gebhart/patrepeval huggingface dataset:
Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study (2017)

Background:Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.Methods:In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (&amp;gt;4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation:These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding: AB Science (Paris, France)
Crystal and molecular structure of viridin (1972)

The title compound crystallises in the orthorhombic system, space group P212121, with a= 16·090, b= 16·162, c= 6·195 Å. The crystal structure has been determined by statistical methods from a three-dimensional X-ray study based on 1580 visually estimated reflection intensities, and refined to a final R value of 0·092. The method of structure solution, and the conformation and geometry of the molecule are discussed in some detail, especially the unique combination of an aromatic ring C and an unsaturated ring E.
Data from Preclinical Efficacy of the Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab in a Mouse Brain Orthotopic Glioma Model Evaluated by Bioluminescence, PET, and MRI (2023)

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 × 10&lt;sup&gt;5&lt;/sup&gt; U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[&lt;sup&gt;18&lt;/sup&gt;F]fluoro-2-deoxy-d-glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate. &lt;i&gt;Clin Cancer Res; 19(20); 5711–21. ©2013 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;
Shared N-terminal sequences in monclonal IgMkappa and IgGkappa proteins from a patient with a complex multiple paraprotein disorder. (1979)

The N-terminal sequence analyses were performed on the heavy (H) and light (L) chains of the idiotypically identical IgM kappa and IgG kappa paraproteins isolated from the serum of patient, Cam. The N-terminal 39 residues of the kappa chains of the IgM and IgG were identical and belonged to the human V kappa III subgroup. This sequenced stretch included the first L chain hypervariable region. The N-terminal 27 residues of the variable regions (VH) of the respective mu and gamma heavy chains were also identical and belonged to the human VHIII subgroup. These identical VH sequences were unique with lysine residues at positions 13 and 19. This dual lysine substitution has not been seen in 37 other human VHIII sequences reported in the literature. This N-terminal sequence homology in the V-regions of Cam IgM kappa and IgG kappa paraproteins and the shared idiotypy expressed by Cam IgM, IgG, and IgA proteins strongly suggest the existence of complete structural homology in the variable regions of the and L chains of these Ig molecules of three separate Ig classes. At the cellular and genetic level, these results point toward a common clonal origin for the idiotypically related Ig molecules and suggest that identical V-region (VH and VL) genes were utilized by the Cam lymphoid clone in the biosynthesis of the respective IgM, IgC, and IgA proteins.
Pharmacophore Mapping in the Laulimalide Series:  Total Synthesis of a Vinylogue for a Late-Stage Metathesis Diversification Strategy (2006)

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.
Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function. (1996)

The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1 (IL-1) was tested by gene transfer in cells expressing only the type I receptor (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1 in terms of NFkappaB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1 beta. Hence defective IL-1 responsiveness of RII-transfected cells requires surface expression of the molecule. RII-transfected cells showed normal responsiveness to TNF, which shares functional properties and elements in the signal transduction pathway with IL-1. Cells transfected with a deletion mutant of RII missing 26 of 29 amino acids of the cytoplasmic portion of the molecule showed impaired responsiveness to IL-2. Cells transfected with full-length or the cytoplasmic deletion mutant of RII released copious amounts of RII in the supernatant. However, transfected cells showed defective responsiveness to brief exposure to IL-1, in the absence of measurable released RII. These results indicate that impairment of the responsiveness to IL-1 following RII gene transfer was dependent upon surface expression of the molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by antiinflammatory signals, whose only known function is to capture and block IL-1.
CHARACTERISTICS OF HETEROEPITAXIALLY GROWN Y₂O₃FILMS BY r-ICB FOR VLSI (1996)

-based metal-insulator-semiconductor (MIS) structure on p-Si(100) has been studied. Films were prepared by UHV reactive ionized cluster beam deposition (r-ICBD) system. The base pressure of the system was about -9/ Torr and the process pressure Torr in oxygen ambience. Glancing X-ray diffraction(GXRD) and in-situ reflection high energy electron diffracton(RHEED) analyses were performed to investigate the crystallinity of the films. The results show phase change from amorphous state to crystalline one with increasingqr acceleration voltage and substrate temperature. It is also found that the phase transformation from (111)//Si(100) to (110)//Si(100) in growing directions takes place between and . Especially as acceleration voltage is increased, preferentially oriented crystallinity was increased. Finally under the condition of above substrate temperature and acceleration voltage 5kV, the films are found to be grown epitaxially in direction of (1l0)//Si(100) by observation of transmission electron microscope(TEM). Capacitance-voltage and current-voltage measurements were conducted to characterize Al//Si MIS structure with varying acceleration voltage and substrate temperature. Deposited films of thickness of nearly 300 show that the breakdown field increases to 7~8MV /cm at the same conditon of epitaxial growing. These results also coincide with XPS spectra which indicate better stoichiometric characteristic in the condition of better crystalline one. After oxidation the breakdown field increases to 13MV /cm because the MIS structure contains interface silicon oxide of about 30. In this case the dielectric constant of only layer is found to be 15.6. These results have demonstrated the potential of using yttrium oxide for future VLSI/ULSI gate insulator applications.
Power density and efficiency optimization of resonant and phase-shift telecom DC-DC converters (2008)

Power density and efficiency are one of the major driving forces in the development of new power supplies for telecommunication and information industry. The phase-shift PWM and the series-parallel resonant DC-DC converter are promising topologies that can meet these demands at high power rates. Based on conventional criteria such as the number of semiconductors/passive components or voltage/current stress it is not possible to identify the topology that offers a higher power density or efficiency. Therefore, an optimization procedure has been developed, which calculates the optimal converter parameters (e.g. switching frequency or transformer design) with respect to the maximal power density and/or efficiency. This procedure is based on detailed analytical models for the converter, semiconductor losses, HF losses in the magnetic components as well thermal and geometrical models of the transformer. With the procedure a 5 kW series-parallel resonant converter and a phase shift converter with capacitive output and with current doubler have been optimized. With the calculated parameters a resonant converter prototype has been constructed and experimental results are presented.
Th1 bias and gender differences in the ex vivo functional capacity of human NKT cells. (89.17) (2010)

Abstract Human NKT cells are a unique T cell subset capable of producing Th1, Th2, or Th17 cytokines. It is hypothesized that the composite cytokine profile of the NKT cell compartment may determine disease pathogenesis. In order to define the functional signature of individual human NKT cells ex vivo with greater resolution, we FACS-Aria sorted NKT cells from fresh PBMC of 12 healthy donors and assessed their functional profiles, on both a population and single cell level, using Luminex and Elispot platforms, respectively. The purified NKT cell populations produced seven of the 14 analytes measured by Elispot, including IL2, IL4, IFNγ, TNFα, MIP1α, MIP1β, and perforin. Surprisingly, IL5, IL6, IL10, and IL17 were not detected from any subjects, and only one subject’s NKT cells produced IL13. Comparison of Elispot numbers with the distribution of several circulating NKT subsets revealed a significant positive association between the percentage of CD4/CD8 Double Negative cells and the number of perforin-secreting cells. NKT functional profiles of age-matched subjects revealed significantly higher frequencies of Th1-producing cells in male donors. These results suggest that 1) the panoply of human NKT Th2 and Th17 responses may not be as pronounced as previously believed, and 2) NKT cells may contribute to the sex bias found in autoimmune and other diseases.
In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators (2018)

Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The <i>Arabidopsis thaliana</i> immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar <i>N</i>B-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the <i>N</i>B-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, <i>At psl5-1</i>. We propose <i>Arabidopsis thaliana</i> as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.
Sheepdog (2004)

Technical support procedures are typically very complex. Users often have trouble following printed instructions describing how to perform these procedures, and these instructions are difficult for support personnel to author clearly. Our goal is to learn these procedures by demonstration, watching multiple experts performing the same procedure across different operating conditions, and produce an executable procedure that runs interactively on the user's desktop. Most previous programming by demonstration systems have focused on simple programs with regular structure, such as loops with fixed-length bodies. In contrast, our system induces complex procedure structure by aligning multiple execution traces covering different paths through the procedure. This paper presents a solution to this alignment problem using Input/Output Hidden Markov Models. We describe the results of a user study that examines how users follow printed directions. We present Sheepdog, an implemented system for capturing, learning, and playing back technical support procedures on the Windows desktop. Finally, we empirically evalute our system using traces gathered from the user study and show that we are able to achieve 73% accuracy on a network configuration task using a procedure trained by non-experts.
Exploiting high-throughput cell line drug screening studies to identify candidate therapeutic agents in head and neck cancer (2014)

HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type.
Mixing at Low Reynolds Numbers by Vibrating Cantilevered Ionic Polymers (2007)

The objective of this research was to develop a novel active device for laminar mixing. The mixing device developed herein capitalized on Nafion ionic polymers, which are a class of active materials that are thin, flexible, inexpensive, and readily deployable in an aqueous medium and offer strains up to 5% under a small (&lt;2V) applied voltage. The effect of these deflections on an incident laminar flow is the mixing mechanism explored in this effort. To the author’s knowledge, this high-risk effort presented herein is the first attempt to exploit ionic polymers as an active mixing device. Several different configurations of ionic polymers were tested and Digital Particle Image Velocimetry (DPIV) measurements were obtained. Resulting analysis using a quantitative mixing metric shows that the polymer creates differences in the flow under some of the configurations. Namely, in some actuation cases, a clear increase in mixing potential is observed in the near-polymer regions. Compared to a simple channel increases in mixing potential that ranged from 150% to over 300% were measured. Although these differences are present, they do not appear consistently in the results. However, only a partial set of flow information was obtained from DPIV, and an improved understanding of the effect of these polymers could be developed from additional experiments. Using ionic polymers for laminar mixing could foster the development of a new generation of efficient micromixing devices, which will improve the capabilities and effectiveness of numerous microfluidic technologies that range across biomedical, lab-on-a-chip, separation and sorting technologies and many more.
A High-Throughput Methodology for Identifying Molecular Targets Overexpressed in Lung Cancers (2003)

As discussed in previous chapters, lung cancer is one of most deadly diseases and conventional treatments for lung cancer patients are largely ineffective. Presented with at least four major histological types oflung cancers, dependable tools for early detection and diagnosis of each type oflung cancers are urgently needed. This chapter focuses on a high-throughput methodology for identifying new molecular targets in lung cancers and these targets will potentially provide diagnostic and therapeutic values for lung cancer patients (1). Previous studies have reported several lung cancer markers including carcinoembryonic antigen (CEA), urokinase plasminogen activator, squamous cell carcinoma antigen (SCC), cytokeratin 19 fragment (CYFRA 21.1) (2–4), PGP 9.5 (5), and RACS1 (6); however, there is room for much improvement in this area.
Ultrasound-modulated fluorescent contrast agent for optical imaging through turbid media (2011)

Optical imaging in a highly scattering medium is effective only at very shallow depths which limits its use as a diagnostic tool in biomedical imaging. By combining optical and acoustic modalities, high-contrast, physiologicallyrelevant optical information at higher spatial resolutions can be achieved. Hybrid imaging modalities such as acoustooptic and photoacoustic imaging improve resolution over conventional optical imaging, but tissue scattering results in poor signal-to-background ratios especially in deeper tissues. To overcome these challenges, we have developed a novel microbubble (MB) contrast agent surface-loaded with a self-quenching fluorophore. In response to ultrasound, the MB expands and contracts, generating changes in fluorophore surface density. The changes in physical separation between fluorophores modulate the quenching efficiency and produce a fluorescence intensity modulation. To our knowledge, this is the first experimental demonstration of ultrasound modulation of fluorescence using a self-quenching MB scheme. The modulation is spatially localized to the ultrasound focal zone where the pressure is greatest and the largest MB oscillations are induced. The modulated signal can be extracted from a large constant light background, increasing detection sensitivity. This technique can enable sensitive optical imaging with ultrasound-scale sub-millimeter spatial resolution, overcoming significant challenges of optical imaging in deep tissue. The contrast agent MBs were prepared with a shell of phospholipid and lipophilic self-quenching fluorophore. MB ultrasound response was studied in a custom setup which monitored fluorescence emitted from an insonified sample. Fluorescence signals displayed clearly modulated intensity and the fast Fourier transform (FFT) showed a strong component at the ultrasound driving frequency.
Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir® drug product (2005)

Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis.