gebhart/patrepeval huggingface dataset:
Comparison of pHH3, Ki-67, and Survivin Immunoreactivity in Benign and Malignant Melanocytic Lesions (2008)

Differentiating malignant melanoma from benign melanocytic lesions can be challenging. We undertook this study to evaluate the use of the immunohistochemical mitosis marker phospho-Histone H3 (pHH3) and the proliferation markers Ki-67 and survivin in separating malignant melanoma from benign nevi. Sixty-six melanocytic lesions (18 malignant melanomas, 8 Spitz nevi, 20 dysplastic nevi, and 20 compound nevi) were stained with antibodies to pHH3, Ki-67, and survivin. No pHH3 expression was detected in the dermis of compound and dysplastic nevi. Rare mitoses were observed in the superficial dermis in 3 of 8 Spitz nevi (37%). Staining for pHH3 was higher in malignant melanomas [average 25 per 10 high-power field (HPF), range 2-75 per 10 HPF] than in Spitz nevi (average 0.5 per 10 HPF, range 0-2 per 10 HPF) and was heterogeneously distributed in the malignant melanomas compared with a superficial dermal location in Spitz nevi. There was no cytoplasmic staining for survivin in any of the 66 melanocytic lesions and no nuclear staining in any of the benign ones. Survivin nuclear staining was present in 12 of 18 cases of malignant melanoma (67%) with an average index of 7% (range 0%-15%). In benign melanocytic lesions, the Ki-67 index was less than 5% (range 0%-4%) and staining was present close to the dermo-epidermal junction compared with an average index of 27% in melanomas (range 5%-50%) and a generally heterogeneous pattern of staining throughout the dermis. pHH3 and Ki-67 can be useful adjuncts to histopathology to separate malignant melanoma from benign nevi. pHH3 is especially useful to highlight mitoses and to rapidly assess the mitotic activity in melanocytic lesions.
In vitro analysis of DNA–protein interactions by proximity ligation (2007)

Protein-binding DNA sequence elements encode a variety of regulated functions of genomes. Information about such elements is currently in a state of rapid growth, but improved methods are required to characterize the sequence specificity of DNA-binding proteins. We have established an in vitro method for specific and sensitive solution-phase analysis of interactions between proteins and nucleic acids in nuclear extracts, based on the proximity ligation assay. The reagent consumption is very low, and the excellent sensitivity of the assay enables analysis of as few as 1-10 cells. We show that our results are highly reproducible, quantitative, and in good agreement with both EMSA and predictions obtained by using a motif finding software. This assay can be a valuable tool to characterize in-depth the sequence specificity of DNA-binding proteins and to evaluate effects of polymorphisms in known transcription factor binding sites.
Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier (2018)

Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) superfamily member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both WT h4-1BB and a dimerization-deficient h4-1BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 and 3.2 Å. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL. We also found that the binding site for the receptor is at the crevice formed between two protomers of h4-1BBL, but that h4-1BB interacts predominantly with only one ligand protomer. Moreover, h4-1BBL lacked the conserved tyrosine residue in the DE loop that forms canonical interactions between other TNFR family molecules and their ligands, suggesting h4-1BBL engages h4-1BB through a distinct mechanism. Of note, we discovered that h4-1BB forms a disulfide-linked dimer because of the presence of an additional cysteine residue found in its cysteine-rich domain 4 (CRD4). As a result, h4-1BB dimerization, in addition to trimerization via h4-1BBL binding, could result in cross-linking of individual ligand-receptor complexes to form a 2D network that stimulates strong h4-1BB signaling. This work provides critical insights into the structural and functional properties of both h4-1BB and h4-1BBL and reveals that covalent receptor dimerization amplifies h4-1BB signaling.
Conceptual Framework for Cutting the Pancreatic Cancer Fuel Supply (2012)

Pancreatic ductal adenocarcinoma (a.k.a. pancreatic cancer) remains one of the most feared and clinically challenging diseases to treat despite continual improvements in therapies. The genetic landscape of pancreatic cancer shows near ubiquitous activating mutations of KRAS, and recurrent inactivating mutations of CDKN2A, SMAD4, and TP53. To date, attempts to develop agents to target KRAS to specifically kill cancer cells have been disappointing. In this regard, an understanding of cellular metabolic derangements in pancreatic cancer could lead to novel therapeutic approaches. Like other cancers, pancreatic cancer cells rely on fuel sources for homeostasis and proliferation; as such, interrupting the use of two major nutrients, glucose and glutamine, may provide new therapeutic avenues. In addition, KRAS-mutant pancreatic cancers have been documented to depend on autophagy, and the inhibition of autophagy in the preclinical setting has shown promise. Herein, the conceptual framework for blocking the pancreatic fuel supply is reviewed.
ChemInform Abstract: Construction of Disaccharidic N‐Glycopeptides. Synthesis of the Transmembrane Neuraminidase Binding Site of Influenza Virus. (1986)

Abstract Ausgehend vom Chitobioseoctaacetat (Ia) (durch acetylierende saure Hydrolyse aus Chitin gewonnen) wird über die Stufen (Ib) und (Ic) das Chitobiosylamin (Id) gewonnen, das mit dem Ester (II) zur Verbindung (IIIa) verknüpft wird.
Electrochemical Bonding of Amines to Carbon Fiber Surfaces Toward Improved Carbon‐Epoxy Composites (1990)

Electrochemical oxidation of ω‐diamines on carbon fibers allows the bonding of these molecules to the carbon fibers. The conditions leading to this surface modification are described, and the influence of the different parameters is discussed. The structure of the bonded layer is studied by voltammetry, XPS, and SIMS. A mechanism is proposed which involves the coupling of a radical cation to the fiber. Toughness of carbon‐epoxy composites is improved when prepared from these modified fibers.
Increased resistance to oncostatin M-induced growth inhibition of human melanoma cell lines derived from advanced-stage lesions. (1993)

Human melanomas can become progressively resistant to the growth-inhibitory effects of a broad family of structurally diverse cytokines which includes interleukin 6 (IL-6). Uncovering this multicytokine resistance was made possible by the availability of cell lines established from early-stage radial growth phase or vertical growth phase primary melanomas as well as more advanced primary lesions and distant metastases. Because Oncostatin M (OSM) is also a member of the IL-6 family we evaluated the effects of this cytokine on the growth of human melanoma cell lines obtained from different stages of disease progression. The results showed that three different cell lines derived from early-stage melanomas were strongly growth inhibited by OSM, as they are by IL-6. Three cell lines, established from advanced-stage melanomas, were growth inhibited by OSM, but much higher concentrations (in the range of 10-fold) were required to obtain 50% growth inhibition; these cell lines were not inhibited by IL-6. Three other cell lines that were IL-6 resistant (two of which were advanced stage) were also found to be OSM resistant. Only one advanced-stage IL-6-resistant cell line was found to be highly sensitive to OSM-mediated growth inhibition. In addition, we found that variants isolated from early-stage WM35 melanoma cells that possess a much more aggressive tumorigenic phenotype in nude mice were significantly more resistant to both OSM- and IL-6-mediated growth inhibition. The results demonstrate that OSM can function as a growth inhibitor of human melanoma cells but that its ability to do so is progressively diminished or lost with disease progression. This finding is consistent with the concept of acquired "multicytokine resistance" during melanoma progression.
Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans (1989)

In a study of serum levels of tumor necrosis factor (TNF alpha) and interleukin-1 beta (IL-1 beta) in patients developing sepsis in the ICU, high TNF alpha levels were found in patients with septic shock. Normal values are 75 +/- 15 pg/ml; in these patients, TNF alpha serum level ranged from 100 to 5000 pg/ml with a mean of 701 +/- 339 pg/ml and a median of 250 pg/ml. There was a correlation between TNF alpha level and sepsis severity score as well as with mortality. In contrast, IL-1 beta serum levels were only slightly increased and were not correlated with severity or mortality.
Hierarchy in Pentose Sugar Metabolism in Clostridium acetobutylicum (2014)

Bacterial metabolism of polysaccharides from plant detritus into acids and solvents is an essential component of the terrestrial carbon cycle. Understanding the underlying metabolic pathways can also contribute to improved production of biofuels. Using a metabolomics approach involving liquid chromatography-mass spectrometry, we investigated the metabolism of mixtures of the cellulosic hexose sugar (glucose) and hemicellulosic pentose sugars (xylose and arabinose) in the anaerobic soil bacterium Clostridium acetobutylicum. Simultaneous feeding of stable isotope-labeled glucose and unlabeled xylose or arabinose revealed that,as expected, glucose was preferentially used as the carbon source. Assimilated pentose sugars accumulated in pentose phosphate pathway (PPP) intermediates with minimal flux into glycolysis. Simultaneous feeding of xylose and arabinose revealed an unexpected hierarchy among the pentose sugars, with arabinose utilized preferentially over xylose. The phosphoketolase pathway (PKP) provides an alternative route of pentose catabolism in C. acetobutylicum that directly converts xylulose-5-phosphate into acetyl-phosphate and glyceraldehyde-3-phosphate, bypassing most of the PPP. When feeding the mixture of pentose sugars, the labeling patterns of lower glycolytic intermediates indicated more flux through the PKP than through the PPP and upper glycolysis, and this was confirmed by quantitative flux modeling. Consistent with direct acetyl-phosphate production from the PKP, growth on the pentose mixture resulted in enhanced acetate excretion. Taken collectively, these findings reveal two hierarchies in clostridial pentose metabolism: xylose is subordinate to arabinose, and the PPP is used less than the PKP.
Abstract 2327: Anti-angiogenic activity of a CovX bi-functional antibody conjugate targeting both activin-receptor like kinase type 1 (ALK-1) and vascular endothelial growth factor (VEGF) (2012)

Abstract Angiogenesis is essential for tumor growth and metastasis, and controlling tumor-associated angiogenesis is a proven therapeutic intervention to limit tumor progression. Several pathways have been involved in tumor-associated angiogenesis and the predominant target of current interventions is the vascular endothelial growth factor (VEGF) pathway. Recently, Activin-receptor like kinase type 1 (ALK-1) has been proven to be a novel and potent target of tumor angiogenesis. Our results indicate that inhibiting VEGF and ALK1 have different effects on tumor vasculature, suggesting that targeting both pathways could have a more potent effect than targeting either pathway alone. We have created a bi-functional antibody conjugate targeting both ALK-1 and VEGF by conjugating VEGF-trap peptides to an anti-ALK1 monoclonal antibody. We demonstrate that our bi-functional molecule binds both ALK-1 and VEGF with high affinity in vitro, blocks both ALK-1 and VEGF pathways in HUVEC primary human endothelial cells and has good pharmacokinetics properties in mice. Finally, in a MDA-MB-231 xenograft model in SCID mice, the ALK-1/VEGF bi-functional antibody conjugate slowed tumor growth and prolonged survival with greater efficacy than anti-VEGF therapy alone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2327. doi:1538-7445.AM2012-2327
Host cell-dependent alterations in envelope components of human immunodeficiency virus type 1 virions (1997)

In addition to gp41 and gp120, an array of cell adhesion molecules is present on the envelope of human immunodeficiency virus type 1 (HIV-1). To examine the role of the host cell in the acquisition of these molecules by virions, both laboratory-adapted and primary isolates were sequentially passaged into different host cells. Viruses obtained from the various host cells were examined for the presence of 10 different cell-derived molecules by a virus binding enzyme-linked immunosorbent assay. Virus progeny raised in peripheral blood mononuclear cells expressed most of the adhesion molecules tested, with the level of LFA-1 being the highest. When viruses were passaged into CEM-SS or SupT1 cells, the expression of most of the adhesion molecules on the virus envelope was lost. In contrast, when viruses were passaged into MT2 cells, the virus progeny bore high levels of LFA-3, ICAM-1, and major histocompatibility complex classes I and II. These studies demonstrate for the first time the host cell dependence of the adhesion molecule profile present on the envelope of primary isolates of HIV-1. The presence of several adhesion molecules that have not previously been identified as components of the envelope of either laboratory or primary isolates is also described. In addition, we show that the adhesion molecule profile of the virions is acquired, or lost, within one passage and is maintained with subsequent passages in the same cell type.
Autotransplantation in Lingual Ectopia of Thyroid Gland (1963)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Otolaryngology–Head & Neck Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Otolaryngology–Head & Neck Surgery journal
Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment (1992)

DBA mice were chronically treated with nicotine by continuous intravenous infusion of 4.0 mg/kg/hr for 10 d. Drug-treated mice were tolerant to the acute effects of nicotine on locomotor activity and body temperature. The effect of chronic treatment on the amount of L-3H-nicotine binding and RNA encoding for alpha 4, the most widely expressed nicotinic alpha-subunit, was measured in three brain regions. Chronic treatment increased L-3H-nicotine binding in cortex and midbrain but had no effect in cerebellum. In contrast, chronic treatment had no effect on the levels of mRNA encoding for alpha 4 in any of the three brain regions. Subsequently brains were sectioned and L-3H-nicotine binding was measured using quantitative autoradiographic methods. In addition, the relative amounts of mRNA for the major nicotinic receptor subunits (alpha 4 and beta 2), as well as for three additional minor subunits (alpha 2, alpha 3, and alpha 5), were determined by in situ hybridization histochemistry followed by quantitation of image intensity. Chronic nicotine treatment resulted in increases in the amount of L-3H-nicotine binding in many but not all brain areas measured. In contrast, chronic treatment had little effect on the intensity of the hybridization signal for the nicotinic subunit mRNA. The results suggest that chronic treatment with nicotine under conditions resulting in maximal steady-state increases in L-3H-nicotine binding has little effect on RNA levels encoding any of four nicotinic alpha-subunits and the beta 2-subunit.
Molecular Basis of Vitamin E Action (2000)

HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than alpha-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of alpha-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60(c-Src) kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4-10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.
Site-specific N-glycosylation of chicken serum IgG (2003)

Avian serum immunoglobulin (IgG or IgY) is functionally equivalent to mammalian IgG but has one additional constant region domain (CH2) in its heavy (H) chain. In chicken IgG, each H-chain contains two potential N-glycosylation sites located on CH2 and CH3 domains. To clarify characteristics of N-glycosylation on avian IgG, we analyze N-glycans from chicken serum IgG by derivatization with 2-aminopyridine (PA) and identified by HPLC and MALDI-TOF-MS. There were two types of N-glycans: (1) high-mannose-type oligosaccharides (monoglucosylated 26.8%, others 10.5%) and (2) biantennary complex-type oligosaccharides (neutral, 29.9%; monosialyl, 29.3%; disialyl, 3.7%) on molar basis of total N-glycans. To investigate the site-specific localization of different N-glycans, chicken serum IgG was digested with papain and separated into Fab [containing variable regions (VH + VL) + CH1 + CL] and Fc (containing CH3 + CH4) fragments. Con A stained only Fc (CH3 + CH4) and RCA-I stained only Fab fractions, suggesting that high-mannose-type oligosaccharides were located on Fc (CH3 + CH4) fragments, and variable regions of Fab contains complex-type N-glycans. MS analysis of chicken IgG-glycopeptides revealed that chicken CH3 domain (structurally equivalent to mammalian CH2 domain) contained only high-mannose-type oligosaccharides, whereas chicken CH2 domain contained only complex-type N-glycans. The N-glycosylation pattern on avian IgG is more analogous to that in mammalian IgE than IgG, presumably reflecting the structural similarity to mammalian IgE.
Structural Characterization of the Rat Carboxypeptidase-E Gene (1991)

Several genomic clones encoding carboxypeptidase-E (CPE) have been isolated and partially sequenced. Southern blot analysis indicates that a single copy of this gene is present in the rat genome. The entire gene spans approximately 50 kilobases and consists of nine exons, each of which contains protein-coding regions. Only one of the exon/intron junctions of the rat CPE gene is present in a comparable position within the genes for carboxypeptidase-A and -B, both of which are only 17-21% homologous to CPE at the amino acid level. Nuclease protection analysis shows that alternative splicing of exons 7, 8, and 9 does not occur, indicating that the heterogeneity of the C-terminal region of CPE is due to posttranslational processing. Primer extension and nuclease protection analyses have identified the 5' end of CPE mRNA to be 105 nucleotides up-stream from the ATG used for protein translation. The 5' flanking region does not contain TATA and/or CCAAT boxes in the near vicinity of the transcription initiation site. The 5' flanking region is GC rich, containing 70% GC residues over nucleotides -1 to -150 (relative to the transcription initiation site). Putative consensus sites for the enhancer elements SP-1, NF-1, Pan-1, and AP-2 are present in the region from -60 to -330. Since this report describes the first neuropeptide-processing enzyme gene to be partially sequenced, it is not possible to compare the sequence with those of other processing enzymes that show similar tissue-specific expression. However, comparison of the CPE sequence with 5' flanking regions of other neuroendocrine genes has revealed a short region (12-18 nucleotides) that is highly conserved among CPE, neuropeptide-Y, oxytocin, insulin, and tyrosine hydroxylase genes.