gebhart/patrepeval huggingface dataset:
Interactions of Pathogenic Neisseriae with Epithelial Cell Membranes (2000)

The closely related bacterial pathogens Neisseria gonorrhoeae (gonococci, GC) and N. meningitidis (meningococci, MC) initiate infection at human mucosal epithelia. Colonization begins at apical epithelial surfaces with a multistep adhesion cascade, followed by invasion of the host cell, intracellular persistence, transcytosis, and exit. These activities are modulated by the interaction of a panoply of virulence factors with their cognate host cell receptors, and signals are sent from pathogen to host and host to pathogen at multiple stages of the adhesion cascade. Recent advances place us on the verge of understanding the colonization process at a molecular level of detail. In this review we describe the Neisseria virulence factors in the context of epithelial cell biology, placing special emphasis on the signaling functions of type IV pili, pilus-based twitching motility, and the Opa and Opc outermembrane adhesin/invasin proteins. We also summarize what is known about bacterial intracellular trafficking and growth. With the accelerated integration of tools from cell biology, biochemistry, biophysics, and genomics, experimentation in the next few years should bring unprecedented insights into the interactions of Neisseriae with their host.
A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice (2012)

These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer.
Hydrogen Sulfide Regulates Ethylene‐induced Stomatal Closure in Arabidopsis thaliana (2012)

Hydrogen sulfide (H2 S) is a newly-discovered signaling molecule in plants and has caused increasing attention in recent years, but its function in stomatal movement is unclear. In plants, H2 S is synthesized via cysteine degradation catalyzed by D-/L-cysteine desulfhydrase (D-/L-CDes). AtD-/L-CDes::GUS transgenic Arabidopsis thaliana (L.) Heynh. plants were generated and used to investigate gene expression patterns, and results showed that AtD-/L-CDes can be expressed in guard cells. We also determined the subcellular localization of AtD-/L-CDes using transgenic plants of AtD-/L-CDes::GFP, and the results showed that AtD-CDes and AtL-CDes are located in the chloroplast and in the cytoplasm, respectively. The transcript levels of AtD-CDes and AtL-CDes were affected by the chemicals that cause stomatal closure. Among these factors, ACC, a precursor of ethylene, has the most significant effect, which indicates that the H2 S generated from D-/L-CDes may play an important role in ethylene-induced stomatal closure. Meanwhile, H2 S synthetic inhibitors significantly inhibited ethylene-induced stomatal closure in Arabidopsis. Ethylene treatment caused an increase of H2 S production and of AtD-/L-CDes activity in Arabidopsis leaves. AtD-/L-CDes over-expressing plants exhibited enhanced induction of stomatal closure compared to the wild-type after ethylene treatment; however, the effect was not observed in the Atd-cdes and Atl-cdes mutants. In conclusion, our results suggest that the D-/L-CDes-generated H2 S is involved in the regulation of ethylene-induced stomatal closure in Arabidopsis thaliana.
Comparison of Markers and Functional Attributes of Human Adipose-Derived Stem Cells and Dedifferentiated Adipocyte Cells from Subcutaneous Fat of an Obese Diabetic Donor (2013)

<b>Objective:</b> Adipose tissue is a robust source of adipose-derived stem cells (ADSCs) that may be able to provide secreted factors that promote the ability of wounded tissue to heal. However, adipocytes also have the potential to dedifferentiate in culture to cells with stem cell-like properties that may improve their behavior and functionality for certain applications. <b>Approach:</b> ADSCs are adult mesenchymal stem cells that are cultured from the stromal vascular fraction of adipose tissue. However, adipocytes are capable of dedifferentiating into cells with stem cell properties. In this case study, we compare ADSC and dedifferentiated fat (DFAT) cells from the same patient and fat depot for mesenchymal cell markers, embryonic stem cell markers, ability to differentiate to adipocytes and osteoblasts, senescence and telomerase levels, and ability of conditioned media (CM) to stimulate migration of human dermal fibroblasts (HDFs). <b>Innovation and Conclusions:</b> ADSCs and DFAT cells displayed identical levels of CD90, CD44, CD105, and were CD34- and CD45-negative. They also expressed similar levels of Oct4, BMI1, KLF4, and SALL4. DFAT cells, however, showed higher efficiency in adipogenic and osteogenic capacity. Telomerase levels of DFAT cells were double those of ADSCs, and senescence declined in DFAT cells. CM from both cell types altered the migration of fibroblasts. Despite reports of ADSCs from a number of human depots, there have been no comparisons of the ability of dedifferentiated DFAT cells from the same donor and depot to differentiate or modulate migration of HDFs. Since ADSCs were from an obese diabetic donor, reprogramming of DFAT cells may help improve a patient's cells for regenerative medicine applications.
Active oligomeric states of pyruvate decarboxylase and their functional characterization (2001)

Homomeric pyruvate decarboxylase (E.C 4.1.1.1) from yeast consists of dimers and tetramers under physiological conditions, a K(d) value of 8.1 microM was determined by analytical ultracentrifugation. Dimers and monomers of the enzyme could be populated by equilibrium denaturation using urea as denaturant at defined concentrations and monitored by a combination of optical (fluorescence and circular dichroism) and hydrodynamic methods (analytical ultracentrifugation). Dimers occur after treatment with 0.5 M urea, monomers with 2.0 M urea independent of the protein concentration. The structured monomers are catalytically inactive. At even higher denaturant concentrations (6 M urea) the monomers unfold. The contact sites of two monomers in forming a dimer as the smallest enzymatically active unit are mainly determined by aromatic amino acids. Their interactions have been quantified both by structure-theoretical calculations on the basis of the X-ray crystallography structure, and experimentally by binding of the fluorescent dye bis-ANS. The contact sites of two dimers in tetramer formation, however, are mainly determined by electrostatic interactions. Homomeric pyruvate decarboxylase (PDC) is activated by its substrate pyruvate. There was no difference in the steady-state activity (specific activity) between dimers and tetramers. The activation kinetics of the two oligomeric states, however, revealed differences in the dissociation constant of the regulatory substrate (K(a)) by one order of magnitude. The tetramer formation is related to structural consequences of the interaction transfer in the activation process causing an improved substrate utilization.
The binding of heparin to type IV collagen: domain specificity with identification of peptide sequences from the α1(IV) and α2(IV) which preferentially bind heparin (1989)

Three distinctive heparin-binding sites were observed in type IV collagen by the use of rotary shadowing: in the NC1 domain and at distances 100 and 300 nm from the NC1 domain. Scatchard analysis indicated different affinities for these sites. Electron microscopic analysis of heparin-type IV collagen interaction with increasing salt concentrations showed the different affinities to be NC1 greater than 100 nm greater than 300 nm. The NC1 domain bound specifically to chondroitin/dermatan sulfate side chains as well. This binding was observed at the electron microscope and in solid-phase binding assays (where chondroitin sulfate could compete for the binding of [3H]heparin to NC1-coated substrata). The triple helix-rich, rod-like domain of type IV collagen did not bind to chondroitin/dermatan sulfate side chains. In solid-phase binding assays only heparin could compete for the binding of [3H]heparin to this domain. In order to more precisely map potential heparin-binding sites in type IV collagen, we chemically synthesized 17 arginine- and lysine-containing peptides from the alpha 1(IV) and alpha 2(IV) chains. Three peptides from the known sequence of the alpha 1(IV) and alpha 2(IV) chains were shown to specifically bind heparin: peptide Hep-I (TAGSCLRKFSTM), from the alpha 1(NC1) chain, peptide Hep-II (LAGSCLARFSTM), a peptide corresponding to the same sequence in peptide Hep-I from the alpha 2 (NC1) chain, and peptide Hep-III (GEFYFDLRLKGDK) which contained an interruption of the triple helical sequence of the alpha 1(IV) chain at about 300 nm from the NC1 domain, were demonstrated to bind heparin in solid-phase binding assays and compete for the binding of [3H]heparin to type IV collagen-coated substrata. Therefore, each of these peptides may represent a potential heparin-binding site in type IV collagen. The mapping of the binding of heparin or related structures, such as heparan sulfate proteoglycan, to specific sequences of type IV collagen could help the understanding of several structural and functional properties of this basement membrane protein as well as interactions with other basement membrane and/or cell surface-associated macromolecules.
Characterization of metalloprotease cleavage products of human articular cartilage (2008)

The use of intact cartilage instead of purified protein substrates in the assay allowed for the identification of novel potential substrates and cleavage sites for individual enzymes under more physiologically relevant conditions. Characterization of these cartilage matrix peptides may help in the development of pharmacodynamic biomarkers of cartilage degradation, and also may contribute to an understanding of the bioactive peptides important in chondrocyte signaling.
Changes in Hormone Sensitivity in the Ventral Prostate of Aging Sprague‐Dawley Rats (2002)

The adult rat ventral prostate, which has been used extensively as a model for hormone-dependent prostate cancer, is composed of hormone-dependent columnar secretory epithelial cells and a mixture of hormone-independent cuboidal epithelial cells, basal epithelial cells, and stromal cells. Androgen ablation causes the gland to regress due to the selective loss of the secretory luminal epithelial cells that undergo apoptosis. Most, if not all, of the studies examining the induction of apoptosis and the mechanism of regression have used young adult males at around 3 months of age. Prostate cancer, however, is a disease of older males, and we have therefore investigated whether age-related changes in hormone sensitivity and apoptosis occur in the ventral prostate of aged animals (12 months old) compared to young animals (3 months old). We have observed distinct differences in the morphology of the prostate between young and old rats prior to castration and a significant slowing in the rate of regression after castration in older animals. These changes are accompanied by changes in lipofuscin accumulation and levels of the antioxidant enzymes catalase and manganese (Mn) superoxide dismutase in the gland.
IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists (2016)

Abstract Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker–IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi+ domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)high T cell Ig mucin-3+ CD8+ T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8+ T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8+ T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti–PD-1/RLI compared with 43 and 6% with RLI or anti–PD-1, respectively. Altogether, this work provides evidence that the sushi–IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti–PD-1 treatment and is a promising approach to stimulate host immunity.
Toward the Rational Design of Superoxide Dismutase Mimics:  Mechanistic Studies for the Elucidation of Substituent Effects on the Catalytic Activity of Macrocyclic Manganese(II) Complexes (1997)

Two new isomeric bis(trans-fused cyclohexano) substituted 1,4,7,10,13-pentaazacyclopentadecane ligands and their Mn(II) complexes, 3 and 4, have been synthesized, and their activity as superoxide dismutase (SOD) catalysts has been studied. Complex 3 is an excellent SOD catalyst with a second-order rate constant at pH = 7.4 of 1.2 × 10+8 M-1 s-1. In contrast, the isomeric complex 4 has virtually no detectable catalytic SOD activity, implying the need to understand the effect that the position, number, and stereochemistry of substituents exert on the catalytic rate. The crystal structure of the complex 4 was determined and reveals that the Mn(II) ion is coordinated in a pentagonal bipyramid array of the five nitrogens of the macrocyclic ligand and capped by two trans-chloro ligands. Crystal data for MnC18H37Cl2N5 are as follows: triclinic at 20 °C, space group P1--Ci2 (no. 2); a = 9.746(3) Å, b = 12.631(6) Å, c = 11.311(5) Å; α = 73.14(4)°, β = 76.39(3)°, γ = 79.98(3)°, V = 1287(1) Å3, and Z = 2 (ρcalc = 1.279 g/cm3; μa Mo Kα = 6.23 mm-1). Mechanistic studies with the complex 3 and the pentamethyl susbstituted complex, 5, including D2O rate studies, are reported and are consistent with the existence of two pathways for the rate-determining electron-transfer from Mn(II) to superoxide: (1) hydrogen atom transfer from a bound water on Mn(II) to HO2• to yield a Mn(III) hydroxo intermediate and (2) the dissociative pathway in which superoxide anion binds to a vacant coordination site on Mn(II) followed by protonation/oxidation to yield a Mn(III)hydroperoxo species. Subsequent reduction of the intermediate Mn(III) with superoxide anion completes the catalytic cycle. Substituent effects on the rates and relative contribution of the two pathways to the overall rate of SOD activity is ascribed to the propensity of the ligand to fold around Mn(II) forming a pseudo-octahedral complex similar in geometry to the oxidized Mn(III) complex. Folding of the pentaaza macrocyclic ligand is confirmed as a relevant structural motif for this series of Mn(II) complexes by the X-ray structure determination of the bis(nitrate) derivative of 1, [Mn(C10H25N5)NO3]NO3, which reveals a six-coordinate structure with a folded conformation of the macrocyclic ligand. Crystal data for [Mn(C10H25N5)NO3]NO3: orthorhombic at −100 °C, space group P212121; a = 9.457(2) Å, b = 12.758(2) Å, c = 13.834(2) Å, V = 1669.1(5) Å3, and Z = 4 (ρcalc = 1.549 g/cm3).
Epidermal Growth Factor-Induced Tumor Cell Invasion and Metastasis Initiated by Dephosphorylation and Downregulation of Focal Adhesion Kinase (2001)

Upregulated epidermal growth factor (EGF) receptor (EGFR) expression and EGFR-induced signaling have been correlated with progression to invasion and metastasis in a wide variety of carcinomas, but the mechanism behind this is not well understood. We show here that, in various human carcinoma cells that overexpress EGFR, EGF treatment induced rapid tyrosine dephosphorylation of focal adhesion kinase (FAK) associated with downregulation of its kinase activity. The downregulation of FAK activity was both required and sufficient for EGF-induced refractile morphological changes, detachment of cells from the extracellular matrix, and increased tumor cell motility, invasion, and metastasis. Tumor cells with downregulated FAK activity became less adherent to the extracellular matrix. However, once cells started reattaching, FAK activity was restored by activated integrin signaling. Moreover, this process of readhesion and spreading could not be abrogated by further EGF stimulation. Interruption of transforming growth factor alpha-EGFR autocrine regulation with an EGFR tyrosine kinase inhibitor led to a substantial increase in FAK tyrosine phosphorylation and inhibition of tumor cell invasion in vitro. Consistent with this, FAK tyrosine phosphorylation was reduced in cells from tumors growing in transplanted, athymic, nude mice, which have an intact autocrine regulation of the EGFR. We suggest that the dynamic regulation of FAK activity, initiated by EGF-induced downregulation of FAK leading to cell detachment and increased motility and invasion, followed by integrin-dependent reactivation during readhesion, plays a role in EGF-associated tumor invasion and metastasis.
Redox signaling and the MAP kinase pathways (2003)

The mitogen-activated protein (MAP) kinases are a large family of proline-directed, serine/threonine kinases that require tyrosine and threonine phosphorylation of a TxY motif in the activation loop for activation through a phosphorylation cascade involving a MAPKKK, MAPKK and MAPK, often referred to as the MAP kinase module. Three separate such modules have been identified, based on the TxY motif of the MAP kinase and the dual-specificity kinases that strictly phosphorylate their specific TxY sequence. They are the extracellular signal regulated kinases (ERKs), c-jun N-terminal kinases (JNKs) and p38 MAPKs. The ERKs are mainly associated with proliferation and differentiation while the JNKs and p38MAP kinases regulate responses to cellular stresses. Redox homeostasis is critical for proper cellular function. While reactive oxygen species (ROS) and oxidative stress have been implicated in injury, a rapidly growing literature suggests that a transient increase in ROS levels is an important mediator of proliferation and results in activation of various signaling molecules and pathways, among which the MAP kinases. This review will summarize the role of ROS in MAP kinase activation in various systems, including in macrophages, cells of myeloid origin that play an essential role in inflammation and express a multi-component NADPH oxidase that catalyzes the receptor-regulated production of ROS.
Clinical Trials of Bispecific Antibody MDX-210 in Women with Advanced Breast or Ovarian Cancer that Overexpresses HER-2/neu (1995)

MDX-210 is a bispecific antibody (BsAb) that recognizes Fc gamma R1 on monocytes and macrophages and the cell surface product of the HER-2/neu oncogene, which is overexpressed on some breast and ovarian cancers. Clinical trials have demonstrated that treatment with MDX-210 is well tolerated and that MDX-210 is both immunologically and clinically active. Optimization of the dose and schedule of MDX-210 and development of combination treatments with cytokines that modulate immune effector cells will greatly enhance the efficacy of this novel BsAb construct for treatment of tumours that overexpress HER-2/neu. We envision that MDX-210 will be effective for treating patients with tumors that overexpress HER-2/neu, especially in the minimal disease setting.
Activated ras alleles in human carcinoma of the prostate are rare. (1991)

Although oncogenically activated ras alleles are common in some types of human cancers, the frequency in human carcinoma of the prostate (CaP) has not previously been addressed. In this paper, we report a comprehensive screening of 19 CaPs and 3 CaP cell lines for activating point mutations in the sequences of the 12th and 61st codons of c-Ha-ras-1 and the c-Ki-ras-2 genes, as well as the 12th, 13th, and 61st codons of the c-N-ras gene. The 19 CaPs were chosen to represent a wide range of stages (B through D), Gleason scores (3 through 10), and DNA ploidy (diploid with low proliferation to nontetraploid-aneuploid). Fifteen of the tumors had been untreated prior to resection and 4 were obtained postradiation therapy. The polymerase chain reaction was used to amplify genomic DNA sequences and transcribed mRNA sequences of the ras genes prior to allele-specific oligonucleotide probe hybridization. We have detected a mutant allele with a point mutation in the second nucleotide of the 61st codon of the c-Ha-ras-1 gene in one specimen. Thus, we conclude that the activation of ras alleles is not significant in the development or progression of most CaPs.
Ethical and Value Issues in Insurance Coverage for Cancer Treatment (2010)

Many new cancer drugs provide only limited benefits, but at very great cost, for example, $200,000-$300,000 per quality-adjusted life year produced. By most standards of value or cost-effectiveness, this does not represent good value. I first review several of the causes of this value failure, including monopoly patents, prohibitions on Medicare's negotiating on drug prices, health insurance protecting patients from costs, and financial incentives of physicians to use these drugs. Besides value or cost-effectiveness, the other principal aim in health care resource allocation should be equity among the population served. I examine several equity considerations-priority to the worse off, aggregation and special priority to life extension, and the rule of rescue-and argue that none justifies greater priority for cancer treatment on the grounds of equity. Finally, I conclude by noting two recent policy changes that are in the wrong direction for achieving value in cancer care, and suggesting some small steps that could take us in the right direction.
Ericsson/Mannesmann GSM field-trials with adaptive antennas (1996)

This paper describes Ericsson's GSM testbed for evaluation of adaptive antenna technology and joint field-trials made by Ericsson and Mannesmann Mobilfunk. The implementation principles and algorithms are described together with the field-trial setup. The field-trials was carried out in Dusseldorf, Germany, by Mannesmann Mobilfunk and Ericsson. The paper also presents results from the field-tests.
Immunosignaturing Can Detect Products from Molecular Markers in Brain Cancer (2012)

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer's disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O(6)-methyl-guanine-DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients.
Direction-Sensitive Gating: A New Approach to Automatic Mixing (1984)

Les melangeurs automatiques sont souvent employes dans les systemes sonores a microphone multiple pour mettre en marche les microphones immediatement en service