gebhart/patrepeval huggingface dataset:
Optimization of Cell Surface Binding Enhances Efficiency and Specificity of Molecular Conjugate Gene Delivery (1998)

Molecular conjugates, or polyplexes, are promising synthetic vectors for targeted, in vivo gene delivery, if their efficiency can be improved. Gaining mechanistic information on conjugate gene delivery can potentially yield significant improvements in transfer efficiency by revealing barriers to conjugate transfer from the cell surface to the nucleus. We have developed an experimental system that employs epidermal growth factor as the ligand to direct delivery of DNA encoding the green fluorescent protein to mouse fibroblasts. We report here that the initial step of delivery, binding of the conjugate to the cell surface, is a barrier to gene transfer. We examined the effects of conjugate charge, ligand cross-linker spacer length, and ligand valency on polyplex cell surface binding, internalization, and gene transfer. We find that delivery is both efficient and specific only within a relatively narrow window of conjugate charge, results that correlate with binding and internalization of radiolabeled conjugate. In addition, increasing the cross-linker length can improve binding affinity and delivery. Finally, there is a significant optimum in gene delivery as a function of ligand valency, due to saturation of receptor binding and internalization. Optimizing parameters that affect surface binding therefore improves the efficiency and specificity of molecular conjugate gene delivery.
Three‐dimensional, sequence order‐independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: Potential implications to evolution and to protein folding (1994)

We have recently developed a fast approach to comparisons of 3-dimensional structures. Our method is unique, treating protein structures as collections of unconnected points (atoms) in space. It is completely independent of the amino acid sequence order. It is unconstrained by insertions, deletions, and chain directionality. It matches single, isolated amino acids between 2 different structures strictly by their spatial positioning regardless of their relative sequential position in the amino acid chain. It automatically detects a recurring 3D motif in protein molecules. No predefinition of the motif is required. The motif can be either in the interior of the proteins or on their surfaces. In this work, we describe an enhancement over our previously developed technique, which considerably reduces the complexity of the algorithm. This results in an extremely fast technique. A typical pairwise comparison of 2 protein molecules requires less than 3 s on a workstation. We have scanned the structural database with dozens of probes, successfully detecting structures that are similar to the probe. To illustrate the power of this method, we compare the structure of a trypsin-like serine protease against the structural database. Besides detecting homologous trypsin-like proteases, we automatically obtain 3D, sequence order-independent, active-site similarities with subtilisin-like and sulfhydryl proteases. These similarities equivalence isolated residues, not conserving the linear order of the amino acids in the chains. The active-site similarities are well known and have been detected by manually inspecting the structures in a time-consuming, laborious procedure. This is the first time such equivalences are obtained automatically from the comparison of full structures. The far-reaching advantages and the implications of our novel algorithm to studies of protein folding, to evolution, and to searches for pharmacophoric patterns are discussed.
Abstract P3-05-07: RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model (2016)

Abstract Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer. Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.
Effectiveness of 980-mm Diode and 1064-nm Extra-Long-Pulse Neodymium-Doped Yttrium Aluminum Garnet Lasers in Implant Disinfection (2009)

The wavelengths used in this research provided bacteria reduction without damaging implant surfaces. New clinical research should be encouraged for the use of this technology in the treatment of peri-implantitis.
Nested-loop neural network vector control of permanent magnet synchronous motors (2013)

With the improvement of battery technology over the past two decades and automotive technology advances, more and more vehicle manufacturers have joined in the race to produce new generation of affordable, high-performance Electric Drive Vehicles (EDVs). Permanent Magnet Synchronous Motors (PMSMs) are at the top of AC motors in high performance drive systems for EDVs. Traditionally, a PMSM is controlled with standard decoupled d-q vector control mechanisms. However, recent studies indicate that such mechanisms show serious limitations. This paper investigates how to mitigate such problems using a nested-loop neural network architecture to control a PMSM. The neural network implements a dynamic programming algorithm and is trained using backpropagation through time. The performance of the neural controller is studied for typical vector control conditions and compared with conventional vector control methods, which demonstrates the neural vector control strategy proposed in this paper is effective. Even in a highly dynamic switching environment, the neural vector controller shows strong ability to track rapidly changing reference commands, tolerate system disturbances, and satisfy control requirements for complex EDV drive needs.
Gain-of-Function Mutagenesis of a Modular Polyketide Synthase (1997)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTGain-of-Function Mutagenesis of a Modular Polyketide SynthaseRobert McDaniel, Camilla M. Kao, Hong Fu, Peter Hevezi, Claes Gustafsson, Mary Betlach, Gary Ashley, David E. Cane, and Chaitan KhoslaView Author Information KOSAN Biosciences, Inc., 1450 Rollins Road Burlingame, California 94010 Departments of Chemical Engineering, Chemistry, and Biochemistry, Stanford University Stanford, California 94305-5025 Department of Chemistry, Box H, Brown University Providence Rhode Island 02912 Cite this: J. Am. Chem. Soc. 1997, 119, 18, 4309–4310Publication Date (Web):May 7, 1997Publication History Received27 January 1997Published online7 May 1997Published inissue 1 May 1997https://pubs.acs.org/doi/10.1021/ja9702531https://doi.org/10.1021/ja9702531rapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views393Altmetric-Citations70LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Biosynthesis,Genetics,Metabolism,Multifunctional,Peptides and proteins Get e-Alerts
Cellular responses to hyperthermia (40–46°C): Cell killing and molecular events (2008)

The goal of this review is to provide a brief introduction to the effects of hyperthermia on cellular structures and physiology. The review focuses on the effects of hyperthermia thought to contribute to the enhancement of cancer therapy namely the mechanisms of cell killing and the sensitization of cells to ionizing radiation or chemotherapeutic agents. Specifically the review addresses four topics: hyperthermia induced cell killing, mathematical models of cell killing, mechanisms of thermal effects in the hyperthermia temperature range and effects on proteins that contribute to resistance to other stresses, i.e., DNA damage. Hyperthermia has significant effects on proteins including unfolding, exposing hydrophobic groups, and aggregation with proteins not directly altered by hyperthermia. Protein aggregation has effects throughout the cell but has a significant impact within the nucleus. Changes in the associations of nuclear proteins particularly those involved in DNA replication cause the stalling of DNA replication forks and lead to the induction of DNA damage such as double strand breaks. It has long been recognized that heat has effects on plasma membrane protein distribution alters the permeability of plasma membranes resulting in a calcium spike and disrupts the mitochondrial membrane potential resulting in the change in the redox status of cells. These effects contribute to the protein unfolding effects of hyperthermia and contribute to effects observed in the nucleus. Thus heat effects on multiple cellular targets can be integrated through global effects on protein folding to affect specific end points such as cell killing and sensitization to additional stresses.
The Nature of an Antigenic Determinant (1966)

Abstract Immunochemistry has sought for many years to understand the exact chemical nature of an antigenic determinant and to know how it reacts with the extraordinarily complex and heterogeneous population of immunoglobulin molecules that possess regions complementary to it, e.g., antibody combining sites.
The thyroid hormone, triiodothyronine, enhances fluoxetine-induced neurogenesis in rats: possible role in antidepressant-augmenting properties (2009)

The thyroid hormone triiodothyronine (T3) may accelerate and augment the action of antidepressants. Antidepressants up-regulate neurogenesis in adult rodent hippocampus. We studied the effect of T3 and T3+fluoxetine in enhancement of hippocampal neurogenesis beyond that induced by fluoxetine alone and the correlation with antidepressant behaviour in the novelty suppressed feeding test (NSFT). Rats were administered fluoxetine (5 mg/kg.d), T3 (50 mug/kg.d), fluoxetine (5 mg/kg.d)+T3 (50 mug/kg.d) or saline, for 21 d. Neurogenesis was studied by doublecortin (DCX) immunohistochemistry in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). In the NSFT, latency to feeding in animals deprived of food was measured. Fluoxetine and fluoxetine+T3 increased the number of doublecortin-positive (DCX+) cells in the SGZ compared to saline (p=0.00005, p=0.008, respectively). There was a trend towards an increased number of DCX+ cells by T3 compared to saline (p=0.06). Combined treatment with fluoxetine+T3 further increased the number of DCX+ cells compared to T3 or fluoxetine alone (p=0.001, p=0.014, respectively). There was no effect of any of the treatments on number of DCX+ cells in the SVZ. In the NSFT, all treatments (T3, fluoxetine+T3 and fluoxetine) reduced latency to feeding compared to saline (p=0.0004, p=0.00001, p=0.00009, respectively). Fluoxetine+T3 further reduced latency to feeding compared to T3 alone (p=0.05). The results suggest that enhancement of antidepressant action by T3 may be related to its effect of increasing hippocampal neurogenesis and that the antidepressant effect of these treatments is specific to the hippocampus and does not represent a general effect on cell proliferation.
Inherited and SomaticCD3ζ Mutations in a Patient with T-Cell Deficiency (2006)

A four-month-old boy with primary immunodeficiency was found to have a homozygous germ-line mutation of the gene encoding the CD3zeta subunit of the T-cell receptor-CD3 complex. CD3zeta is necessary for the development and function of T cells. Some of the patient's T cells had low levels of the T-cell receptor-CD3 complex and carried the Q70X mutation in both alleles of CD3zeta, whereas other T cells had normal levels of the complex and bore the Q70X mutation on only one allele of CD3zeta, plus one of three heterozygous somatic mutations of CD3zeta on the other allele, allowing expression of poorly functional T-cell receptor-CD3 complexes.
Video input driven animation (VIDA) (2003)

There are many challenges associated with the integration of synthetic and real imagery. One particularly difficult problem is the automatic extraction of salient parameters of natural phenomena in real video footage for subsequent application to synthetic objects. We can ensure that the hair and clothing of a synthetic actor placed in a meadow of swaying grass will move consistently with the wind that moved that grass. The video footage can be seen as a controller for the motion of synthetic features, a concept we call video input driven animation (VIDA). We propose a schema that analyzes an input video sequence, extracts parameters from the motion of objects in the video, and uses this information to drive the motion of synthetic objects. To validate the principles of VIDA, we approximate the inverse problem to harmonic oscillation, which we use to extract parameters of wind and of regular water waves. We observe the effect of wind on a tree in a video, estimate wind speed parameters from its motion, and then use this to make synthetic objects move. We also extract water elevation parameters from the observed motion of boats and apply the resulting water waves to synthetic boats.
Intensity based surface plasmon resonance sensor using a nanohole rectangular array (2011)

We show high resolution measurements of a surface plasmon resonance (SPR) sensor based on a rectangular nanohole array in a metal film. This SPR setup uses balanced intensity detection between two orthogonal polarizations of a He-Ne laser beam, which allows for sensitivity improvement, noise reduction and rejection of any uncorrelated variation in the intensity signal. A bulk sensitivity resolution of 6.4 x 10(-6) RIU is demonstrated. The proposed methodology is promising for applications in portable nanoplasmonic multisensing and imaging.
[Paraneoplastic bullous dermatoses]. (1990)

The author analyzes the clinical data and paraclinical characteristics of patients with paraneoplastic bullous dermatoses, followed up at the Research Institute of Skin and Sexually Transmitted Diseases in the town of Gorki since 1980. Clinical features of Duhring's paraneoplastic dermatoses were detected, consisting in dissemination of the process with involvement of facial skin and with essential itching. Paraclinical characteristics are as follows: neither eosinophils, nor acantholytic cells are detectable in the vesicular contents, Jadassohn's test is negative, histomorphologic examination shows intraepidermal localization of the vesicle. In paraneoplastic pemphigus involvement of the mucosae alone was recorded, and the painful syndrome whose severity did not correlate with the depth of the pathologic foci; corticosteroid therapy has proved ineffective. The author recommends thorough examinations of patients with bullous dermatoses if they present with the aforesaid clinical and paraclinical characteristics.
Expression of the adenovirus E1A oncogene during cell transformation is sufficient to induce susceptibility to lysis by host inflammatory cells. (1986)

Mammalian cells transformed by nononcogenic human adenoviruses exhibit high susceptibility to destruction by host mononuclear inflammatory cells. We have analyzed the viral gene regulation of the susceptibility of transformed cells to lysis by natural killer cells and activated macrophages. Comparisons of target cell lines transformed by overlapping segments of the adenovirus E1-transforming gene region revealed that isolated expression of a single oncogene, E1A, was sufficient to cause increased cytolytic susceptibility in the absence of detectable transformed cell-surface expression of viral transplantation antigens and irrespective of histocompatibility antigen identity between killer cells and target cells. These results suggest that oncogene functions that are not linked to the expression of previously recognized cell-surface target structures may actively induce neoplastic cell elimination by components of the host immune surveillance system.
Roles of Stem Cell Factor/c-Kit and Effects of Glivec®/STI571 in Human Uveal Melanoma Cell Tumorigenesis (2004)

The B-Raf(V599E)-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409-42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of (V599E)B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of (V599E)B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.
Time-dependent CYP inhibition (2007)

Time-dependent inhibition (TDI) of CYP refers to a change in potency during an in vitro incubation or dosing period in vivo. Potential mechanisms include the formation of inhibitory metabolites and mechanism-based inhibition (MBI). In vitro experiments are configured to assess TDI and MBI is inferred, at least initially. MBI is more profound after multiple-dosing and the recovery period is independent of continued drug exposure. Advances in in vitro-in vivo extrapolations for competitive inhibition and the potential relationship between MBI and reactive metabolite-mediated toxicity, have redirected emphasis to CYP TDI. In contrast, with reversible inhibition, strategies for projecting the risks from TDI are less developed and the traditional I/K(i) model often yields a dramatic underprediction. This review explores the contribution of TDI to drug-drug interactions and idiosyncratic drug toxicity.
Neoplastic reversion accomplished by high efficiency adenoviral-mediated delivery of an anti-ras ribozyme. (1995)

Strategies have been developed to abrogate the aberrant expression of dominant oncogenes as a means to accomplish targeted tumor eradication. We have demonstrated previously the utility of this approach using a hammerhead ribozyme designed to cleave the mutant sequence in codon 12 of the activated H-ras oncogene transcript. To develop this strategy into a practical means to approach malignant disease, methods must be developed to accomplish high efficiency delivery of the ribozyme to target neoplastic cells. To accomplish this, a recombinant adenovirus was designed that encoded a gene cassette for the H-ras ribozyme. By using this virus, it was possible to accomplish high efficiency reversion of the neoplastic phenotype in mutant H-ras expressing tumor cells without the need for any selection steps. The demonstration of the utility of adenoviral-mediated delivery of anticancer ribozymes will allow the practical development of gene therapy strategies on this basis.
Cell-Free DNA in Human Blood Plasma (1998)

The amount of non-cell-associated DNA free in blood plasma from pancreatic cancer patients usually exceeds that from healthy donors. We have evaluated the plasma DNA by gel electrophoresis and measured the variation in length of soluble DNA fragments by electron microscopy in plasma from three patients with pancreatic cancer and from three healthy controls. Whereas electrophoresis of nick-translated DNA isolated from plasma obtained from healthy controls showed autoradiographic bands at sizes equivalent to whole-number multiples (1-5x) of nucleosomal DNA (185-200 bp), in the samples obtained from pancreatic cancer patients, stronger ladder patterns appeared. Likewise, strand length distributions of DNA (DNA-SL) in the two groups differ. The DNA-SL distribution data include 2,752 measurements made from cancer patient plasma and 3,291 for control plasma. The shortest DNA-SL measured approximately 30 nm (approximately 88 bp calculated at 0.34 nm/bp) and the largest approximately 28,000 nm (>80,000 bp), with 50% of all lengths measuring between 100 and 900 nm long. The average plasma DNA-SL in controls (311 nm; median, 273 nm) exceeded that in cancer patients (231 nm; median, 185 nm). Small excesses of DNA at approximately 63, approximately 126, approximately 189, approximately 252, and approximately 315 nm, corresponding to small multiples of lengths associated with nucleosomes, were more prominent in the cancer patient plasma than in the healthy control plasma. This study provides evidence indicating differences in non-cell-associated DNA in plasma between cancer patients and healthy controls and indicates that a significant amount of this DNA is probably derived from apoptosis in neoplastic and/or normal cells.