gebhart/patrepeval huggingface dataset:
CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. (2016)

3001 Background: Nivo + ipi is approved in adv melanoma and has demonstrated clinical activity and manageable safety in various solid tumors. CheckMate 012 is a phase I study of nivo monotherapy or combined with other therapies in 1L adv NSCLC; we report updated results, including tumor growth dynamic (TGD) modeling, from N+I dosing schedules explored to optimize safety and permit synergistic activity. Methods: Patients ([pts] N=148, any NSCLC histology) received N+I (mg/kg) across 4 dose cohorts (Table). Primary objective was safety; secondary objectives were ORR (RECIST v1.1) and 24-wk PFS rate; exploratory endpoints were OS and efficacy by tumor programmed death ligand 1 (PD-L1) expression. The effect of N+I dosing was assessed by TGD modeling generated using individual tumor assessments; model-predicted tumor shrinkage at wk 12 was compared across cohorts. Results: Treatment-related (TR) adverse events (AEs) and select TRAEs were manageable (Table). TRAEs leading to discontinuation (DC) were comparable to nivo alone (10%), with no TR deaths. Across cohorts, ORRs ranged from 13%–39% (Table), and median duration of response was not reached. Responses were noted regardless of PD-L1 expression, with a higher magnitude of benefit in tumors that expressed PD-L1. TGD modeling predicted enhanced tumor shrinkage for N3 + I1 schedules compared with nivo alone or any N1-containing schedule. Based on integrated efficacy/safety/TGD data, N3 Q2W + I1 Q6W was proposed for further evaluation. Conclusions: 1L therapy with N+I demonstrates clinical activity and a manageable safety profile. Updated safety and efficacy across cohorts (by histology, EGFR, smoking status, PD-L1 expression) and TGD modeling data will be presented. Clinical trial information: NCT01454102. N1 + I1 Q3W x 4 cycles, then N3 Q2W (n=31) N1 Q2W + I1 Q6W (n=40) N3 Q2W + I1 Q12W (n=38) N3 Q2W + I1 Q6W (n=39) TRAEs, % Any gr 77 73 74 69 Gr 3–4 29 35 29 28 Select TRAEs, gr 3–4, % Skin 13 5 3 5 Gastrointestinal 0 8 5 5 Endocrine 6 8 3 5 Hepatic 6 10 0 5 Pulmonary 3 0 3 3 Renal 0 0 5 0 Hypersensitivity/Infusion 0 0 0 0 TRAEs leading to DC, % 13 8 5 10 ORR, % 13 25 39 31 mPFS, mo 10.6 4.9 8.0 8.3 24-wk PFS rate, % 55 NC 63 NC Median follow-up, mo 16.6 6.2 8.4 7.7 NC = not calculated; Gr = grade.
Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T cell hybridoma and induction of unresponsiveness. (1995)

Major histocompatibility complex (MHC) class I molecules are cell-surface proteins that present peptides to CD8+ T cells. These peptides are mostly derived from endogenously synthesized protein. Recombinant, soluble MHC class I molecules were produced, purified, and loaded homogeneously with synthetic peptide. These MHC-peptide complexes were used to activate a T cell hybridoma. While monomers of MHC-peptide bound to the T cell, they showed no stimulatory activity. Dimers fully triggered the T cell hybridoma to secrete interleukin 2. This response was followed by a state in which the T cell was refractory to restimulation as a result of defective signal transduction through the T cell receptor.
Peptostreptococcus micros has a uniquely high capacity to form hydrogen sulfide from glutathione (1993)

There are high amounts of hydrogen sulfide in deep periodontal pockets. This volatile sulfur compound may be formed from L-cysteine, but only low levels of this amino acid can be expected to be present in periodontal pockets. Glutathione, L-gamma-glutamyl-L-cysteinylglycine, is in high concentration in most tissue cells, and this tripeptide may be more readily available as a source of hydrogen sulfide formation in the pockets. The ability of 37 different species of oral bacteria to utilize glutathione in hydrogen sulfide formation was studied. Of these species, only 2 species of Peptostreptococcus and 5 species of Fusobacterium formed high amounts of hydrogen sulfide from glutathione within 24 h. Since the initial rate of hydrogen sulfide formation was more than 5 times higher in Peptostreptococcus micros than in any of the other bacterial species, the kinetics of sulfide formation from glutathione by P. micros was further elucidated. The formation of sulfide followed quite closely hyperbolic Michaelis-Menten kinetics. The maximal initial rate of sulfide formation (Vmax) was 163 +/- 2 nmol sulfide per minute per milligram of cellular protein. Half maximal initial rate (Km) was obtained at 7.4 +/- 0.8 microM glutathione. The initial rate of sulfide formation from L-cysteine was much slower and was almost proportional to L-cysteine concentration. This difference in kinetics of sulfide formation between glutathione and L-cysteine strongly suggested that glutathione was actively transported into the cell, whereas the transport of L-cysteine was more or less controlled by diffusion. The sulfide formation from the dipeptide L-cysteinylglycine also followed quite closely hyperbolic Michaelis-Menten kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)
Enhancement of the plasma density and deposition rate in rf discharges (1986)

The peak and time averaged electron density in rf excited silane-helium mixtures increased significantly above the cw value by square wave modulating the source. The deposition rate of amorphous hydrogenated silicon films is also enhanced and apparently follows the electron density. Attachment to the discharge products appears to be responsible.
A Structural Basis for RNA−Ligand Interactions (1997)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA Structural Basis for RNA−Ligand InteractionsChristine S. Chow and Felicia M. BogdanView Author Information Department of Chemistry, Wayne State University, Detroit, Michigan 48202 Cite this: Chem. Rev. 1997, 97, 5, 1489–1514Publication Date (Web):August 5, 1997Publication History Received10 December 1996Revised8 April 1997Published online5 August 1997Published inissue 1 August 1997https://pubs.acs.org/doi/10.1021/cr960415whttps://doi.org/10.1021/cr960415wresearch-articleACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views2588Altmetric-Citations189LEARN 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:Chemical structure,Genetics,Ligands,Nucleic acid structure,Peptides and proteins Get e-Alerts
A Scheduling Heuristic for Job Shop Manufacturing System (2006)

In the past, many production-scheduling methods were developed to achieve high due-date and short manufacturing lead times performance. Among them, DRUM-BUFFER-ROPE (DBR) has been recognized as one of the excellent solutions. However, there are some implementation constraints (e.g., time buffer determination, setup ratio evaluation, non-CCR subordination etc.) limit its implementation performance. To overcome these limits and enhance the DBR implementation, we present a novel scheduling heuristic algorithm for job shop manufacturing system based on Capacity
Mitogenic signals through CD28 activate the protein kinase Ctheta-NF-kappaB pathway in primary peripheral T cells (2003)

Mitogenic anti-CD28 antibody stimulates all peripheral T cells to proliferate in the absence of TCR ligation, providing an exception to the two-signal requirement of T cell responses. This antibody preferentially recognizes a mobilized signaling-competent form of CD28, normally induced following TCR ligation, thus providing a unique non-physiological tool to dissect CD28-specific signals leading to T cell proliferation. The protein kinase C (PKC)theta-NF-kappaB pathway has recently been shown to integrate TCR- and CD28-derived signals in co-stimulation. We now demonstrate that this pathway is activated by mitogenic anti-CD28 antibody stimulation. In contrast to conventional anti-CD28 antibody, mitogenic anti-CD28 antibody induced activation of phospholipase Cgamma and Ca(2+) flux in peripheral rat T cells despite no or low levels of inducible tyrosine phosphorylation of TCRzeta chain, TCRzeta-associated protein of 70 kDa (ZAP-70) or linker for activation of T cells (LAT)-critical components of the TCR signaling machinery. Nevertheless, PKCtheta kinase activity in vitro was increased following mitogenic anti-CD28 antibody stimulation, as was membrane association of both PKCtheta and Bcl10. As downstream targets of PKCtheta activation, NF-kappaB components translocated to the nucleus at levels comparable to those after TCR-CD28 co-stimulation. NF-kappaB translocation was diminished by PKCtheta inhibition, as was induction of the NF-kappaB/AP-1 responsive activation marker CD69. We propose that co-stimulation is a sequential process in which appropriate TCR engagement is required to mobilize CD28 into a signaling-competent form which then activates the PKCtheta-NF-kappaB pathway necessary for IL-2 production and proliferation.
Large matrix proteoglycans, versican and perlecan, are expressed and secreted by human leukemic monocytes. (2003)

THP-1 is a monocytic cell line originally derived from a patient with acute monocytic leukemia. Interactions of THP-1 cells with other cells and their microenvironment are largely determined by proteoglycans (PGs), the identity of which has not been determined. Previous studies on glycosaminoglycan expression by THP-1 cells and peripheral blood mononuclear cells from healthy individuals showed that both cell types secrete mainly chondroitin sulfate PGs to the culture medium, whereas heparan sulfate PGs are mainly retarded at the cell membrane. However, limited data on the type of PGs synthesized by THP-1 is available. In this study, the identification of PG types synthesised by THP-1 cells, which are not differentiated to macrophages, was examined. Analysis at the mRNA level by RT-PCR showed the expression of six cell membrane-associated PGs: syndecan-1, -2 and -4, glypican-1, thrombomodulin and CD44. Cell extraction, ion-exchange chromatography and dot blot analysis of the isolated PG populations with monoclonal antibodies showed the presence of syndecan-1 and thrombomodulin; the other two syndecans were not detected in any of the isolated populations. The synthesis of matrix PGs was also studied. THP-1 monocytes were positive for the mRNA encoding for versican and perlecan, but not for those encoding for decorin, biglycan, betaglycan and fibromodulin. The mRNA encoding for two versican splice variants V0 (351 bp) and V1 (386 bp), but not for V2, were identified. Biochemical analysis showed the presence of perlecan and of two populations of versican in culture medium with protein cores of average molecular sizes similar to those of V0 and V1. The production of these large matrix PGs by THP-1 monocytes is reported for the first time and may be of importance in monocyte malignant transformation and differentiation.
Increased Epidermal Growth Factor Receptor (EGFR) Associated with Hepatocyte Growth Factor (HGF) and Symptom Severity in Children with Autism Spectrum Disorders (ASDs) (2014)

These results suggest a relationship between increased plasma EGFR levels and designated symptom severity in autistic children. A strong correlation between plasma EGFR and HGF and HMGB1 suggests that increased EGFR levels may be associated with the HGF/Met signaling pathway, as well as inflammation.
The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells (2015)

The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.
Human Cytomegalovirus Infection of Caco-2 Cells Occurs at the Basolateral Membrane and Is Differentiation State Dependent (1999)

Epithelial cells are known to be a major target for human cytomegalovirus (HCMV) infection; however, the analysis of virus-cell interactions has been difficult to approach due to the lack of in vitro models. In this study, we established a polarized epithelial cell model using a colon epithelial cell-derived cell line (Caco-2) that is susceptible to HCMV infection at early stages of cellular differentiation. Infection of polarized cells was restricted to the basolateral surface whereas virus was released apically, which was consistent with the apical and not basolateral surface localization of two essential viral glycoproteins, gB and gH. HCMV infection resulted in the development of a cytopathology characteristic of HCMV infection of colon epithelium in vivo, and infection did not spread from cell to cell. The inability of HCMV to infect Caco-2 cells at late stages of differentiation was due to a restriction at the level of viral entry and was consistent with the sequestration of a cellular receptor for HCMV. These observations provide the first evidence that restriction of HCMV replication in epithelial cells is due to a receptor-mediated phenomenon.
Influenza viral neuraminidase: the forgotten antigen (2011)

Influenza is the most common cause of vaccine-preventable morbidity and mortality despite the availability of the conventional trivalent inactivated vaccine and the live-attenuated influenza vaccine. These vaccines induce an immunity dominated by the response to hemagglutinin (HA) and are most effective when there is sufficient antigenic relatedness between the vaccine strain and the HA of the circulating wild-type virus. Vaccine strategies against influenza may benefit from inclusion of other viral antigens in addition to HA. Epidemiologic evidence and studies in animals and humans indicate that anti-neuraminidase (NA) immunity will provide protection against severe illness or death in the event of a significant antigenic change in the HA component of the vaccine. However, there is little NA immunity induced by trivalent inactivated vaccine and live-attenuated influenza vaccine. The quantity of NA in influenza vaccines is not standardized and varies significantly among manufacturers, production lots and tested strains. The activity and stability of the NA enzyme is influenced by concentration of divalent cations. If immunity against NA is desirable, a better understanding of how the enzymatic properties affect the immunogenicity is needed.
Acrolein Is a Product of Lipid Peroxidation Reaction (1998)

Lipoprotein peroxidation, especially the modification of apolipoprotein B-100, has been implicated to play an important role in the pathogenesis of atherosclerosis. However, there have been few detailed insights into the chemical mechanism of derivatization of apolipoproteins during oxidation. In the present study, we provide evidence that the formation of the toxic pollutant acrolein (CH2=CH-CHO) and its conjugate with lysine residues is involved in the oxidative modification of human low density lipoprotein (LDL). Upon incubation with LDL, acrolein preferentially reacted with lysine residues. To determine the structure of acrolein-lysine adduct in protein, the reaction of acrolein with a lysine derivative was carried out. Employing Nalpha-acetyllysine, we detected a single product, which was identified to be a novel acrolein-lysine adduct, Nalpha-acetyl-Nepsilon-(3-formyl-3,4-dehydropiperidino )lysine. The acid hydrolysis of the adduct led to the derivative that was detectable with amino acid analysis. It was revealed that, upon in vitro incubation of LDL with acrolein, the lysine residues that had disappeared were partially recovered by Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine. In addition, we found that the same derivative was detected in the oxidatively modified LDL with Cu2+ and that the adduct formation was correlated with LDL peroxidation assessed by the consumption of alpha-tocopherol and cholesteryl ester and the concomitant formation of cholesteryl ester hydroperoxide. Enzyme-linked immunosorbent assay that measures free acrolein revealed that a considerable amount of acrolein was released from the Cu2+-oxidized LDL. Furthermore, metal-catalyzed oxidation of arachidonate was associated with the formation of acrolein, indicating that polyunsaturated fatty acids including arachidonate represent potential sources of acrolein generated during the peroxidation of LDL. These results indicate that acrolein is not just a pollutant but also a lipid peroxidation product that could be ubiquitously generated in biological systems.
Optimization of Cis-Acting Elements for Gene Expression from Nonviral Vectors In Vivo (2003)

While naked DNA gene transfer in vivo usually results in transient gene expression, in some cases long-term transgene expression can be achieved. Here we demonstrate that cis-acting DNA elements flanking the transgene expression cassette and components in the plasmid backbone can significantly influence expression levels from nonviral vectors. To demonstrate this, we administered our most robust human coagulation factor IX (hFIX) expression cassette placed in two different plasmid backbones, into the livers of mice, by hydrodynamic transfection. We found that placing the expression cassette within a minimal plasmid vector pHM5, a modified version of pUC19, resulted in 10 times higher serum hFIX expression levels (up to 20,000 ng/ml, 400% of normal hFIX serum levels), compared to a pBluescript backbone. To optimally increase expression levels from a nonviral vector, we added matrix attachment regions (MARs) as cis-acting DNA elements flanking the hFIX expression cassette. We detected five fold higher hFIX expression levels in vivo for up to 1-year posttransfection from a vector that contained the chicken MAR from the lysozyme locus. Together, the present work demonstrates that in addition to the transgene expression cassette, cis-acting DNA elements within and outside of the plasmid backbone need to be evaluated to achieve optimal expression levels in a nonviral gene therapy approach.
Micromechanics of Dipolar Chains Using Optical Tweezers (1999)

Here we present our initial study of the micromechanical properties of dipolar chains and columns in a magnetorheological (MR) suspension. Using dual-trap optical tweezers, we are able to directly measure the deformation of the dipolar chains parallel and perpendicular to the applied magnetic field. We observe the field dependence of the mechanical properties such as resistance to deformation, chain reorganization, and rupturing of the chains. These forms of energy dissipation are important for understanding and tuning the yield stress and rheological behavior of an MR suspension.
No Association between Presenilin 1 Intron Gene or Butyrylcholinesterase K Variant and Alzheimer's Disease in Japanese Populations (2001)

Background : One of the purposes of this study was to examine whethe apolipoprotein E (ApoE) ɛ4 allele as a risk factor for Alzheimer's disease (AD) may be associated with the higher prevalence of AD in women compared with men. Recently, the polymorphic K variant of the butyrylcholinest erase (BChE‐K) gene and presenilin 1 (PS1) intronic polymorphism have been reported to be associated with AD respectively. Thus we have reexamined the frequency of BChE‐K, PS1 intronic polymorphism, and the ApoE ɛ4 allele in a large series of Japanese AD patients and controls. Methods : We have genotyped a large series of Japanese AD and age‐and sex‐matched controls by the method of polymerase chain reaction and restriction fragment length polymorphism for ApoE, BChE‐K, and PS1 intronic polymorphism. Results : The frequency of ApoE ɛ4 allele was significantly higher in AD patients than in controls, confirming the previous reports. In comparison between men and women, the number of individuals carrying one ɛ4 allele was much greater in women with AD than in men with this illness. Kaplan‐Meier analyses, plotting the ɛ4 gene doses against age of onset for men and women, revealed significant differences in age‐of‐onset curves between men and women.
Multiplex gas chromatography by thermal modulation of a fused silica capillary column (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMultiplex gas chromatography by thermal modulation of a fused silica capillary columnJohn B. Phillips, Derhsing. Luu, Janusz B. Pawliszyn, and Glenn C. CarleCite this: Anal. Chem. 1985, 57, 14, 2779–2787Publication Date (Print):December 1, 1985Publication History Published online1 May 2002Published inissue 1 December 1985https://pubs.acs.org/doi/10.1021/ac00291a010https://doi.org/10.1021/ac00291a010research-articleACS PublicationsRequest reuse permissionsArticle Views339Altmetric-Citations82LEARN 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