gebhart/patrepeval huggingface dataset:
Structural Insights into the Down-regulation of Overexpressed p185 Protein of Transformed Cells by the Antibody chA21 (2011)

p185(her2/neu) belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185(her2/neu) monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185(her2/neu) mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185(her2/neu)-overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185(her2/neu), which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185(her2/neu). We propose a structure-based model in which chA21 cross-links two p185(her2/neu) molecules on separate homo- or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process."
Progress in the Diagnosis of Appendicitis (2012)

Patients who were not imaged during workup for suspected appendicitis had more than 3 times the odds of NA as those who were imaged. Routine imaging in the evaluation of patients suspected to have appendicitis can safely reduce unnecessary operations. Programs such as SCOAP improve care through peer-led, benchmarked practice change.
Gene therapy for thyroid cancer (2004)

Thyroid carcinomas are suitable targets for gene therapy because they can be highly lethal on one hand, while being susceptible to specific tumour targeting on the other hand. Several gene therapy modalities have been evaluated so far in experimental models of thyroid cancer, including tumour suppressor gene replacement, oncogene inhibition, suicide gene therapy, immunotherapy, antiangiogenesis, and viral oncolysis. All of these strategies have shown promising results, but clinical studies are lacking. Based on the clinical experience achieved in a pilot study in patients with advanced thyroid cancer and on clinical results in other types of solid cancer, it is suggested that combined gene therapy approaches, as well as multimodality therapeutic regimens, including gene therapy and conventional treatments, should be pursued to achieve clinically significant results.
Oxygen tension regulates the expression of a group of procollagen hydroxylases (2003)

In this study, we have characterized the influence of hypoxia on the expression of hydroxylases crucially involved in collagen fiber formation, such as prolyl-4-hydroxylases (Ph4) and procollagen lysyl-hydroxylases (PLOD). Using the rat vascular smooth muscle cell line A7r5, we found that an hypoxic atmosphere caused a characteristic time-dependent five- to 12-fold up-regulation of the mRNAs of the two P4h alpha-subunits [alphaI (P4ha1) and alphaII (P4ha2)] and of two lysylhydroxylases (PLOD1 and PLOD2). These effects of hypoxia were mimicked by the iron-chelator deferoxamine (100 micro m) and by cobaltous chloride (100 micro m). The hypoxic induction of these genes was also seen in the mouse juxtaglomerular As4.1 cell line and mouse hepatoma cell line Hepa1 but was almost absent in the mutant cell line Hepa1C4, which is defective for the hypoxia-inducible transcription factor 1 (HIF-1). In addition, the enzyme expression was induced by hypoxia in mouse embryonic fibroblasts but not in embryonic fibroblasts lacking the HIF-1alpha subunit. These findings indicate that hypoxia stimulates the gene expression of a cluster of hydroxylases that are indispensible for collagen fiber formation. Strong indirect evidence, moreover, suggests that the expression of these enzymes during hypoxia is coordinated by HIF-1.
Adaptive Optics Retinal Imaging (2008)

<b>Invest Ophthalmol Vis Sci</b> <b>High-Resolution Imaging With Adaptive Optics in Patients With Inherited Retinal Degeneration</b> Jacque L. Duncan; Yuhua Zhang; Jarel Gandhi; Chiaki Nakanishi; Mohammad Othman; Kari E. H. Branham; Anand Swaroop; Austin Roorda <h3></h3> <b>Purpose:</b>To investigate macular photoreceptor structure in patients with inherited retinal degeneration using high-resolution images and to correlate the findings with clinical phenotypes and genetic mutations. <b>Methods:</b>Adaptive optics scanning laser ophthalmoscopy (AOSLO) images of photoreceptors were obtained in 16 eyes: 5 with retinitis pigmentosa (RP), 3 with cone-rod dystrophy (CRD), and 8 without retinal disease. A quadratic model was used to illustrate cone spacing as a function of retinal eccentricity. Cone spacing at 1° eccentricity was compared with standard measures of central visual function, including best-corrected visual acuity (BCVA), foveal threshold, and multifocal electroretinogram (mfERG) amplitude and timing. Intervisit variations were studied in 1 patient with RP and 1 patient with CRD. Screening of candidate disease genes identified mutations in 2 patients, one with RP (a rhodopsin mutation) and the other with CRD (a novel<i>RPGR</i>-ORF15 mutation). <b>Results:</b>Cone spacing values were significantly different from normal for patients with RP (<i>P</i> = .01) and CRD (<i>P</i> &lt; .0001) and demonstrated a statistically significant correlation with foveal threshold (<i>P</i> = .0003), BCVA (<i>P</i> = .01), and mfERG amplitude (<i>P</i> = .008). Although many RP patients showed normal cone spacing within 1° of fixation, cones could not be unambiguously identified in several retinal regions. Cone spacing increased in all CRD patients, even those with early disease. Little variation was observed in cone spacing measured during 2 sessions fewer than 8 days apart. <b>Conclusions:</b>AOSLO images can be used to study macular cones with high resolution in patients with retinal degeneration. The authors present the first report of cone structure in vivo in patients with mutations in rhodopsin and<i>RPGR</i>-ORF15 and show that macular cones display distinct characteristics, depending on the underlying disease. AOSLO imaging, therefore, can provide new insight into possible mechanisms of cone vision loss in patients with retinal degeneration. <i>Invest Ophthalmol Vis Sci.. 2007;48(7):3283-3291.</i>
Automatic ventricular cavity boundary detection from sequential ultrasound images using simulated annealing (1989)

An automatic algorithm has been developed for high-speed detection of cavity boundaries in sequential 2-D echocardiograms using an optimization algorithm called simulated annealing (SA). The algorithm has three stages. (1) A predetermined window of size nxm is decimated to size n'xm' after low-pass filtering. (2) An iterative radial gradient algorithm is employed to determine the center of gravity (CG) of the cavity. (3) 64 radii which originate from the CG defined in stage 2 are bounded by the high-probability region. Each bounded radius is defined as a link in a 1-D, 64-member cyclic Markov random field. This algorithm is unique in that it compounds spatial and temporal information along with a physical model in its decision rule, whereas most other algorithms base their decisions on spatial data alone. This is the first implementation of a relaxation algorithm for edge detection in echocardiograms. Results attained using this algorithm on real data have been highly encouraging.
Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis (2014)

In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).
Lead(II)-Induced Allosteric G-Quadruplex DNAzyme as a Colorimetric and Chemiluminescence Sensor for Highly Sensitive and Selective Pb2+ Detection (2010)

The lead ion (Pb(2+)) has been proven to induce a conformational change of K(+)-stabilized G-quadruplex DNAzyme and inhibit the peroxidase-like activity [Li, T.; Wang, E.; Dong, S. J. Am. Chem. Soc. 2009, 131, 15082-15083]. This provides a rationale for utilizing Pb(2+)-induced allosteric G-quadruplex DNAzyme to probe aqueous Pb(2+). Here, we choose a common G-quadruplex DNAzyme named PS2.M to develop a novel Pb(2+) sensor with two detection means: colorimetry and chemiluminescence (CL). In the presence of K(+), PS2.M (with hemin as a cofactor) exhibits a superior DNAzyme activity and effectively catalyzes the H(2)O(2)-mediated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) or luminol, which results in a color change or generates CL emission. Upon the addition of Pb(2+), K(+)-stabilized PS2.M is induced to convert to the Pb(2+)-stabilized structure with higher stability but lower DNAzyme activity, which is reflected by an obvious increase in DNA melting temperature but a sharp decrease in readout signal. This allows us to utilize PS2.M for quantitative analysis of aqueous Pb(2+) using the ABTS-H(2)O(2) colorimetric system and luminol-H(2)O(2) CL system. In each case, the readout signal is linearly dependent on the logarithm of Pb(2+) concentration within a certain range. Nevertheless, two sensing systems provide different sensitivity for Pb(2+) analysis. With colorimetry, Pb(2+) can be detected at a level of 32 nM (approximately 7 ppb), whereas the detection limit of Pb(2+) is 1 nM (0.2 ppb) when utilizing the CL method. In addition to high sensitivity, the above sensing systems exhibit good selectivity for Pb(2+) over other metal ions. These results demonstrate the facility and effectivity of our introduced DNAzyme-based sensor for quantitative Pb(2+) analysis.
The Copper(I)-Catalyzed Decarboxylation of Malonic Acids; A New Mild and Quantitative Method (1986)

A novel catalytic decarboxylation of malonic acids under mild conditions is proposed. This simple copper(I)-catalyzed reaction affords the corresponding monocarboxylic acids in good purity and nearly quantitative yields.
Genetical Studies on the Mode of Inheritance and Localization of the amo1 (High Amylose) Gene in Barley (1992)

Abstract In the high amylose starch mutant ‘Glacier AC38’, a single recessive gene designated amo1 is responsible for an amylose content of up to 45%. A rapid technique was established in order to evaluate the amylose/amylopectin ratio in half kernels. To localize this gene, crosses with multiple marker lines and trisormes were conducted. In addition, RFLP markers were used to determine their mapping distance to amo1 . Two markers are located 2 cM and 7 cM, respectively, from amo1 on chromosome 5S (1HS). The relationship between the wx and amo1 genes was also examined and the role of the amo1 gene in starch synthesis is discussed.
Molecular Cloning and Expression of Rat Squalene Epoxidase (1995)

Squalene epoxidase (SE) (EC 1.14.99.7) catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway. Rat SE cDNA was isolated by selecting yeast transformants expressing rat cDNA in the presence of transformants expressing rat cDNA in the presence of terbinafine, an inhibitor specific for fungal SE. The expression of rat SE in the isolated terbinafine-resistant clone was confirmed by its survival in the presence of either terbinafine or an inhibitor specific for mammalian SE, NB-598, but not in the presence of both terbinafine and NB-598. Rat SE polypeptide deduced from the nucleotide sequence contains 573 amino acids, and its molecular weight is 63,950 Da. The amino acid sequence reveals one potential transmembrane domain, a hydrophobic segment (Leu27 to Tyr43) in the NH2-terminal region. This region also contains a beta 1-alpha A-beta 2 motif, which is the consensus sequence for an FAD binding domain, suggesting that SE is a flavoenzyme. This deduced rat SE sequence is 30.2% identical to the ERG 1 gene, which encodes SE from an allylamine-resistant Saccharomyces cerevisiae mutant. Expression of a full-length rat SE protein in Escherichia coli confirms this polypeptide as a functional SE. This is the first report of the molecular cloning of mammalian SE.
Guideline for anti-TNF-α therapy in psoriatic arthritis (2005)

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy with a prevalence between 0.1 and 1% and an equal sex distribution [1]. Psoriasis affects 1–3% of the population, with approximately a third of patients developing PsA [2]. The course of PsA is variable and unpredictable ranging from a mild nondestructive disease to a severe debilitating erosive arthropathy. Erosive and deforming arthritis occurs in 40–60% of PsA patients (followed at hospital clinics), and is progressive from within the first year of diagnosis [3, 4]. The classification of PsA is an area of ongoing international discussion. The five subgroups proposed by Moll and Wright [5] are still frequently used, although considerable overlap between these groups is now recognized. For the purpose of these guidelines we have differentiated between peripheral joint disease in PsA and axial disease alone. Psoriatic spondylitis is similar to ankylosing spondylitis (AS), although it is often less symptomatic, less limiting and radiologically tends to be asymmetrical and less severe [6]. However, despite these differences, until such time as there is evidence that psoriatic spondylitis responds in a different manner from AS to TNFblockade, we recommend that AS guidelines for anti-TNFtreatment are used for the management of psoriatic spondylitis [7]. Much like rheumatoid arthritis (RA), PsA can lead to chronic joint damage, increased disability [8, 9] and increased mortality [10, 11]. Social and financial implications are also important, both in terms of personal loss and the impact of direct (e.g. medical care) and indirect (e.g. inability to work) costs to the state. It is recognized that psoriasis is associated with an increased risk of non-melanoma skin cancers [12], most probably a result of excessive exposure to sunlight and enhanced by use of psoralen and ultraviolet A (PUVA) therapy [13]. The guidelines recognize that these risks that may be potentiated by anti-TNFtreatment and specific recommendations have been made accordingly (see sections headed Exclusion criteria and Monitoring and Toxicity). Need for guideline
Antigenicity of HIV‐derived T helper determinants in the context of carrier recombinant proteins: effect on T helper cell repertoire selection (1996)

T helper (Th) epitopes can be included in a recombinant protein with B and CTL epitopes to create more effective immunogens. To determine whether the antigenicity of HIV Th epitopes is preserved in this altered molecular context, human Th clones specific for peptides of HIV gp120 and reverse transcriptase p66 were challenged with recombinant proteins carrying the antigenic epitopes in different sites. We found that a given epitope was recognized by a specific T cell clone only when it was inserted in a particular position of the carrier. However, the permissive position was not the same for all epitopes. Enzymatic excision from a nonpermissive context or insertion of a polyserine spacer between the epitope and the carrier restored antigenicity. Nevertheless, antigenicity was not abolished in a synthetic peptide encompassing the epitope and the neighboring residues from the nonpermissive location. These data suggest that, in this case, the primary sequence of the chimeric protein flanking the HIV peptide is not responsible for loss of antigenicity. Furthermore, constructs carrying the epitope in a given position were recognized by peptide-specific Th clones raised from some individuals, but not from others. We show that this is due neither to individual modes of processing nor to the use of distinct major histocompatibility complex MHC class II restriction elements, but rather that it is related to the fine specificity of the clones. To study the effect of epitope context on selection of T cell repertoire in a naive individual, T cell lines were generated in vitro by stimulation with different peptide constructs. This resulted in the induction of diverse clonotypes defined by the pattern of recognition of different constructs, by T cell receptor V beta gene usage and by fine epitope mapping.
Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus (2009)

Elevated serum sST2 level in SLE patients was found to correlate with disease activity and was sensitive to change, suggesting a potential role as a surrogate marker of disease activity.
Insights into mechanisms of corticotropin‐releasing hormone receptor signal transduction (2012)

During evolution, mammals have developed remarkably similar molecular mechanisms to respond to external challenges and maintain survival. Critical regulators of these mechanisms are the family of 'stress'-peptides that consists of the corticotropin-releasing hormone (CRH) and urocortins (Ucns). These neuropeptides 'fine-tune' integration of an intricate series of physiological responses involving the autonomic, endocrine, immune, cardiovascular and reproductive systems, which induce a spectrum of behavioural and homeostatic changes. CRH and Ucns exert their actions by activating two types of CRH receptors (CRH-R), CRH-R1 and CRH-R2, which belong to the class-B1 family of GPCRs. The CRH-Rs exhibit signalling promiscuity facilitated by their ability to couple to multiple G-proteins and regulate diverse intracellular networks that involve intracellular effectors such as cAMP and an array of PKs in an agonist and tissue-specific manner, a property that allows them to exert unique roles in the integration of homeostatic mechanisms. We only now begin to unravel the plethora of CRH-R biological actions and the transcriptional and post-translational mechanisms such as alternative mRNA splicing or phosphorylation-mediated desensitization developed to tightly control CRH-Rs biological activity and regulate their physiological actions. This review summarizes the current understanding of CRH-R signalling complexity and regulatory mechanisms that underpin cellular responses to CRH and Ucns.
Porcine Embryonic Brain Cell Cytotoxicity Mediated by Human Natural Killer Cells (1999)

Intracerebral transplantation of porcine embryonic dopamine-producing neurons has been suggested as a method to treat patients with Parkinson's disease. Even though the brain is an immunologically privileged site, neuronal xenografts are usually rejected within a few weeks. T cells are important for this process, but the exact cellular events leading to rejection are poorly characterized. Brain cells from ventral mesencephalon of 26-27-day-old pig embryos were used as target cells in flow cytometry-assessed cytotoxicity assays using non- and IL-2-activated CD3- CD16+ CD56+ human natural killer (NK) cells as effector cells. The ability of human NK cells to kill pig embryonic brain cells by antibody-dependent cellular cytotoxicity (ADCC) in the presence of nondepleted and anti-Gal alpha1,3Gal antibody-depleted human blood group AB serum (AB serum) was evaluated using the same assay. Both nondepleted and anti-Gal alpha1,3Gal antibody-depleted AB serum could mediate ADCC of pig embryonic VM cells when human NK cells were used as effector cells. Nonactivated NK cells did not show any direct cytotoxic effect on freshly isolated VM cells, whereas IL-2-activated NK cells killed approximately 50% of the VM cells at an effector-to-target ratio of 50:1 in a 4-h cytotoxicity assay. Activation of VM cells by TNF-alpha did not change their sensitivity to human NK cell cytotoxicity. Human NK cells may thus contribute to a cellular rejection of pig neuronal xenografts by ADCC, or following IL-2 activation, by a direct cytotoxic effect.
Functional role of proteolytic cleavage at arginine-275 of human tissue plasminogen activator as assessed by site-directed mutagenesis (1987)

Activation of the zymogen form of a serine protease is associated with a conformational change that follows proteolysis at a specific site. Tissue-type plasminogen activator (t-PA) is homologous to mammalian serine proteases and contains an apparent activation cleavage site at arginine-275. To clarify the functional consequences of cleavage at arginine-275 of t-PA, site-specific mutagenesis was performed to convert arginine-275 to a glutamic acid. The mutant enzyme (designated Arg-275----Glu t-PA) could be converted to the two-chain form by Staphylococcus aureus V8 protease but not by plasmin. The one-chain form was 8 times less active against the tripeptide substrate H-D-isoleucyl-L-prolyl-L-arginine-p-nitroanilide (S-2288), and the ability of the enzyme to activate plasminogen in the absence of fibrinogen was reduced 20-50 times compared to the two-chain form. In contrast, one-chain Arg-275----Glu t-PA has equal activity to the two-chain form when assayed in the presence of physiological levels of fibrinogen and plasminogen. Fibrin bound significantly more of the one-chain form of t-PA than the two-chain form for both the wild-type and mutated enzymes. One- and two-chain forms of the wild-type and mutated plasminogen activators slowly formed complexes with plasma protease inhibitors, although the one-chain forms showed decreased complex formation with alpha 2-macroglobulin. The one-chain form of t-PA therefore is fully functional under physiologic conditions and has an increased fibrin binding compared to the two-chain form.
Novel replication-incompetent adenoviral B-group vectors: high vector stability and yield in PER.C6 cells (2006)

Adenoviral vectors based on adenovirus type 35 (rAd35) have the advantage of low natural vector immunity and induce strong, insert-specific T- and B-cell responses, making them prime-candidate vaccine carriers. However, severe vector-genome instability of E1-deleted rAd35 vectors was observed, hampering universal use. The instability of E1-deleted rAd35 vector proved to be caused by low pIX expression induced by removal of the pIX promoter, which was located in the E1B region of B-group viruses. Reinsertion of a minimal pIX promoter resulted in stable vectors able to harbour large DNA inserts (> 5 kb). In addition, it is shown that replacement of the E4-Orf6 region of Ad35 by the E4-Orf6 region of Ad5 resulted in successful propagation of an E1-deleted rAd35 vector on existing E1-complementing cell lines, such as PER.C6 cells. The ability to produce these carriers on PER.C6 contributes significantly to the scale of manufacturing of rAd35-based vaccines. Next, a stable rAd35 vaccine was generated carrying Mycobacterium tuberculosis antigens Ag85A, Ag85B and TB10.4. The antigens were fused directly, resulting in expression of a single polyprotein. This vaccine induced dose-dependent CD4+ and CD8+ T-cell responses against multiple antigens in mice. It is concluded that the described improvements to the rAd35 vector contribute significantly to the further development of rAd35 carriers for mass-vaccination programmes for diseases such as tuberculosis, AIDS and malaria.