolysis in isolated microsomes. In contrast, no proteolysis of CYP2B1 occurred under the conditions used. The microsomal Mg(2+)-ATP-dependent CYP2E1 proteolysis could not be solubilized with high salt and 0.05% sodium cholate, indicating the action of membrane-integrated protease(s). Subfractionation of microsomes revealed that the Mg(2+)-ATP-dependent proteolytic system active on CYP2E1 was present in both rough and smooth endoplasmic reticulum. It is suggested that hepatic cytochromes P450 are degraded both in a bulk process, according to the autophagosomal/lysosomal pathway and more rapidly, in a hormone- and substrate-regulated fashion, by a specific proteolytic system in the endoplasmic reticulum, active on physiologically or exogenously modified molecules.
An Ileal Crohn's Disease Gene Signature Based on Whole Human Genome Expression Profiles of Disease Unaffected Ileal Mucosal Biopsies (2012)

Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.
Mucoid Pseudomonas aeruginosa , TNF-α, and IL-1 β, but Not IL-6, Induce Human β-Defensin-2 in Respiratory Epithelia (2000)

Cultured lung epithelial cells release antibacterial activity upon contact with Pseudomonas aeruginosa (PA), which is impaired in cystic fibrosis (CF). In order to identify the factors responsible for killing PA by a biochemical approach, we purified antimicrobial activity from supernatants of the A549 lung epithelial cell line, previously stimulated with PA bacteria, by subsequent high performance liquid chromatography. NH(2)-terminal sequencing of a major bactericidal compound revealed it to be identical with human beta-defensin-2 (hBD-2). A mucoid phenotype of PA, but not two nonmucoid PA strains, high concentrations (> 10 microg/ml) of PA lipopolysaccharide, tumor necrosis factor alpha, and interleukin (IL)-1beta, but not IL-6, dose-dependently induced hBD-2 messenger RNA in cultured normal bronchial, tracheal, as well as normal and CF-derived nasal epithelial cells. Genomic analysis of hBD-2 revealed a promoter region containing several putative transcription factor binding sites, including nuclear factor (NF) kappaB, activator protein (AP)-1, AP-2, and NF-IL-6, known to be involved in the regulation of inflammatory responses. Thus, hBD-2 represents a major inducible antimicrobial factor released by airway epithelial cells either on contact with mucoid PA or by endogenously produced primary cytokines. Therefore, it might be important in lung infections caused by mucoid PA, including those seen in patients with CF.
Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles (2002)

Human neutrophils have an important role in host defense against microbial infection. At different stages of an infectious process, neutrophils progressively up-regulate receptors and release various effector molecules. These are stored in several distinct types of granules with varying propensity to be secreted. Heparin-binding protein (HBP), also known as CAP37 or azurocidin, is a multifunctional, inactive serine-protease homologue. The present work shows that HBP is released from neutrophils on stimulation with secretagogues that do not trigger the secretion of azurophilic granule content. Therefore, the subcellular localization of HBP was investigated in more detail. Immunofluorescence microscopy revealed that HBP was localized close to the plasma membrane. Further analysis by fractionation of postnuclear supernatants from cavitated neutrophils showed that HBP is stored in azurophilic granules and secretory vesicles but that it is also detected to a minor extent in the plasma membrane. These findings were confirmed by immunoelectron microscopy showing that HBP colocalized with marker proteins of azurophilic granules and secretory vesicles. The presence of HBP in secretory vesicles possibly depends on the stage of cell differentiation, since the promyelocytic cell line HL-60 contains less HBP than mature neutrophils, stored exclusively in the less easily mobilized azurophilic granules. Our findings suggest that HBP can be synthesized or targeted to easily mobilized compartments at a late stage of neutrophil maturation. The ability of neutrophils to secrete HBP from secretory vesicles may be important for proinflammatory functions of this protein, such as the alteration of vascular permeability.
The Vesta parallel file system (1996)

The Vesta parallel file system is designed to provide parallel file access to application programs running on multicomputers with parallel I/O subsystems. Vesta uses a new abstraction of files: a file is not a sequence of bytes, but rather it can be partitioned into multiple disjoint sequences that are accessed in parallel. The partitioning—which can also be changed dynamically—reduces the need for synchronization and coordination during the access. Some control over the layout of data is also provided, so the layout can be matched with the anticipated access patterns. The system is fully implemented and forms the basis for the AIX Parallel I/O File System on the IBM SP2. The implementation does not compromise scalability or parallelism. In fact, all data accesses are done directly to the I/O node that contains the requested data, without any indirection or access to shared metadata. Disk mapping and caching functions are confined to each I/O node, so there is no need to keep data coherent across nodes. Performance measurements shown good scalability with increased resources. Moreover, different access patterns are show to achieve similar performance.
Environmentally persistent alkylphenolic compounds are estrogenic. (1994)

We show that a number of alkylphenolic compounds, used in a variety of commercial products and found in river water, are estrogenic in fish, birds, and mammals. 4-Octylphenol (OP), 4-nonylphenol, 4-nonylphenoxycarboxylic acid, and 4-nonylphenoldiethoxylate were each capable of stimulating vitellogenin gene expression in trout hepatocytes, gene transcription in transfected cells, and the growth of breast cancer cell lines. The most potent of the chemicals is OP, which was able to stimulate these biological responses to a similar extent as 17 beta-estradiol itself, albeit at a 1000-fold greater concentration. The action of alkylphenols is mediated by the estrogen receptor, as their effects depended on its presence and was blocked by estrogen antagonists. OP, 4-nonylphenol, and 4-nonylphenoxycarboxylic acid appear to possess intrinsic estrogenic activity, because they compete for binding to the estrogen receptor. Moreover, it is likely that they interact with a similar region of the hormone-binding domain as 17 beta-estradiol, because the mutant receptor G-525R, which is defective in estrogen binding, is also insensitive to OP. Like 17 beta-estradiol, OP is capable of stimulating the activity of both transcriptional activation functions, TAF-1 and TAF-2, in the receptor, as judged by analyzing the activity of the wild-type and mutant receptors in transiently transfected cells. The significance of our results will depend to a large extent on the degree of exposure of wildlife and humans to these estrogenic alkylphenolic compounds.
DIFFERENTIATION OF MAXIMAL FROM SUBMAXIMAL STATIC ELBOW FLEXOR EFFORTS BY MEASUREMENT VARIABILITY (1987)

Thirty-one young women subjects performed four maximal and four submaximal elbow flexion efforts. The strength of each effort was measured using make tests and a hand-held dynamometer. The variability of repeated maximal and submaximal tests was determined by calculating CVs for each subject. Every subject's CV was greater during submaximal than during maximal trials. Furthermore, the mean CV was significantly greater during submaximal trials than during maximal trials. No subject demonstrated a CV greater than 7.5 per cent for maximal trials, but most had CVs greater than 7.5 per cent for submaximal trials. The results suggest that for the subjects tested CVs greater than 7.5 per cent were consistent with feigned weakness. Coefficients of variation above 7.5 per cent were not, however, limited to subjects feigning weakness. Further investigations of strength variability are needed under different conditions before confident judgements can be made about patient performance.
Oncogenic forms of p53 inhibit p53-regulated gene expression (1992)

Mutant forms of the gene encoding the tumor suppressor p53 are found in numerous human malignancies, but the physiologic function of p53 and the effects of mutations on this function are unknown. The p53 protein binds DNA in a sequence-specific manner and thus may regulate gene transcription. Cotransfection experiments showed that wild-type p53 activated the expression of genes adjacent to a p53 DNA binding site. The level of activation correlated with DNA binding in vitro. Oncogenic forms of p53 lost this activity. Moreover, all mutants inhibited the activity of coexpressed wild-type p53, providing a basis for the selection of such mutants during tumorigenesis.
Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2011)

Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development. Recent work has shown that these destabilizing influences are counterbalanced by homeostatic plasticity mechanisms that act to stabilize neuronal and circuit activity. One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms may allow local changes in synaptic activation to generate local synaptic adaptations, and network-wide changes in activity to generate network-wide adjustments in the balance between excitation and inhibition. The signaling pathways underlying these various forms of homeostatic plasticity are currently under intense scrutiny, and although dozens of molecular pathways have now been implicated in homeostatic plasticity, a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged. On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.