gebhart/patrepeval huggingface dataset:
The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase (2012)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that, when genetically altered by mutation, amplification, chromosomal translocation or inversion, has been shown to play an oncogenic role in certain cancers. Small molecule inhibitors targeting the kinase activity of ALK have proven to be effective therapies in certain ALK-driven malignancies and one such inhibitor, crizotinib, is now approved for the treatment of EML4-ALK-driven, non-small cell lung cancer. In neuroblastoma, activating point mutations in the ALK kinase domain can drive disease progression, with the two most common mutations being F1174L and R1275Q. We report here crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations. Also included are crystal structures of ALK in complex with novel small molecule ALK inhibitors, including a classic type II inhibitor, that stabilize previously unobserved conformations of the ALK activation loop. Collectively, these structures illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R1275Q mutation. The novel active site topologies presented here may also aid the structure-based drug design of a new generation of ALK inhibitors.
Expressive genomic hybridisation: gene expression profiling at the cytogenetic level (2003)

This technique will assist in the analysis of overexpressed genes within amplicons and could resolve a controversial issue in cancer cytogenetics; namely, the relation between genetic amplifications and overexpression.
Peptide‐Based Biomimetic Materials (2010)

This chapter contains sections titled: Introduction Peptides as Building Blocks for the Bottom-up Fabrication of Various Nanostructures Peptide–Inorganic Hybrids Applications of Peptide Biomimetic Nanomaterials Conclusions and Perspectives References
MRI monitoring of laser ablation using optical flow (1998)

The optical flow method is used for visualizing and quantifying the dynamics of tissue changes observed by MRI during thermal ablations. An approach was implemented for parallel two-dimensional optical flow calculations including the replacement of spurious velocities. Velocity magnitude results were found to be accurate in low-noise cases in tests using series of synthetic images. Optical flow results are presented from thermal ablation experiments utilizing a homogeneous polyacrylamide gel phantom and heterogeneous rabbit liver tissue in vivo, exhibiting heating and cooling with the accompanying quantitative characterization of the dilation and contraction of the thermally affected region. Results demonstrate that optical flow is capable of noninvasive real-time monitoring and control of interstitial laser therapy (ILT).
Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity (2000)

Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-gamma production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.
Violene/Cyanine Hybrids: A General Structure for Electrochromic Systems (1999)

Reversible redox systems for electrochromics with closed-shell colored species are provided by a combination of violene and cyanine structure types according to a general scheme shown in the figure.
Establishment of PCR for the early diagnosis of herpes simplex encephalitis (1990)

The early detection of herpes simplex encephalitis (HSE) represents a major problem in viral diagnostics. We have now established a test system based on PCR for the specific amplification of HSV-DNA in cerebrospinal fluid (CSF) samples followed by oligonucleotide hybridization. The test proved to be very sensitive. Five molecules of HSV 1 DNA still yielded positive signals after hybridization. The assay was applied to CSF samples from 6 patients with confirmed HSE. All except one CSF sample obtained from the 2nd to the 8th day after onset of neurological symptoms yielded positive results. The primers used also exhibit a certain degree of crossreactivity with HSV 2, as revealed by testing of a CSF sample from an HSV 2-infected child. No positive signals were obtained with human DNA and with DNA from CMV- and VZV-infected fibroblasts. Also 42 CSF samples of patients suffering from other diseases of the CNS yielded negative results. The present results indicate that the detection of HSV DNA in CSF by PCR represents a valuable tool for the early diagnosis of HSE.
Calcitonin gene-related peptide receptor antagonists for migraine (2010)

CGRP receptor antagonists will provide an additional and valuable therapeutic option for the treatment of headaches.
DTB Project: A Behavioral Model for Detecting Insider Threats (2005)

This paper describes the Detection of Threat Behavior (DTB) project, a joint effort being conducted by George Mason University (GMU) and Information Extraction and Transport, Inc. (IET). DTB uses novel approaches for detecting insiders in tightly controlled computing environments. Innovations include a distributed system of dynamically generated document-centric intelligent agents for document control, object oriented hybrid logic-based and probabilistic modeling to characterize and detect illicit insider behaviors, and automated data collection and data mining of the operational environment to continually learn and update the underlying statistical and probabilistic nature of characteristic behaviors. To evaluate the DTB concept, we are conducting a human subjects experiment, which we will also include in our discussion.
Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration‐resistant prostate cancer in a mouse xenograft model (2009)

Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis.
Dead Bugs Don’t Mutate: Susceptibility Issues in the Emergence of Bacterial Resistance (2003)

The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.
Fabrication of high-aspect-ratio PZT thick film structure using sol-gel technique and SU-8 photoresist (2003)

An optimized sol-gel process and an SU-8 photoresist were used to produce thick and high-aspect-ratio lead zirconate titanate (PZT) structures on platinized silicon substrates. The fabrication process involved single coating, lapping of the gel, and rapid firing. The PZT structures made with this new process were crack-free and had good crystallinity. Their XRD patterns and ferroelectric properties showed that the structures were high quality PZT. Values of relative permittivity and dielectric loss of the PZT were over 300 and 0.03, respectively. The structures had thickness of 20 /spl mu/m or higher, and had aspect ratio of over one.
Using a stochastic context-free grammar as a language model for speech recognition (2002)

This paper describes a number of experiments in adding new grammatical knowledge to the Berkeley Restaurant Project (BeRP), our medium-vocabulary (1300 word), speaker-independent, spontaneous continuous-speech understanding system. We describe an algorithm for using a probabilistic Earley parser and a stochastic context-free grammar (SCFG) to generate word transition probabilities at each frame for a Viterbi decoder. We show that using an SCFG as a language model improves the word error rate from 34.6% (bigram) to 29.6% (SCFG), and the semantic sentence recognition error from from 39.0% (bigram) to 34.1% (SCFG). In addition, we get a further reduction to 28.8% word error by mixing the bigram and SCFG LMs. We also report on our preliminary results from using discourse-context information in the LM.
In vivo immunomodulation by monoclonal anti-CD4 antibody. II. Effect on T cell response to myelin basic protein and experimental allergic encephalomyelitis. (1988)

In vivo administration of anti-CD4 mAb (GK1.5) has been shown to be effective in preventing acute and relapsing experimental allergic encephalomyelitis (EAE). In the present report we have studied the depletion of CD4+ cells by a single dose of GK1.5 on the immune response to myelin basic protein and in the development of EAE. Our studies show that depletion of CD4 cells in mice that had received encephalitogenic CD4+ T cells altered the kinetics of acute and relapsing EAE, but did not prevent disease altogether. The in vitro T cell proliferative response to myelin basic protein in lymph node cells was maintained in the presence of significant depletion of CD4+ cells. These studies indicate that the population of Ag-reactive cells to be large and relatively refractory to antibody therapy. The implication of these results to therapy of human autoimmune disease is discussed.
A BRCA1 mutant alters G2-M cell cycle control in human mammary epithelial cells. (1997)

Mutations in BRCA1 increase the risk of breast and ovarian cancer. Although the mechanism by which mutant BRCA1 alters growth regulation is unknown, the COOH terminus of BRCA1 appears to play a critical role. To examine this, we introduced a vector expressing BRCA1 COOH-terminal residues 1293-1863 (CT-BRCA1) into nontumorigenic human breast epithelial cells. Overexpression of CT-BRCA1 led to a reduction in the doubling time (from 64 to 44 h) and a decreased reliance on growth factors, suggesting that this CT-BRCA1 may function in a dominant-negative manner. Expression of CT-BRCA1 induced alterations in cell cycle control, mainly in G2-M, including a loss of G2-M block by colchicine. These results suggest that one function of BRCA1-related growth control occurs by governing checkpoint(s) between DNA replication and mitosis.
Endothelial lipase provides an alternative pathway for FFA uptake in lipoprotein lipase–deficient mouse adipose tissue (2005)

Lipoprotein lipase (LPL) is thought to be the only enzyme responsible for the catabolism of triglycerides (TGs) associated with TG-rich lipoproteins in adipose tissue (AT). However, LPL deficiency in humans and induced mutant mice is not associated with decreased fat mass. We investigated whether endothelial lipase (EL), a recently discovered phospholipase, might represent an alternative mechanism for the uptake of phospholipid-derived fatty acids in murine lipoprotein-deficient AT. When LPL was expressed in AT and isolated murine adipocytes, EL mRNA was not detectable. In contrast, mouse AT and isolated adipocytes that lacked LPL expressed large amounts of EL mRNA. The cellular phospholipase activity in LPL-deficient fat pads was increased 4-fold compared with control fat pads and could be inhibited to control levels by a specific EL antibody. Fatty acids produced by EL activity were absorbed by adipocytes and incorporated into the TG moiety of AT. Our results suggest that EL activity in AT and other peripheral tissues might contribute to the tissue uptake of free fatty acids, which could have important implications for the metabolism of plasma lipoproteins.
Subsystem Fault Tolerance with the Bacon-Shor Code (2007)

We discuss how the presence of gauge subsystems in the Bacon-Shor code [D. Bacon, Phys. Rev. A 73, 012340 (2006)10.1103/PhysRevA.73.012340 (2006)] leads to remarkably simple and efficient methods for fault-tolerant error correction (FTEC). Most notably, FTEC does not require entangled ancillary states, and it can be implemented with nearest-neighbor two-qubit measurements. By using these methods, we prove a lower bound on the quantum accuracy threshold, 1.94 x 10(-4) for adversarial stochastic noise, that improves previous lower bounds by nearly an order of magnitude.
Comparative effects of pacing-induced and balloon coronary occlusion ischemia on left ventricular diastolic function in man. (1991)

The upward shift of the diastolic LV P-RL plot, which was used as an index of decreased regional diastolic LV distensibility, was larger immediately after pacing than at the end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for a decrease in diastolic distensibility of the ischemic segment because of the higher %SS of the ischemic segment immediately after pacing, and because of the correlation at the end of CO between the upward shift of the diastolic LV P-RL plot and %SS of the ischemic segment.
Somatic glypican 3 (GPC3) mutations in Wilms' tumour (2002)

Tumour and normal tissue from 41 male cases of Wilms' tumour were screened to determine the presence of sequence variants in the glypican 3 (GPC3) gene. Two non-conservative single base changes were present in tumour tissue only. These findings imply a possible role for GPC3 in Wilms' tumour development.
The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia (1993)

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.
The Middelheim Frontality Score: a behavioural assessment scale that discriminates frontotemporal dementia from Alzheimer's disease (2004)

The MFS is a clinical and behavioural assessment scale that measures frontal lobe features and that was shown to reliably discriminate FTD from AD patients.
Nanoparticle Delivery of Mycophenolic Acid Upregulates PD-L1 on Dendritic Cells to Prolong Murine Allograft Survival (2011)

Conventional immunosuppressive drug delivery requires high systemic drug levels to provide therapeutic benefit, but frequently results in toxic side effects. Novel drug delivery methods, such as FDA-approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), are promising drug delivery platforms to reduce drug doses and minimize toxicity. Using murine models of skin transplantation, we investigated whether PLGA NPs would effectively deliver mycophenolic acid (MPA), a common clinical immunosuppressant, and avoid the toxicity of conventional drug delivery. We found that intermittent treatment with NPs encapsulated with MPA (NP-MPA) resulted in a significant extension of allograft survival than intermittent conventional MPA treatment even though the concentration of MPA within NP-MPA was a 1000-fold lower than conventional drug. Importantly, recipients who were administered NP-MPA intermittently avoided drug toxicity, whereas those treated with daily conventional drug manifested cytopenias. Dendritic cells (DCs) endocytosed NP-MPA to upregulate programmed death ligand-1 (PD-L1) and displayed a decreased ability to prime alloreactive T cells. Importantly, the ability of NP-MPA to promote allograft survival was partly PD-L1 dependent. Collectively, this study indicates that NPs are potent drug delivery tools that extend allograft survival without drug toxicity. Conventional immunosuppressive drug delivery requires high systemic drug levels to provide therapeutic benefit, but frequently results in toxic side effects. Novel drug delivery methods, such as FDA-approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), are promising drug delivery platforms to reduce drug doses and minimize toxicity. Using murine models of skin transplantation, we investigated whether PLGA NPs would effectively deliver mycophenolic acid (MPA), a common clinical immunosuppressant, and avoid the toxicity of conventional drug delivery. We found that intermittent treatment with NPs encapsulated with MPA (NP-MPA) resulted in a significant extension of allograft survival than intermittent conventional MPA treatment even though the concentration of MPA within NP-MPA was a 1000-fold lower than conventional drug. Importantly, recipients who were administered NP-MPA intermittently avoided drug toxicity, whereas those treated with daily conventional drug manifested cytopenias. Dendritic cells (DCs) endocytosed NP-MPA to upregulate programmed death ligand-1 (PD-L1) and displayed a decreased ability to prime alloreactive T cells. Importantly, the ability of NP-MPA to promote allograft survival was partly PD-L1 dependent. Collectively, this study indicates that NPs are potent drug delivery tools that extend allograft survival without drug toxicity.
Gene Therapy Technologies, Applications and Regulations (1999)

Gene Therapy Technologies, Applications and Regulations From Laboratory to Clinic Edited by Anthony Meager Division of Immunobiology, The National Institute for Biological Standards and Control, South Mimms, UK The development of gene-based technologies has been rapid over the past decade and has consequently resulted in a surge of interest in human gene therapy, the deliberate transfer of genes to somatic cells to cure or alleviate disease symptoms. Hundreds of clinical protocols involving variously designed vectors for efficient gene transfer have been developed. However, the use of such complex 'gene medicines' containing potentially heritable genes has raised numerous concerns regarding quality, efficacy and safety. Encompassing recent developments in the field and addressing current concerns this book:<br> * surveys many of the current technologies for preparing vectors for use in gene therapy protocols<br> * reviews the application of gene-mediated therapies to a range of medical conditions<br> * considers the regulatory aspects of gene therapy including product quality and safety requirements<br> * appraises the transfer of technologies from laboratory to clinic with regard to the attendant requirements and facilities for:<br> * good laboratory practice (GLP) conditions in the R&D laboratory<br> * large-scale production methods and good manufacturing practice (GMP)<br> * current in-process and final product testing<br> <br> Written by international experts knowledgeable about many aspects of human somatic gene therapy, this book will be an essential guide for those embarking on gene therapy technologies relevant to specifications of production and testing of products (and procedures) required to meet existing regulations, including quality, efficacy and safety considerations.
Drying as an immiscible displacement process with fluid counterflow (1987)

Experiments with refractive-index--matched materials show that evaporation of a liquid from a porous medium produces a modified form of immiscible displacement. In this process the displaced fluid is removed from the pore structure by counterflow in the same pore channels as the displacing fluid. Pressure gradients that arise from fluid flow result in displacement fronts that, unlike conventional displacement fronts, are inherently stable irrespective of the relative viscosities of the fluids.
Genetically engineered E. coli as a protein delivery vehicle for killing cancer cells. (2004)

Extract: The beneficial effects of bacteria on rejection of and resistance to tumors have been observed since the 18th century. Physicians have recorded hundreds of cases of spontaneous regression of many types of cancer following bacterial infections, such as staphylococcal or mixed infections, or bacterial vaccines. For example, significantly lower recurrence and number of metastases were recorded in sarcoma patients with concurrent streptococcal infection occurring either spontaneously or by inoculation. More recently, a decreased incidence of malignancy has been recorded in areas or subsets of populations where infectious diseases are endemic. For example, a Swiss study of hospitalized patients over a 20 year period recorded that the previous incidence of acute infections and acute inflammatory episodes was almost nil in groups of cancer patients, compared with a much higher incidence in the non-cancerous groups. Studies in the 1960s with Clostridium showed that this anaerobic bacterium could selectively target and grow inside experimental tumors in mice, leading to tumor regression. However, clinical trials with Clostridium had to be abandoned due to severe toxicities. In the last few years interest in using bacteria as cancer therapies has been reignited. Advances in genetic engineering have enabled modifications of bacteria to reduce toxicity, however, clinical trials with attenuated bacteria such as Salmonella have failed to provide therapeutic benefits that outweigh toxicities in cancer patients.