gebhart/patrepeval huggingface dataset:
Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer (2010)

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17beta-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
Recombinant immunotoxins for cancer therapy (2001)

Recombinant immunotoxins consist of Fv regions of tumour-selective antibodies fused to toxins found in bacteria, plants or fungi. These toxins must be modified to remove normal-tissue binding sites but to retain all other functions of cytotoxicity. The recombinant antibody fragments target the modified toxin to cancer cells which are killed, either by direct inhibition of protein synthesis, or by concomitant induction of apoptosis. Cells that are not recognised by the antibody fragment because they do not carry the tumour antigen, are spared. Many factors influence the in vivo antitumour activity of recombinant immunotoxins. Among them are considerations of which types of cancer may be the best targets for immunotoxin therapy as well as tumour specificity of the antigen that is targeted by the recombinant antibody. Other relevant issues are the affinity of immunotoxins and their ability to enter and penetrate into tissues and tumours, which in turn is dependent on the size of the protein. A great deal of protein-engineering is required to stabilise the recombinant antibody moiety of immunotoxins, since stability of the molecules is crucial for good clinical efficacy. Excellent activity and specificity can be observed for many recombinant immunotoxins in in vitro assays using cultured cancer cells as well as in animal tumour models. Ongoing clinical trials provide examples where the promising preclinical data correlate with successful results in experimental cancer therapy.
Biochemical and Cellular Mechanisms of Pulmonary Fibrosis (1991)

This review summarizes the manner in which a variety of agents may induce fibrogenic reactions in the lung. The extent of reaction is dependent on dose, time scale of exposure, and chemical reactivity. The regime of multiple dosing with chemicals or gases with recovery periods is important in disease progression. The means by which biochemists and histopathologists assess fibrosis, the advantages and disadvantages of each of the methods as related to subjectivity, quantitation, and speed of analysis are compared. The mechanisms which control the step from fibrogenesis (a potentially reversible reaction) to fibrosis (irreversible) may be linked to the maturation of collagen, calcification, or the formation of cross-linked protein masses. Attention is given to hydroxylysine cross-links in newly formed “fibrotic” collagen but focusses on γ-glutamyl-∊-lysyl cross-links formed by calcium-dependent transglutaminases. It is suggested that these enzymes, released by replacement epithelial cells, could be responsible for the formation of stabilized protein masses in the lung, thus contributing to a progressive fibrosis.
High-performance fully depleted silicon nanowire (diameter /spl les/ 5 nm) gate-all-around CMOS devices (2006)

This paper demonstrates gate-all-around (GAA) n- and p-FETs on a silicon-on-insulator with /spl les/ 5-nm-diameter laterally formed Si nanowire channel. Alternating phase shift mask lithography and self-limiting oxidation techniques were utilized to form 140- to 1000-nm-long nanowires, followed by FET fabrication. The devices exhibit excellent electrostatic control, e.g., near ideal subthreshold slope (/spl sim/ 63 mV/dec), low drain-induced barrier lowering (/spl sim/ 10 mV/V), and with I/sub ON//I/sub OFF/ ratio of /spl sim/10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sup> . High drive currents of /spl sim/ 1.5 and /spl sim/1.0 mA/μm were achieved for 180-nm-long nand p-FETs, respectively. It is verified that the threshold voltage of GAA FETs is independent of substrate bias due to the complete electrostatic shielding of the channel body.
Structural and kinetic studies of a series of mutants of galactose oxidase identified by directed evolution (2004)

Galactose oxidase (GO; E.C. 1.1.3.9) is a copper- containing enzyme that oxidizes a range of primary alcohols to aldehydes. This broad substrate specificity is reflected in a high K(M) for substrates. Directed evolution has previously been used to select variants of GO that exhibit enhanced expression and kinetic properties. In assays using unpurified enzyme samples, the variant C383S displayed a 5-fold lower K(M) than wild-type GO. In the present study, we have constructed, expressed, purified and characterized a number of single, double and triple mutants at residues Cys383, Tyr436 and Val494, identified in one of the directed evolution studies, to examine their relative contributions to improved catalytic activity of GO. We report kinetic studies on the various mutant enzymes. In addition, we have determined the three-dimensional structure of the C383S variant. As with many mutations identified in directed evolution experiments, the availability of structural information does not provide a definitive answer to the reason for the improved K(M) in the C383S variant protein.
Reduction of syndecan-1 mRNA in cervical-carcinoma cells is involved with the 3? untranslated region (1999)

Syndecan-1 is a transmembrane proteoglycan expressed predominantly in epithelial cells. Studies with immunohistochemistry have shown that syndecan-1 expression is reduced in carcinoma derived from human epidermis. Here we show that syndecan-1 mRNA, which is abundant in human primary keratinocyte (HK) and HaCaT spontaneous immortalized keratinocyte, is decreased in cervical-carcinoma cell lines. Further, in relation to a long and well-conserved 3' untranslated region (3' UTR) of syndecan-1 cDNA, we examined whether 3' UTR is involved with syndecan-1-mRNA reduction in cervical-carcinoma cells. A stable transfection experiment showed that addition of the 3' UTR does not affect expression in HaCaT, but that syndecan-1 cDNA containing the 3' UTR is not expressed efficiently selectively in cervical-carcinoma cell lines. The transient assay with CAT reporter plasmids linking the 3' UTR confirmed this, and indicated that the 3' end of the 3' UTR (nt 2285-2410) is required to influence expression in cervical-carcinoma cells. Further excessive expression of syndecan-1 suppressed growth in cervical-carcinoma cells. These results demonstrate that the reduction of syndecan-1 mRNA involved with the 3' untranslated region gives growth advantage to cervical-carcinoma cells.
Textbook of interventional cardiology (1994)

Textbook of interventional cardiology , Textbook of interventional cardiology , کتابخانه دیجیتال جندی شاپور اهواز
Histone Deacetylase Inhibitors Globally Enhance H3/H4 Tail Acetylation Without Affecting H3 Lysine 56 Acetylation (2012)

Histone deacetylase inhibitors (HDACi) represent a promising avenue for cancer therapy. We applied mass spectrometry (MS) to determine the impact of clinically relevant HDACi on global levels of histone acetylation. Intact histone profiling revealed that the HDACi SAHA and MS-275 globally increased histone H3 and H4 acetylation in both normal diploid fibroblasts and transformed human cells. Histone H3 lysine 56 acetylation (H3K56ac) recently elicited much interest and controversy due to its potential as a diagnostic and prognostic marker for a broad diversity of cancers. Using quantitative MS, we demonstrate that H3K56ac is much less abundant than previously reported in human cells. Unexpectedly, in contrast to H3/H4 N-terminal tail acetylation, H3K56ac did not increase in response to inhibitors of each class of HDACs. In addition, we demonstrate that antibodies raised against H3K56ac peptides cross-react against H3 N-terminal tail acetylation sites that carry sequence similarity to residues flanking H3K56.
Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations (2010)

The therapeutic management of severe radiation burns remains a challenging issue today. Conventional surgical treatment including excision, skin autograft, or flap often fails to prevent unpredictable and uncontrolled extension of the radiation-induced necrotic process. In a recent very severe accidental radiation burn, we demonstrated the efficiency of a new therapeutic approach combining surgery and local cellular therapy using autologous mesenchymal stem cells (MSC), and we confirmed the crucial place of the dose assessment in this medical management. The patient presented a very significant radiation lesion located on the arm, which was first treated by several surgical procedures: iterative excisions, skin graft, latissimus muscle dorsi flap, and forearm radial flap. This conventional surgical therapy was unfortunately inefficient, leading to the use of an innovative cell therapy strategy. Autologous MSC were obtained from three bone marrow collections and were expanded according to a clinical-grade protocol using platelet-derived growth factors. A total of five local MSC administrations were performed in combination with skin autograft. After iterative local MSC administrations, the clinical evolution was favorable and no recurrence of radiation inflammatory waves occurred during the patient's 8-month follow-up. The benefit of this local cell therapy could be linked to the "drug cell" activity of MSC by modulating the radiation inflammatory processes, as suggested by the decrease in the C-reactive protein level observed after each MSC administration. The success of this combined treatment leads to new prospects in the medical management of severe radiation burns and more widely in the improvement of wound repair.
Mechanisms of Mucosal and Parenteral Tuberculosis Vaccinations: Adenoviral-Based Mucosal Immunization Preferentially Elicits Sustained Accumulation of Immune Protective CD4 and CD8 T Cells within the Airway Lumen (2005)

The mechanisms underlying better immune protection by mucosal vaccination have remained poorly understood. In our current study we have investigated the mechanisms by which respiratory virus-mediated mucosal vaccination provides remarkably better immune protection against pulmonary tuberculosis than parenteral vaccination. A recombinant adenovirus-based tuberculosis (TB) vaccine expressing Mycobacterium tuberculosis Ag85A (AdAg85A) was administered either intranasally (i.n.) or i.m. to mice, and Ag-specific CD4 and CD8 T cell responses, including frequency, IFN-gamma production, and CTL, were examined in the spleen, lung interstitium, and airway lumen. Although i.m. immunization with AdAg85A led to activation of T cells, particularly CD8 T cells, in the spleen and, to a lesser extent, in the lung interstitium, it failed to elicit any T cell response in the airway lumen. In contrast, although i.n. immunization failed to effectively activate T cells in the spleen, it uniquely elicited higher numbers of Ag-specific CD4 and CD8 T cells in the airway lumen that were capable of IFN-gamma production and cytolytic activities, as assessed by an intratracheal in vivo CTL assay. These airway luminal T cells of i.n. immunized mice or splenic T cells of i.m. immunized mice, upon transfer locally to the lungs of naive SCID mice, conferred immune protection against M. tuberculosis challenge. Our study has demonstrated that the airway luminal T cell population plays an important role in immune protection against pulmonary TB, thus providing mechanistic insights into the superior immune protection conferred by respiratory mucosal TB vaccination.
Anticancer compounds. Further analogs of 1-(4-dimethylaminobenzylidene)indene (1973)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAnticancer compounds. Further analogs of 1-(4-dimethylaminobenzylidene)indeneCarl T. Bahner, Norma H. Bingham, David H. Brotherton, Jane Cline, Dan Darby, Harry D. Harmon, Lydia M. Rives, Bill L. Stump, and L. Watson Jr.Cite this: J. Med. Chem. 1973, 16, 4, 421–425Publication Date (Print):April 1, 1973Publication History Published online1 May 2002Published inissue 1 April 1973https://pubs.acs.org/doi/10.1021/jm00262a029https://doi.org/10.1021/jm00262a029research-articleACS PublicationsRequest reuse permissionsArticle Views114Altmetric-Citations4LEARN 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
Thalidomide effects in Behçet's syndrome and pustular vasculitis. (1986)

Pustular vasculitis is a new disease concept that links cutaneous, and possibly systemic, aspects of Behçet's, bowel bypass, bowel-associated dermatosis-arthritis, and disseminated gonorrhea syndromes. The pathomechanism of pustular vasculitic lesion generation may relate to circulating immune complex (CIC)-mediated vessel damage and serum enhancement of neutrophil migration. Thalidomide, an oral pharmaceutical available on strict protocol, has therapeutic effects based on proposed modulation of CIC- and neutrophil-mediated cytotoxicity. Thalidomide therapy was started for four patients with significant morbidity from Behçet's syndrome and for one patient with bowel-associated dermatosis-arthritis syndrome. Clinical benefit was dramatic in all patients who completed sequential four-week "on" and "off" thalidomide therapeutic cycles. In three of four patients, in vivo testing for CIC after histamine injection immunopathology converted from positive (immunoreactant deposition in dermal vasculature [four hours after histamine] and CIC-mediated vasculitis [24 hours after histamine]) to negative during therapy. No effects were noted on neutrophil migration or on the LFA-1/Mac-1/p150,95 family of glycoproteins associated with neutrophil adherence as assessed qualitatively by tritium labelling of neutrophil cell surfaces. In this small patient group, thalidomide was a clinically effective, safe (with rigid monitoring) therapy whose mechanism of action may relate more to inhibitory effects on CIC-induced vasculitis than to effects on neutrophil-mediated cytotoxicity.
Current molecular models for NADPH oxidase regulation by Rac GTPase (2002)

Reactive oxygen species (ROS) have been increasingly recognized as important components of cell signaling in addition to their well-established roles in host defense. The formation of ROS in phagocytic and nonphagocytic cells involves membrane-localized and Rac guanosine triphosphatase (GTPase)-regulated reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase(s). We discuss here the current molecular models for Rac GTPase action in the control of the phagocytic leukocyte NADPH oxidase. As a mechanistically detailed example of Rac GTPase signaling, the NADPH oxidase provides a potential paradigm for signaling by Rho family GTPases in general.
Integrin Signaling in Cancer Cell Survival and Chemoresistance (2012)

Resistance to apoptosis and chemotherapy is a hallmark of cancer cells, and it is a critical factor in cancer recurrence and patient relapse. Extracellular matrix (ECM) via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy. Several studies over the last decade have demonstrated that ECM/integrin signaling provides a survival advantage to various cancer cell types against numerous chemotherapeutic drugs and against antibody therapy. In this paper, we will discuss the major findings on how ECM/integrin signaling protects tumor cells from drug-induced apoptosis. We will also discuss the potential role of ECM in malignant T-cell survival and in cancer stem cell resistance. Understanding how integrins and their signaling partners promote tumor cell survival and chemoresistance will likely lead to the development of new therapeutic strategies and agents for cancer treatment.
Regional Blood Flow by Fractional Distribution of Indicators (1958)

K 42 Cl, Rb 86 Cl and iodoantipyrine (I 131 ) were given in single intravenous injections to rats. The isotope content of the organs and the arterial blood concentrations were studied as a function of time. K 42 Cl and Rb 86 Cl reached a stable level in all organs other than the brain in 6–9 seconds and maintained this level until 64 seconds. The arterial concentration curves for the isotopes showed that the injected dose was almost completely transferred into the arterial system at about 6–8 seconds. The isotopes showed subsequent recirculation amounting to about 40% of the original dose between the first recirculation and 64 seconds. The organs which displayed stability during the period of recirculation must have had extraction ratios from zero time less than 1.00 but equal to that of the whole body. The fractional uptake of indicator by such organs must therefore have been equal to their blood flow fraction of the cardiac output. The brain reached its maximum content of Rb 86 and K 42 in 5–6 seconds; both isotopes then disappeared rapidly. The brain was thus shown to have a lower extraction ratio toward these isotopes than the body as a whole; its flow fraction could not therefore be measured by their use. Most organs failed to show stability of their iodoantipyrine content between 9 and 64 seconds; this indicator is not suitable for the measurement of the flow fraction of such organs. By combining values for the cardiac output and the fractional uptake of K 42 in dog organs, regional blood flow values were obtained. For those other organs where flow values by other methods are available, the agreement was good. The following blood flow values were obtained in the major organs of the dog: Heart (coronary flow), 1.0 ml/gm/min.; kidney, 3.0 ml/gm/min.; liver, 1.2 ml/gm/min. (0.4 ml/gm/min. hepatic artery, 0.8 ml/gm/min. portal vein); skin, 0.07 ml/gm/min.
Novel PI Analogues Selectively Block Activation of the Pro-survival Serine/Threonine Kinase Akt (2003)

The synthesis from l-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream of ras such as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.
The Long-term Fate of Fresh and Frozen Orthotopic Bone Allografts in Genetically Defined Rats (1985)

Fresh and frozen orthotopic iliac crest bone grafts in rats were studied histologically for determination of the long-term effects of histocompatibility matching and the freezing process on orthotopic bone graft incorporation. Grafts exchanged between groups of inbred rats, syngeneic or differing with respect to major or minor histocompatibility loci, were studied histologically at 20, 30, 40, 50, and 150 days after bone transplantation. A numerical histologic scoring system was developed and used by three observers for evaluation of coded hematoxylin and eosin sections. All frozen graft groups had the same fate regardless of histocompatibility relations between donors and recipients, and all grafts were inferior to fresh syngeneic grafts. Both fresh allograft groups received similar scores and initially at 20 and 30 days had scores similar to those of the fresh syngeneic groups. In the later intervals, however, the fresh allografts were inferior to the fresh syngeneic grafts and similar to the frozen groups. This is consistent with an older model describing two distinct phases of osteogenesis. In the long term, frozen syngeneic and fresh and frozen allografts across major and minor histocompatibility barriers were comparable, but all were significantly inferior to fresh syngeneic bone grafts.
Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor (2010)

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Novel approaches to improving qualities of maize endosperm (2011)

xiii Preface xiv Rationale xiv Dissertation organization xiv Authors’ roles xiv Chapter 1. General Introduction 1 Malnutrition 1 The problem of malnutrition 1 Potential solutions to malnutrition 1 Biofortification 3 Iron deficiency and improvements in dietary iron 4 Iron deficiency and absorption 4 Inhibitors and enhancers of iron bioavailability 5 Iron forticants 6 Biofortification of iron 8 Hemoglobin 9 Plant hemoglobin 9 Protein deficiency and seed storage proteins in maize 11 Protein deficiency 11 Dietary requirements for protein 12