gebhart/patrepeval huggingface dataset:
Activation of the Canonical Wnt Pathway during Genital Keratinocyte Transformation: A Model for Cervical Cancer Progression (2005)

Cervical carcinoma, the second leading cause of cancer deaths in women worldwide, is associated with human papillomavirus (HPV). HPV-infected individuals are at high risk for developing cervical carcinoma; however, the molecular mechanisms that lead to the progression of cervical cancer have not been established. We hypothesized that in a multistep carcinogenesis model, HPV provides the initial hit and activation of canonical Wnt pathway may serve as the second hit. To test this hypothesis, we evaluated the canonical Wnt pathway as a promoting factor of HPV-induced human keratinocyte transformation. In this in vitro experimental cervical carcinoma model, primary human keratinocytes immortalized by HPV were transformed by SV40 small-t (smt) antigen. We show that smt-transformed cells have high cytoplasmic beta-catenin levels, a hallmark of activated canonical Wnt pathway, and that activation of this pathway by smt is mediated through its interaction with protein phosphatase-2A. Furthermore, inhibition of downstream signaling from beta-catenin inhibited the smt-induced transformed phenotype. Wnt pathway activation transformed HPV-immortalized primary human keratinocytes even in the absence of smt. However, activation of the Wnt pathway in the absence of HPV was not sufficient to induce transformation. We also detected increased cytoplasmic and nuclear staining of beta-catenin in invasive cervical carcinoma samples from 48 patients. We detected weak cytoplasmic and no nuclear staining of beta-catenin in 18 cases of cervical dysplasia. Our results suggest that the transformation of HPV expressing human keratinocytes requires activation of the Wnt pathway and that this activation may serve as a screening tool in HPV-positive populations to detect malignant progression.
COBEpro: a novel system for predicting continuous B-cell epitopes (2008)

Accurate prediction of B-cell epitopes has remained a challenging task in computational immunology despite several decades of research. Only 10% of the known B-cell epitopes are estimated to be continuous, yet they are often the targets of predictors because a solved tertiary structure is not required and they are integral to the development of peptide vaccines and engineering therapeutic proteins. In this article, we present COBEpro, a novel two-step system for predicting continuous B-cell epitopes. COBEpro is capable of assigning epitopic propensity scores to both standalone peptide fragments and residues within an antigen sequence. COBEpro first uses a support vector machine to make predictions on short peptide fragments within the query antigen sequence and then calculates an epitopic propensity score for each residue based on the fragment predictions. Secondary structure and solvent accessibility information (either predicted or exact) can be incorporated to improve performance. COBEpro achieved a cross-validated area under the curve (AUC) of the receiver operating characteristic up to 0.829 on the fragment epitopic propensity scoring task and an AUC up to 0.628 on the residue epitopic propensity scoring task. COBEpro is incorporated into the SCRATCH prediction suite at http://scratch.proteomics.ics.uci.edu.
Biochemical characterization and lysosomal localization of the mannose-6-phosphate protein p76 (hypothetical protein LOC196463) (2007)

Most soluble lysosomal proteins carry Man6P (mannose 6-phosphate), a specific carbohydrate marker that enables their binding to cellular MPRs (Man6P receptors) and their subsequent targeting towards the lysosome. This characteristic was exploited to identify novel soluble lysosomal proteins by proteomic analysis of Man6P proteins purified from a human cell line. Among the proteins identified during the course of the latter study [Journet, Chapel, Kieffer, Roux and Garin (2002) Proteomics, 2, 1026-1040], some had not been previously described as lysosomal proteins. We focused on a protein detected at 76 kDa by SDS/PAGE. We named this protein 'p76' and it appeared later in the NCBI protein database as the 'hypothetical protein LOC196463'. In the present paper, we describe the identification of p76 by MS and we analyse several of its biochemical characteristics. The presence of Man6P sugars was confirmed by an MPR overlay experiment, which showed the direct and Man6P-dependent interaction between p76 and the MPR. The presence of six N-glycosylation sites was validated by progressive peptide-N-glycosidase F deglycosylation. Experiments using N- and C-termini directed anti-p76 antibodies provided insights into p76 maturation. Most importantly, we were able to demonstrate the lysosomal localization of this protein, which was initially suggested by its Man6P tags, by both immunofluorescence and sub-cellular fractionation of mouse liver homogenates.
Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in COVID-19 (2020)

Abstract IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc-tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated binding and killing activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG which are of minor abundance in humans (∼6% of total IgG) are specifically formed against surface epitopes of enveloped viruses after natural infections or immunization with attenuated viruses, while protein subunit immunization does not elicit this low fucose response. This can give beneficial strong responses, but can also go awry, resulting in a cytokine-storm and immune-mediated pathologies. In the case of COVID-19, the critically ill show aggravated afucosylated-IgG responses against the viral spike protein. In contrast, those clearing the infection unaided show higher fucosylation levels of the anti-spike protein IgG. Our findings indicate antibody glycosylation as a potential factor in inflammation and protection in enveloped virus infections including COVID-19.
Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for retinoic acid (1997)

Retinoic acid (RA) exerts diverse biological effects in the control of cell growth in embryogenesis and oncogenesis. These effects of RA are thought to be mediated by the nuclear retinoid receptors. Mannose-6-phosphate (M6P)/insulin-like growth factor-II (IGF-II) receptor is a multifunctional membrane glycoprotein that is known to bind both M6P and IGF-II and function primarily in the binding and trafficking of lysosomal enzymes, the activation of transforming growth factor-beta, and the degradation of IGF-II. M6P/IGF-II receptor has recently been implicated in fetal development and carcinogenesis. Despite the functional similarities between RA and the M6P/IGF-II receptor, no direct biochemical link has been established. Here, we show that the M6P/IGF-II receptor also binds RA with high affinity at a site that is distinct from those for M6P and IGF-II, as identified by a photoaffinity labeling technique. We also show that the binding of RA to the M6P/IGF-II receptor enhances the primary functions of this receptor. The biological consequence of the interaction appears to be the suppression of cell proliferation and/or induction of apoptosis. These findings suggest that the M6P/IGF-II receptor mediates a RA response pathway that is important in cell growth regulation. This discovery of the interaction of RA with the M6P/IGF-II receptor may have important implications for our understanding of the roles of RA and the M6P/IGF-II receptor in development, carcinogenesis, and lysosomal enzyme-related diseases.
Bronchodilator action of inhaled nitric oxide in guinea pigs. (1992)

The effects of inhaling nitric oxide (NO) on airway mechanics were studied in anesthetized and mechanically ventilated guinea pigs. In animals without induced bronchoconstriction, breathing 300 ppm NO decreased baseline pulmonary resistance (RL) from 0.138 +/- 0.004 (mean +/- SE) to 0.125 +/- 0.002 cmH2O/ml.s (P less than 0.05). When an intravenous infusion of methacholine (3.5-12 micrograms/kg.min) was used to increase RL from 0.143 +/- 0.008 to 0.474 +/- 0.041 cmH2O/ml.s (P less than 0.05), inhalation of 5-300 ppm NO-containing gas mixtures produced a dose-related, rapid, consistent, and reversible reduction of RL and an increase of dynamic lung compliance. The onset of bronchodilation was rapid, beginning within 30 s after commencing inhalation. An inhaled NO concentration of 15.0 +/- 2.1 ppm was required to reduce RL by 50% of the induced bronchoconstriction. Inhalation of 100 ppm NO for 1 h did not produce tolerance to its bronchodilator effect nor did it induce substantial methemoglobinemia (less than 2%). The bronchodilating effects of NO were additive with the effects of inhaled terbutaline, irrespective of the sequence of NO and terbutaline administration. Inhaling aerosol generated from S-nitroso-N-acetylpenicillamine also induced a rapid and profound decrease of RL from 0.453 +/- 0.022 to 0.287 +/- 0.022 cmH2O/ml.s, which lasted for over 15 min in guinea pigs broncho-constricted with methacholine. Our results indicate that low levels of inhaled gaseous NO, or an aerosolized NO-releasing compound are potent bronchodilators in guinea pigs.
YIGSR, a Synthetic Laminin Pentapeptide, Inhibits Experimental Metastasis Formation (1987)

The invasion of tumor cells through basement membranes is a critical step in the formation of metastases. The binding of the malignant cells to laminin in the basement membranes allows their attachment and activates their invasiveness. Recently a synthetic nonapeptide from the B1 chain sequence of laminin was identified as a major site for cell binding. A pentapeptide within the nonapeptide sequence was found to reduce the formation of lung colonies in mice injected with melanoma cells and also to inhibit the invasiveness of the cells in vitro.
Separation of Transactivation and AP1 Antagonism Functions of Retinoic Acid Receptor α (1995)

Retinoic acid receptors (RARs) regulate gene expression either by directly binding to the RAR-responsive elements or by antagonizing the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis, rheumatoid arthritis and in tumor metastases. We demonstrate here that synthetic retinoids inhibit 12-O-tetradecanoylphorbol-14-acetate-induced transcription from the stromelysin AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR beta and RAR gamma, but not for RAR alpha, in transactivation assays, are able to inhibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it should be possible to develop retinoids that are completely specific for AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and AP1 antagonism functions of RARs.
Emerging Technology: Hyperspectral Imaging (2004)

Clinical decision-making in managing the patient with peripheral vascular disease is dependent upon patient history, physical examination, and noninvasive and invasive testing. Noninvasive testing currently includes the ankle-brachial index, pulse volume recordings, and transcutaneous oximetry. Each test yields information regarding perfusion and tissue oxygenation, but has limitations. The ankle-brachial index compares lower extremity blood pressure with the upper extremity, but it must be interpreted with caution in a patient with calcified atherosclerotic vessels, as is seen with diabetic patients, which can lead to an overestimation of actual pressure. Pulse volume recordings are mainly a qualitative estimation of distal perfusion and are highly dependent on the operator, which introduces both intraobserver and interobserver variability. Duplex ultrasound evaluation looses sensitivity in the small vessels of the limb and can be limited by instrument and operator. Transcutaneous oximetry is a quantitative measure of skin (end organ) oxygenation, but is limited by only evaluating one small area of the foot at a given time. Hyperspectral imaging was developed to possibly provide quantitative information regarding the spatial tissue oxygen saturation in patients with peripheral vascular disease.
Increased Cardiac Adrenergic Drive Precedes Generalized Sympathetic Activation in Human Heart Failure (1997)

These results indicate a selective increase in cardiac adrenergic drive (increased amounts of transmitter available at neuroeffector junctions) in patients with mild-to-moderate CHF. This increase appears to precede the augmented sympathetic outflow to the kidneys and skeletal muscle found in advanced CHF.
Feed-forward timing recovery for digital magnetic recording (2002)

Square-law and fourth-power timing recovery for magnetic recording channels modeled by a Lorentzian transition response are investigated. It is shown that these timing recovery techniques perform extremely well at practical linear densities. It is also shown that the feed-forward timing recovery overcomes a lot of problems associated with decision-directed timing recovery at low input signal-to-noise ratios. Bit-by-bit simulations show that the square-law timing recovery performs better than the fourth-power timing recovery.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Gene Transfer to Hematopoietic Cells (1996)

Although diseases of blood cells constitute a relatively small proportion of clinical disorders, many valuable studies of gene transfer have relied on hematopoietic stem cells or their progeny. What features of these cells explain their appeal in gene therapy? Perhaps most important is their hierarchical pattern of development (Figure 1). Fewer than 1 in 100,000 bone marrow cells are pluripotent, self-renewing hematopoietic stem cells, but these rare cells yield progeny that multiply by many hundredfold and, in the process, follow a particular blood-cell lineage (monocytic, lymphocytic, granulocytic, megakaryocytic, or erythrocytic). These committed progenitors then multiply by a hundredfold or more . . .
Anti‐phagocytic mechanisms of Streptococcus pyogenes: binding of fibrinogen to M‐related protein (2005)

A key attribute of invasive Streptococcus pyogenes is their ability to resist phagocytosis and multiply in human blood. M-related protein (Mrp) is a major anti-phagocytic factor but the mechanism whereby it helps streptococci to evade phagocytosis has not been demonstrated. We investigated phagocytosis resistance in a strain of serotype M4 by inactivating the mrp gene and also the emm, enn, sof and sfbX genes and by analysing the effect on streptococcal growth in blood and on complement deposition on the bacterial surface. Inactivation of enn4 and sfbX4 had little impact on growth in blood, but ablation of mrp4, emm4 or sof4 reduced streptococcal growth in human blood, confirming that Mrp and Emm are required for optimal resistance to phagocytosis and providing the first indication that Sof may be an anti-phagocytic factor. Moreover, antisera against Mrp4, Emm4 and Sof4 promoted the killing of S. pyogenes, but anti-SfbX serum had no effect. Growth of S. pyogenes in blood was dependent on the presence of fibrinogen and in the absence of fibrinogen there was a twofold increase in complement deposition. Inactivation of mrp4 resulted in a loss of fibrinogen-binding and caused a twofold increase in the binding of C3b that was inhibited by Mg-EGTA. Mrp contained two fibrinogen-binding sites, one of which is within a highly conserved region. These findings indicate that Mrp-fibrinogen interactions prevent surface deposition of complement via the classical pathway, thereby contributing to the ability of these streptococci to resist phagocytosis. This may be a common mechanism for evasion of phagocytosis because Mrp is expressed by approximately half of the clinical isolates of S. pyogenes.
A Selective Galactose–Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model (2016)

Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.
Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia (2009)

The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S(65) residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML.
Detection of minority point mutations by modified PCR technique: a new approach for a sensitive diagnosis of tumor-progression markers (1989)

The detection of point mutations correlated with diseases, in enzymatically amplified DNA sequences (Polymerase Chain Reaction), is currently performed by digestion of PCR products when an existing restriction site disappears at least in one allele of the amplified mutated sequence or by allele specific radiolabeled probes in all other cases. These methods are the most sensitive but they cannot detect a mutation if it is present in less than 5% of the studied cells. We describe here a method based on the introduction of an artificial restriction site, using a modified primer during the PCR, which creates a RFLP indicative of the studied mutation. This RFLP is detected by a radiolabeled oligonucleotide probe which is not related to the mutation. Our approach multiplies the sensitivity by a factor of 1000 and it is practical for use in screening purposes and the detection, after treatment, of the residual disease in human malignancies. Using this method we detected 20% more mutations at codon 12 in the Ki ras oncogene in DNA from colorectal cancers that were undetectable with all the previous methods.
Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature (2016)

The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.
Biomechanical evaluation of the Milwaukee brace (1998)

Although, the history of orthotic treatment for idiopathic scoliosis goes back more than fifty years, the mechanism of curve control by spinal orthosis is still controversial. Hypothetical explanations have been provided but few, if any, have been tested clinically. This study aims at the biomechanical evaluation of a spinal orthosis (Milwaukee brace) in order to improve understanding about the mechanism of curves control in orthotic movement. From the results of the study, the change of the interface pressure between the patient's body and thoracic pad, and the tension of the thoracic strap were highly correlated (r = 0.84) as patients performed different lying postures and daily activities. Lying on the thoracic pad is found to have the highest correctional force among different lying postures that may be favourable for preventing curve deterioration. The findings indicate that an increase in tension of the thoracic strap will increase the interface pressure on the thoracic pad and thus increase the resultant force exerted on the patient's body by the thoracic pad. Care must be taken as an excessive strap tension will increase discomfort and restrict body shifting exercises. The results also suggest that in scoliosis with thoracic lordosis, a short outrigger (small pulling angle of the thoracic strap) should be used as it will decrease the anteriorly directed force component so as to prevent exaggerating the thoracic lordosis.
Serum Sialyl-Tn Antigen Levels in Patients with Digestive Cancers (1991)

Serum levels of sialyl-Tn antigen (STN) were measured using a one-step radioimmunoassay kit in 257 patients with digestive cancers, 121 patients with benign digestive diseases, and in 64 healthy controls. With 45 U/ml regarded as the cutoff value, the positive rates of serum STN in digestive cancers were as follows: pancreas 40.0%, stomach 28.1, colon and rectum 27.8, biliary tract 25.0, liver 7.1, and esophagus 0%. In benign digestive diseases, the positive rate of STN was low (4.1%). In gastric and colorectal cancers, simultaneous measurements of STN and carcinoembryonic antigen (CEA) revealed that the positive rates of STN, CEA, and STN and/or CEA were 28, 42, and 55%, respectively. There was no significant correlation between STN and CEA in these cancers. STN may be a useful serum marker for digestive cancers, especially gastric and colorectal cancers.