gebhart/patrepeval huggingface dataset:
Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts) (2007)

10004 Background: The MetaGIST project aims to further explore the data of the two randomized studies comparing two doses of imatinib (400 mg od vs bid) for the treatment of GIST: EORTC/ISG/AGITG 62005 (EU-AUS) and SWOG/CALGB/NCI-C/ECOG/ICAS S0033 (US-CDN). Methods: End-points were progression free (PFS) and overall survival (OS). Investigated cofactors included age, sex, performance status (PS), primary tumor site, time from diagnosis, prior therapies, baseline biology, and KIT / PDGFRa mutations for a subset of 772 pts (47%). The logrank test (stratified) and the Cox multivariate model with interaction terms were used for the analysis. Results: The median follow-up was 45 months. A small but significant PFS advantage was documented for the high dose arm, consistently in both studies. OS was identical in the two arms (see table ). Males and pts with a poor PS, GIST from bowel origin, baseline low hemoglobin and high neutrophils counts (ANC) had a significant worse PFS (multivariate analysis); these factors are consistent between studies. In pts analyzed for mutations, wild type pts (HR=1.56), KIT exon 9 mutants (HR=2.17) and pts with other mutations (HR=2.56) had a worse prognosis than KIT exon 11 mutants (univariate analysis); all 3 factors remained in the multivariate model. The US-CDN study included significantly (P&lt;0.01) more females, more GIST from bowel or stomach origin, less KIT exon 9 mutants and pts with a lower baseline ANC. In KIT exon 9 mutants, the PFS advantage with high dose imatinib previously reported in the EU- AUS study was not confirmed in the US-CDN dataset, but remains significant in the pooled dataset. The interaction between dose effect on PFS and prognostic factors was siginficant for KIT exon 9 mutations but not for other factors. Conclusions: This analysis confirms a small PFS advantage of high dose imatinib, essentially amongst KIT exon 9 mutants, but no OS advantage. Heterogeneity between the two studies is being further explored. [Table: see text] [Table: see text]
Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response (2004)

Maintenance of protective humoral immunity depends on the generation and survival of antibody-secreting cells. The bone marrow provides niches for long-term survival of plasma cells generated in the course of systemic immune responses in secondary lymphoid organs. Here, we have analyzed migratory human plasma blasts and plasma cells after secondary vaccination with tetanus toxin. On days 6 and 7 after immunization, CD19(+)/CD27(high)/intracellular immunoglobulin G(high) (IgG(high))/HLA-DR(high)/CD38(high)/CD20(-)/CD95(+) tetanus toxin-specific antibody-secreting plasma blasts were released in large numbers from the secondary lymphoid organs into the blood. These cells show chemotactic responsiveness toward ligands for CXCR3 and CXCR4, probably guiding them to the bone marrow or inflamed tissue. At the same time, a population of CD19(+)/CD27(high)/intracellular IgG(high)/HLA-DR(low)/CD38(+)/CD20(-)/CD95(+) cells appeared in the blood in large numbers. These cells, with the phenotype of long-lived plasma cells, secreted antibodies of unknown specificity, not tetanus toxoid. The appearance of these plasma cells in the blood indicates successful competition for survival niches in the bone marrow between newly generated plasma blasts and resident plasma cells as a fundamental mechanism for the establishment of humoral memory and its plasticity.
Domain Organization and Functional Analysis of Type IIS Restriction Endonuclease Eco31I (2008)

Type IIS restriction endonuclease Eco31I harbors a single HNH active site and cleaves both DNA strands close to its recognition sequence, 5'-GGTCTC(1/5). A two-domain organization of Eco31I was determined by limited proteolysis. Analysis of proteolytic fragments revealed that the N-terminal domain of Eco31I is responsible for the specific DNA binding, while the C-terminal domain contains the HNH nuclease-like active site. Gel-shift and gel-filtration experiments revealed that a monomer of the N-terminal domain of Eco31I is able to bind a single copy of cognate DNA. However, in contrast to other studied type IIS enzymes, the isolated catalytic domain of Eco31I was inactive. Steady-state and transient kinetic analysis of Eco31I reactions was inconsistent with dimerization of Eco31I on DNA. Thus, we propose that Eco31I interacts with individual copies of its recognition sequence in its monomeric form and presumably remains a monomer as it cleaves both strands of double-stranded DNA. The domain organization and reaction mechanism established for Eco31I should be common for a group of evolutionary related type IIS restriction endonucleases Alw26I, BsaI, BsmAI, BsmBI and Esp3I that recognize DNA sequences bearing the common pentanucleotide 5'-GTCTC.
Non‐starch polysaccharides of canola meal: Quantification, digestibility in poultry and potential benefit of dietary enzyme supplementation (1990)

Abstract The non‐starch polysaccharide (NSP) content as determined by gas chromatography (component neutral sugars) and colorimetry (uronic acids) was shown to be 16–22% in ten different samples of defatted canola (low glucosinolate rapeseed) seed. The non‐cellulosic components of NSP accounted for 13–16% of the meal and on average consisted of arabinose (33%), xylose (13%), galactose (13%), glucose (5%), mannose (3%), rhamnose (2%), fucose (2%) and uronic acids (30%). Yellow‐seeded and brown‐seeded samples of canola contained similar contents of total dietary fibre although the composition of the fibre components tended to differ with the former showing a low content of lignin and associated polyphenols and a high content of NSP as compared with the latter type. NDF values tended to be lower for yellow‐seeded than for brown‐seeded canola due to the relatively high content of NSP in neutral detergent solubles of yellow‐seeded canola. An initial balance study with laying hens showed low (&lt;3%) digestibility of the polysaccharide components, and further studies were conducted with a commercial enzyme preparation (SP249, Novo Laboratories Ltd, Lachine, Quebec) to enhance the in‐vivo hydrolysis of the NSP fraction of the meal. Laying hens were fed a semipurified diet containing 40% commercial canola meal with and without enzyme (1%). NSP digestibility was increased to 37% by the enzyme supplementation.
Detailed Characterization of T Cell Responses to Herpes Simplex Virus-2 in Immune Seronegative Persons (2010)

In 2003, we described a small cohort of subjects (n = 6) who possessed no detectable serum Abs to HSV-1 or HSV-2 and no clinical or virological evidence of mucosal HSV infection yet possessed consistently detectable HSV-specific T cell responses measured primarily by lymphoproliferative (LP) and CTL assays to whole HSV-2 Ag. We termed these persons immune seronegative (IS). This report characterizes the T cell responses in 22 IS subjects largely recruited from studies of HSV-seronegative subjects in ongoing sexual relationships with HSV-2-seropositive (HSV-2(+)) partners using pools of overlapping peptides spanning 16 immuno-prevalent HSV-2 proteins. Overall, 77% of IS subjects had HSV-specific LP responses, 85% had IFN-gamma ELISPOT responses to at least one HSV-2 peptide pool, and 55% had both LP and IFN-gamma ELISPOT responses. In some cases, IFN-gamma ELISPOT responses were in excess of 500 spot-forming cells per 10(6) PBMCs and persisted for over 5 y. Although HSV-2(+) subjects (n = 40) had frequent responses to glycoproteins and tegument and immediate-early (IE) proteins of HSV-2, T cell responses in IS subjects were directed primarily at UL39 and the IE proteins ICP4 and ICP0. These data suggest that the antigenic repertoire of T cells in IS subjects is skewed compared with that of HSV-2(+) subjects and that IS subjects had more frequent T cell responses to IE proteins and infrequent T cell responses to virion components. Understanding the mechanism(s) by which such responses are elicited may provide important insights in developing novel strategies for preventing acquisition of sexually acquired HSV-2.
Differential impact of Cetuximab, Pertuzumab and Trastuzumab on BT474 and SK‐BR‐3 breast cancer cell proliferation (2007)

The extent of decelerated or blocked cell proliferation after antibody treatment that is targeted to EGFR and to Her2 depends both on EGFR and Her2 co-expression and on antibody combination used in the treatment setting. Cetuximab did not enhance any inhibitory effect of Trastuzumab or Pertuzumab, most probably due to the dominant overexpression of Her2. Cell susceptibility to Trastuzumab/Pertuzumab, both targeted to Her2, was defined by the ratio of EGFR/Her2 co-expression.
Inhibitory effects of brain chondroitin sulfate proteoglycans on neurite outgrowth from PC12D cells. (1991)

Soluble chondroitin sulfate proteoglycans (CSPGs), prepared from 10-d-old rat brain, were added to the culture medium of PC12D cells containing NGF to examine the effects on NGF-induced neurite outgrowth from the cells. PC12D cells, a flat-shaped variant of PC12 pheochromocytoma cells, are characteristic of prompt neurite formation in response not only to NGF, but also to cAMP-enhancing reagents such as forskolin. Brain CSPGs inhibited the neurite elongation irreversibly in a dose-dependent manner; complete inhibition was observed at a concentration of 50 nmol uronic acid/ml. Closely similar dose-dependent inhibition was observed in the forskolin-induced neurite outgrowth from PC12D cells. NGF-induced neurite outgrowth from conventional PC12 cells was also inhibited completely by 50 nmol uronic acid/ml CSPGs. Some brain CSPGs seemed to be inhibitory, but the cartilage-unique CSPG did not show any inhibitory effect. Chondroitin sulfate, a polysaccharide moiety of CSPGs, did not show any inhibitory effect even at a concentration of 250 nmol uronic acid/ml, while core proteins prepared from brain CSPGs by digestion with chondroitinase ABC exhibited inhibitory activity similar to that of intact CSPGs. This indicates that the site of the inhibitory activity exists in the core protein moiety of brain CSPGs. From these observations, it is conceivable that brain CSPGs are involved in the regulation of neuronal differentiation.
Packet recovery and error correction in high-speed wide-area networks (2003)

The author presents a novel technique for reducing packet loss rate in high-speed wide-area networks in which the BER (bit-error rate) is low. Grouping packets into blocks and adding a packet that computes parity over bits of all packets in a block allow a data recipient to reconstruct any single packet in a block, using the other packets and the block parity packet. The missing packet is identified by observing a sequence-number gap in the stream of incoming packets. Adding another packet containing parity information over the diagonals of a series of blocks allows the decoder to correct a single bit error and reconstruct a missing packet, both occurring in the same block. The performance of the scheme was evaluated using a model of a single-server, discrete-time, finite-capacity queue. It was found that, if the input rate of packets to the queue is such that the packet rejection probability is 10/sup -3/ and below, it is possible to find a proper value of block size for which the decoding yields a substantial reduction in packet loss rate. Further reductions are possible if the server discards not necessarily newly arrived packets but takes into consideration their block affiliations and attempts to distribute the rejected packets among the blocks to maximize the decoding capability.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Strategies for Protein Purification (1995)

This discussion unit presents information on classification of proteins according to shape, oligomeric structure, and function. In addition, strategies for purifying different types of proteins are discussed based on their location and associations within the cell. Specifically, critical issues are detailed for extracellular, cytoplasmic, and membrane-associated proteins, as well as for insoluble proteins. Finally, strategies for the purification of both soluble and insoluble (inclusion bodies) recombinantly expressed proteins are provided.
Prostaglandin J2--anti-tumour and anti-viral activities and the mechanisms involved. (1990)

PGD2 undergoes dehydration in aqueous media to form PGJ2 and in the presence of albumin they convert to delta 12-PGJ2. Delta 12-PGJ2 is one of the ultimate metabolites of PGD2 in human body fluids and is excreted in urine, approximately 152 ng/24 h for males and 66 ng/24 h for females. Delta 12-PGJ2 and also PGA2 are actively incorporated into cells and transferred to the nuclei. Both PGs lead to cell cycle arrest at G1 phase and inhibit viral replication at non-toxic doses. Several genes including myc oncogene family expressions are suppressed and several specific proteins, mainly the heat-shock protein family, are induced prior to G1 arrest or to inhibition of viral replication. Thus cyclopentenone PGs, i.e., PGJ and A series containing a reactive alpha, beta-unsaturated carbonyl constitute a different PG category from other classical PGs. Recently other biological activities of delta 12-PGJ2 such as immunomodulation and stimulated osteogenesis have been found. The author reviews PGJ2 research and introduces several new aspects.
Basic Principles of the Pharmacokinetics of Antisense Oligonucleotide Drugs (2007)

References ......................................................................................................................................2117.1 INTRODUCTIONThe pharmacokinetic properties of antisense oligonucleotides (ASOs) are best understood in the context of their physical and chemical properties. Charge, molecular weight, and amphipathic nature of the ASOs all influence the pharmacokinetics of phosphorothioate ASOs. This review will concentrate on how chemical modifications, particularly, the phosphorothioate modification and the 2-methoxyethyl (MOE) modification, of second-generation ASOs improve the pharmacokinetic properties.
In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography (2013)

The adaptive optics scanning light ophthalmoscope (AOSLO) allows visualization of microscopic structures of the human retina in vivo. In this work, we demonstrate its application in combination with oral and intravenous (IV) fluorescein angiography (FA) to the in vivo visualization of the human retinal microvasculature. Ten healthy subjects ages 20 to 38 years were imaged using oral (7 and/or 20 mg/kg) and/or IV (500 mg) fluorescein. In agreement with current literature, there were no adverse effects among the patients receiving oral fluorescein while one patient receiving IV fluorescein experienced some nausea and heaving. We determined that all retinal capillary beds can be imaged using clinically accepted fluorescein dosages and safe light levels according to the ANSI Z136.1-2000 maximum permissible exposure. As expected, the 20 mg/kg oral dose showed higher image intensity for a longer period of time than did the 7 mg/kg oral and the 500 mg IV doses. The increased resolution of AOSLO FA, compared to conventional FA, offers great opportunity for studying physiological and pathological vascular processes.
Envelope cross-reactivity between human immunodeficiency virus types 1 and 2 detected by different serological methods: correlation between cross-neutralization and reactivity against the main neutralizing site (1990)

A total of 70 human immunodeficiency virus type 1 (HIV-1) and 42 HIV-2 antibody-positive serum samples, collected from groups of individuals in which only one type of HIV prevails, were tested for cross-reactivity against HIV-2 and HIV-1 proteins by Western blot (WB) (immunoblot), radioimmunoprecipitation assay (RIPA), neutralization analysis, and enzyme-linked immunosorbent assay with as antigen synthetic peptides representing selected parts of the envelope (env) glycoproteins. Cross-reactions against the env glycoproteins were observed by WB in 10% (7 of 70) and by RIPA in 40% (28 of 70) of the HIV-1 antibody-positive serum samples and by WB in 29% (12 of 42) and by RIPA in 48% (20 of 42) of the HIV-2 antibody-positive serum samples. Testing by enzyme-linked immunosorbent assay against a 36-amino-acid peptide (Cys-301-Cys-336) of the external glycoprotein of strain HTLV-IIIB of HIV-1 (HIV-1HTLV-IIIB) (known to represent a dominating, linear neutralizing site) showed type-specific reactions in 67% (38 of 57) of HIV-1 antibody-positive serum samples. Type-specific reactions against a homologous 35-amino-acid peptide of strain SBL-6669 of HIV-2 (HIV-2SBL-6669) were found in 75% (30 of 40) of HIV-2 antibody-positive serum samples, and these reactions were correlated to neutralization against HIV-2SBL-6669. Cross-reactions against these peptides were seen in 23% (13 of 57) and 33% (13 of 40) of the HIV-1 and HIV-2 antibody-positive serum samples, respectively. These cross-reactions were correlated to cross-neutralization against HIV-1HTLV-IIIB and HIV-2SBL-6669. Cross-neutralization against one heterotypic virus strain was demonstrated in 16% (9 of 57) of HIV-1 antibody-positive serum samples and in 22% (5 of 22) of HIV-2 antibody-positive serum samples, but no correlation was found between cross-neutralization and env cross-reactivity in WB or RIPA.
Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction (2006)

In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-gamma remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23-IL-17 axis, rather than the IL-12-IFN-gamma axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation.
Plasma chromium and chromium excretion in diabetes. (1985)

Journal Article Plasma chromium and chromium excretion in diabetes. Get access B W Morris, B W Morris Search for other works by this author on: Oxford Academic Google Scholar G J Kemp, G J Kemp Search for other works by this author on: Oxford Academic Google Scholar C A Hardisty C A Hardisty Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 31, Issue 2, 1 February 1985, Pages 334–335, https://doi.org/10.1093/clinchem/31.2.334 Published: 01 February 1985
THERAPEUTIC PROGRESS—REVIEW XXXIII: ARE WE MAKING PROGRESS IN THE DRUG TREATMENT OF OESOPHAGEAL DISEASE? (1988)

Oesophageal problems are common. There are three areas where drug treatment can be helpful, namely in the control of gastro-oesophageal reflux and its symptoms, the treatment of oesophageal motility disorders and when oesophageal infection occurs. In this review the management of these three disorders is considered.
Molecular and evolutionary basis of limb field specification and limb initiation (2012)

Specification of limb field and initiation of limb development involve multiple steps, each of which is tightly regulated both spatially and temporally. Recent developmental analyses on various vertebrates have provided insights into the molecular mechanisms that specify limb field and have revealed several genetic interactions of signals involved in limb initiation processes. Furthermore, new approaches to the study of the developmental mechanisms of the lateral plate mesoderm of amphioxus and lamprey embryos have given us clues to understand the evolutionary scenarios that led to the acquisition of paired appendages during evolution. This review highlights such recent findings and discusses the mechanisms of limb field specification and limb bud initiation during development and evolution.
Gene Mapping and Positive Identification of the Non-structural Proteins NS2A, NS2B, NS3, NS4B and NS5 of the Flavivirus Kunjin and Their Cleavage Sites (1988)

Summary Partial N-terminal amino acid analyses of five radiolabelled non-structural (ns) proteins specified by Kunjin (KUN) virus provided positive identification of NS3, NS5 and three previously hypothetical ns proteins of flaviviruses, ns2a, ns2b and ns4b. Their correct gene order was obtained from their deduced amino acid sequences. Thus the gene order for KUN virus relative to that proposed for yellow fever (YF) virus was as follows: KUN 5′…GP44·P19·P10·P71·(?)·P21·P98-3′, YF 5′…NS1·ns2a·ns2b·NS3·ns4a·ns4b·NS5-3′. The identity of GP44 as NS1 was assumed from the known nucleotide and deduced amino acid sequences; ns4a was not identified. The cleavage sites in the polyprotein for KUN NS2B, NS3 and NS5 were identical, Lys-Arg↓Gly, similar in form to the sequence Arg-Arg↓Ser defined at the cleavage sites of YF NS3 and NS5. A new consensus cleavage site for NS1, NS2A and NS4B in the form Val-X-Ala↓, where X is any one of several uncharged amino acids, was found at corresponding sites homologous to those of KUN virus in all published flavivirus sequences (a total of 18 sites). NS1 and NS4B, but not NS2A, were preceded by a putative signal sequence.
Open label evaluation of the novel antipsychotic compound BW234U in chronic schizophrenics (1985)

Abstract In a 28‐day open label study, 15 inpatients with chronic schizophrenia in relapse were treated with BW234U. Approximately half of the patients showed marked improvement. Four patients showed no change and three dropped out. Thought disturbance improved markedly. The compound was tolerated very well.
The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics (2013)

The Antibody Drug Conjugate (ADC) is a therapeutic modality consisting of a monoclonal antibody attached to a cytotoxic, small-molecule payload. The antibody portion of the ADC serves as a transport vehicle that recognizes and binds to a protein antigen expressed in tumor tissues. The localized delivery and release of the payload within or near malignant cells allows for targeted delivery of a potent cytotoxic agent to diseased tissue, while reducing damage to antigen-negative, normal tissues. Recent years have witnessed an explosive increase in ADC-based therapies, due mainly to clinical reports of activity in both hematologic and epithelial cancers. Accompanying this upsurge in ADC development is a renewed interest in natural product cytotoxins, which are typically highly potent cell-killing agents, but suffer from poor drug-like properties and narrow safety margins when systemically administered as conventional chemotherapeutics. In this review, we discuss recent advances related to the construction of ADCs, the optimization of ADC safety and efficacy, and the increasingly pivotal roles of natural product payloads in the current and future landscape of ADC therapy.