gebhart/patrepeval huggingface dataset:
Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor (2009)

3542 Background: PX-866 is an orally available nanomolar pan-inhibitor of PI-3K whose administration results in antitumor activity and pathway (AKT, S6 and mTOR) inhibition in animal models. Loss of PTEN and/or PI 3K mutations have been associated with enhanced susceptibility to PX-866. PX-866 is being evaluated in a phase 1 clinical trial to determine the MTD, and measure safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in PBMCs and tumor tissue in patients with solid tumors. Methods: Patients with advanced metastatic cancers receive PX-866 orally once daily for 5 of 7 days for 2 weeks in a 28-day cycle. Dose levels of 0.5, 1, 2, 3, 4.5, 6, 8, and 10 mg are planned. PK and PD samples are collected days 1, 2, 5, 8, 12, and 15 of cycle one and days 1 and 12 of cycle two. A PD assay has been developed that utilizes flow cytometry to test the inhibition of S6RP and mTOR in PBMC. Once the MTD of this PX-866 schedule of administration has been identified, an expansion cohort is planned to investigate tumor PD events and correlate tumor and PBMC endpoints with efficacy. Results: Four cohorts (0.5, 1, 2, 3 mg) comprising 12 patients (age 42–74, median PS 1) have completed accrual, with the 4.5 mg cohort actively enrolling. The total number of cycles to date is 30 (median 2, range 1–5+). Abdominal discomfort and mild diarrhea have been possibly associated with PX-866. No drug-related severe adverse events or dose-limiting toxicities have occurred. Of the 6 patients treated in the first 2 cohorts, 3 previously progressing patients had stable disease (SD) as best response and were on study for 105, 147 and 162+ (still active) days. Two patients (squamous cell skin cancer and melanoma) had decrease in pain allowing discontinuation of analgesics. Proof-of-concept PD studies in PBMCs evidenced a dose dependent inhibition of both p-S6RP and p-mTOR levels. Conclusions: PX-866 is a novel oral PI-3K inhibitor that is undergoing development in a clinical trial with built-in PD endpoints. PX-866 has shown to have a mild side effect profile while inducing stabilization of disease in previously progressing cancer patients. Oral PX-866 provides target inhibition even at low drug doses and inhibition is maintained for an extended time following the last dose. Updated clinical, PK and PD results will be presented. [Table: see text]
Scarlett (2011)

To improve data availability and resilience MapReduce frameworks use file systems that replicate data uniformly. However, analysis of job logs from a large production cluster shows wide disparity in data popularity. Machines and racks storing popular content become bottlenecks; thereby increasing the completion times of jobs accessing this data even when there are machines with spare cycles in the cluster. To address this problem, we present Scarlett, a system that replicates blocks based on their popularity. By accurately predicting file popularity and working within hard bounds on additional storage, Scarlett causes minimal interference to running jobs. Trace driven simulations and experiments in two popular MapReduce frameworks (Hadoop, Dryad) show that Scarlett effectively alleviates hotspots and can speed up jobs by 20.2%.
XCIII.—Polynuclear heterocyclic aromatic types. Part I. Some indenoquinoline derivatives (1922)

leads to the conclusion that many aromatic types as yet unknown should be capable of existence, and in the present series of investigations it is proposed to survey the field of the heterocyclic substances from this point of view and with the particular object of throwing light on the conditions underlying the manifestation of the phenomenon of cyclic conjugation. At the present time, authentic derivatives of pentamethine, (CH),, the lower ring homologue of benzene, are
[Immunologic laboratory testing in clinical practice for rheumatoid arthritis]. (2006)

The recent clinical practices for rheumatoid arthritis have changed greatly. First, biologic agents such as tumor necrosis factor blocker have been developed as well as disease-modifying antirheumatic drugs, with great efficacy in intractable RA. On the other hand, the importance of early effective therapeutic intervention has been recognized since early treatment prevents the progression of joint damage. However, early diagnosis of RA is not so easy because of the lack of appropriate diagnostic criteria. New laboratory tests have appeared for the diagnosis and prognostic prediction of RA. Among them, anticyclic citrullinated peptide antibodies (anti-CCP), which bind epitopes containing citrulline, seem to be attracting the most attention. Although rheumatoid factor (RF) is the only serologic marker among the seven classification criteria of the American College of Rheumatology (ACR) for RA, variability of the RF assay within laboratories and/or between laboratories, and quality assurance has not been established. We must address the standardization of RF assay as soon as possible.
Micropatterning Neuronal Cells on Polyelectrolyte Multilayers (2004)

This paper describes an approach to adhere retinal cells on micropatterned polyelectrolyte multilayer (PEM) lines adsorbed on poly(dimethylsiloxane) (PDMS) surfaces using microfluidic networks. PEMs were patterned on flat, oxidized PDMS surfaces by sequentially flowing polyions through a microchannel network that was placed in contact with the PDMS surface. Polyethyleneimine (PEI) and poly(allylamine hydrochloride) (PAH) were the polyions used as the top layer cellular adhesion material. The microfluidic network was lifted off after the patterning was completed and retinal cells were seeded on the PEM/PDMS surfaces. The traditional practice of using blocking agents to prevent the adhesion of cells on unpatterned areas was avoided by allowing the PDMS surface to return to its uncharged state after the patterning was completed. The adhesion of rat retinal cells on the patterned PEMs was observed 5 h after seeding. Cell viability and morphology on the patterned PEMs were assayed. These materials proved to be nontoxic to the cells used in this study regardless of the number of stacked PEM layers. Phalloidin staining of the cytoskeleton revealed no apparent morphological differences in retinal cells compared with those plated on polystyrene or the larger regions of PEI and PAH; however, cells were relatively more elongated when cultured on the PEM lines. Cell-to-cell communication between cells on adjacent PEM lines was observed as interconnecting tubes containing actin that were a few hundred nanometers in diameter and up to 55 microm in length. This approach provides a simple, fast, and inexpensive method of patterning cells onto micrometer-scale features.
Predictive Markers in Breast and Other Cancers: A Review (2005)

Currently, the only recommended predictive markers in oncology are ER and PR for selecting endocrine-sensitive breast cancers and HER-2 for identifying breast cancer patients with metastatic disease who may benefit from trastuzumab. For malignancies other than breast cancers, validated predictive markers do not exist at present.
Specific immune responses of dairy cattle after primary inoculation with recombinant bovine interferon-gamma as an adjuvant when vaccinating against mastitis. (1996)

rBoIFN-gamma may safely enhance specific immunity in the bovine mammary gland and may be an effective adjuvant in mastitis immunization protocols.
Using a topical anaesthetic cream to reduce pain during sharp debridement of chronic leg ulcers (2001)

This multicentre, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of using Emla (lignocaine/prilocaine) anaesthetic cream to achieve pain control during sharp debridement of chronic leg ulcers of arterial, venous or arteriovenous aetiology. A total of 101 patients (51 Emla, 50 placebo), aged 29-99 years, who had experienced pain associated with previous debridement were included. Patients with an amide anaesthetic allergy, anaesthetic diabetic ulcers, or ulcers > 50 cm2 were excluded. Debridement was initiated approximately 30 minutes after the application of a thick layer of Emla or placebo cream to an ulcer occluded with a plastic wrap. The patient and investigator assessed the pain associated with debridement on a 100 mm visual analogue scale (VAS). The median patient VAS scores were 18 mm and 53.5 mm in the Emla and placebo groups, respectively (p < 0.0001). The corresponding investigator values in the two groups were 20 mm and 49.5 mm, respectively (p = 0.004). Local reactions were mainly transient and mild, and were observed in roughly the same percentage of placebo and Emla-treated patients. After a 30-minute application Emla cream significantly reduced the pain of debridement compared with the placebo.
In vivo 3.0‐tesla magnetic resonance T1ρ and T2 relaxation mapping in subjects with intervertebral disc degeneration and clinical symptoms (2010)

The purpose of this study is (1) to determine the correlation between T(1rho) and T(2) and degenerative grade in intervertebral discs using in vivo 3.0-T MRI, and (2) to determine the association between T(1rho) and T(2) and clinical findings as quantified by the SF-36 Questionnaire and Oswestry Disability Index. Sixteen subjects participated in this study, and each completed SF-36 and Oswestry Disability Index questionnaires. MRI T(1rho) and T(2) mapping was performed to determine T(1rho) (77 discs) and T(2) (44 discs) in the nucleus of the intervertebral disc, and T(2)-weighted images were acquired for Pfirrmann grading of disc degeneration. Pfirrmann grade was correlated with both T(1rho) (r = -0.84; P < 0.01) and T(2) (r = -0.61; P < 0.01). Mixed-effects models demonstrate that only T(1rho) was associated with clinical questionnaires (R(2) (SF-36) = 0.55, R(2) (O.D.I.) = 0.56; P < 0.05). Although the averaged values of T(1rho) and T(2) were significantly correlated, they presented differences in spatial distribution and dynamic range, thus suggesting different sensitivities to tissue composition. This study suggests that T(1rho) may be sensitive to early degenerative changes (corroborating previous studies) and clinical symptoms in intervertebral disc degeneration.
Risk factors for persistent disease in papillary thyroid carcinoma with lymph node metastasis (2016)

Despite the presence of LN involvement, most patients may become disease free with therapy. Patients with extrathyroidal invasion, lateral cervical LN involvement, and those at least 45 years old at initial diagnosis are more likely to have persistent disease. However, disease control can be achieved with close clinical follow-up and therapy.
Parabolic Quantitative Structure‐Activity Relationships and Photodynamic Therapy: Application of a Three‐Compartment Model with Clearance to the In Vivo Quantitative Structure‐Activity Relationships of a Congeneric Series of Pyropheophorbide Derivatives Used as Photosensitizers for Photodynamic Therapy (1999)

Abstract An open three‐compartment pharmacokinetic model was applied to the in vivo quantitative structure‐activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K 0+ . The measured octanol‐water partition coefficients, P 1 (where i is the number of carbons in the alkyl chain) and the clearance rate K 0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three‐compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic‐based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose‐response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.
International Arbitration of Patent Disputes, 10 J. Marshall Rev. Intell. Prop. L. 384 (2011) (2011)

This paper discusses the concept of using international arbitration as a method of resolving patent disputes. First, this paper examines the arbitrability of patent validity disputes from a public policy viewpoint. The question is whether, or to what extent, the subject matter of patent validity disputes may be settled by international commercial arbitration. Second, this paper provides suggestions on strategies for organizational decision-makers to consider whether it is proper to choose arbitration as a more favorable tool when confronted with a patent dispute. Finally, this paper discusses how to choose the seat of arbitral institution and the applicable law.
Recent Advances in the Search for the μ-Opioidergic System: The Antinociceptive Properties of Endomorphin-1 and Endomorphin-2 in the Mouse (2002)

Two highly selective mu-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous mu-opioid receptor ligands. The present minireview describes the antinociceptive properties with the tail-flick test of these two ligands given intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in ICR mice. EM-1 or EM-2 given i.c.v. or i.t. dose-dependently produce antinociception. These antinociceptive effects induced by EM-1 and EM-2 given i.c.v. or i.t. are selectively mediated by the stimulation of mu-, but not delta- or kappa-opioid receptors. Like other mu-opioid agonists morphine and DAMGO ([D-Ala2,NMePhe4,Gly5-ol]enkephalin), EM-1 and EM-2 given i.c.v. activate descending pain controls by the releases of noradrenaline and 5-HT and subsequently act on alpha2-adrenoceptors and 5-HT receptors, respectively, in the spinal cord to produce antinociception. However, the antinociception induced by EM-2 given i.c.v. or i.t. also contain an additional component, which is mediated by the release of dynorphin A(1-17) acting on kappa-opioid receptors at the supraspinal and spinal sites. In addition, the antinociception induced by EM-2 given i.c.v. contains another component, which is mediated by the release of Met-enkephalin acting on delta2-opioid receptors in the spinal cord. It is proposed that there are two subtypes of mu-opioid receptors,which are involved in EM-1- and EM-2-induced antinociception. One subtype of mu-opioid receptors is stimulated by EM-1, EM-2 and other mu-opioid agonists morphine and DAMGO; and another subtype of mu-opioid is sorely stimulated by EM-2 and is involved in the releases of dynorphin A(1-17) and Met-enkephalin for the production of antinociception.
Flight Testing of an Advanced Airborne Natural Gas Leak Detection System (2005)

ITT Industries Space Systems Division (Space Systems) has developed an airborne natural gas leak detection system designed to detect, image, quantify, and precisely locate leaks from natural gas transmission pipelines. This system is called the Airborne Natural Gas Emission Lidar (ANGEL) system. The ANGEL system uses a highly sensitive differential absorption Lidar technology to remotely detect pipeline leaks. The ANGEL System is operated from a fixed wing aircraft and includes automatic scanning, pointing system, and pilot guidance systems. During a pipeline inspection, the ANGEL system aircraft flies at an elevation of 1000 feet above the ground at speeds of between 100 and 150 mph. Under this contract with DOE/NETL, Space Systems was funded to integrate the ANGEL sensor into a test aircraft and conduct a series of flight tests over a variety of test targets including simulated natural gas pipeline leaks. Following early tests in upstate New York in the summer of 2004, the ANGEL system was deployed to Casper, Wyoming to participate in a set of DOE-sponsored field tests at the Rocky Mountain Oilfield Testing Center (RMOTC). At RMOTC the Space Systems team completed integration of the system and flew an operational system for the first time. The ANGEL system flew 2 missions/day for the duration for the 5-day test. Over the course of the week the ANGEL System detected leaks ranging from 100 to 5,000 scfh.
Self-referenced spectral phase retrieval of dissimilar optical frequency combs via multiheterodyne detection (2012)

We present a method to independently measure the spectral phase of an optical frequency comb by heterodyning it with a second comb of arbitrarily detuned repetition rate and appropriately processing the resulting electrical frequency comb.
Use of Magnetic Beads in Selection and Detection of Biotoxin Aptamers by Electrochemiluminescence and Enzymatic Methods (2002)

Systematic evolution of ligands by exponential enrichment (SELEX) was used to develop DNA ligands (aptamers) to cholera whole toxin and staphylococcal enterotoxin B (SEB). Affinity selection of aptamers was accomplished by conjugating the biotoxins to tosyl-activated magnetic beads. The use of magnetic beads reduces the volumes needed to perform aptamer selection, thus obviating alcohol precipitation and allowing direct PCR amplification from the bead surface. Following five rounds of SELEX, 5'-biotinylated aptamers were bound to streptavidin-coated magnetic beads and used for the detection of ruthenium trisbypyridine [Ru(bpy)3(2+)]-labeled cholera toxin and SEB by an electrochemiluminescence methodology. A comparison of control (double-stranded) aptamer binding was made with aptamers that were heat denatured at 96 degrees C (single-stranded) and allowed to cool (conform) in the presence of biotoxin-conjugated magnetic beads. Results suggest that control aptamers performed equally well when compared to heat-denatured DNA aptamers in the cholera toxin electrochemiluminescence assay and a colorimetric microplate assay employing peroxidase-labeled cholera toxin and 5'-amino terminated aptamers conjugated to N-oxysuccinimide-activated microtiter wells. Interestingly, however, in the SEB electrochemiluminescence assay, double-stranded aptamers exceeded the performance of single-stranded aptamers. The detection limits of all aptamer assays were in the low nanogram to low picogram ranges.
Managing Hyperkalemia Caused by Inhibitors of the Renin–Angiotensin–Aldosterone System (2004)

Hyperkalemia can develop as a result of treatment with angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers. This side effect is most common in patients with risk factors such as diabetes mellitus, heart failure, chronic kidney disease, or advanced age. This review explains the pathophysiology and offers clinical guidance for management.
Patterns of Protein Accumulation in Developing Anthers of Lilium longiflorum Correlate with Histological Events (1992)

Differentiation in the anther of Lilium longiflorum occurs in discrete stages that correlate well with flower bud length. Using both sodium dodecyl sulfate and two-dimensional polyacrylamide gel electrophoresis, detectable proteins that accumulated during the development of lily anthers were documented. In terms of histology and protein patterns, anther ontogeny was divided into three major phases. Phase I encompassed early proliferative stages as well as the differentiation of the locules. Phase II extended from the onset of meiosis through to mature microspores. Phase III began after microspore mitosis occurred to form pollen. Ten floral organ-enriched and 17 floral organ-specific polypeptides were detected during development. The appearance and disappearance of these polypeptides correlated well with the transitions between phases. Two groups of floral organ-specific proteins in Phase II were chosen for further analysis. Both groups of polypeptides were stamen-specific. The 15.0 kD proteins were anther-specific and were the most abundant floral proteins detected; the 75.0 kD proteins were detected in both the anther and filament.
Benzocycloheptapyridines. Analogs of azatadine (1986)

Abstract Certain 3‐substituted derivatives of cyproheptadine ( 1a ) have been shown to possess potent pharmacological properties. The structural analogy between cyproheptadine and azatadine ( 2 ) prompted the preparation of 9‐substituted derivatives of 2 and its 5,6‐dehydro analog for pharmacological comparison. The 9‐cyano and 9‐trifluoromethylthio derivatives were prepared by direct displacement of the corresponding 9‐bromo compounds. Acid hydrolysis of the nitriles generated the carboxylic acids. Oxidation of the trifluoromethylthio compounds 15a and 18a gave the epoxy sulfones 19a and 19b , which could not be deoxygenated. Therefore, the trifluoromethylsulfonyl moiety was introduced prior to the formation of the exocyclic olefin.
Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components. (1995)

Mycobacterium tuberculosis infection is accompanied by acute and chronic inflammatory infiltrates associated with necrotizing granulomas in lung tissue. The cellular infiltrate is characterized by inflammatory cells which include neutrophils, lymphocytes, and macrophages. In animal and in vitro models of mycobacterial infection, cytokines including tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin-1 beta (IL-1 beta) participate in granulomatous inflammation. We hypothesized that interleukin-3, a potent chemoattractant for neutrophils and lymphocytes, could be released by activated alveolar macrophages after exposure to M. tuberculosis or its components and contribute to granulomatous lung inflammation. A quantitative immunoassay revealed that IL-8 protein release was significantly elevated in supernatants of macrophages and in lavage fluid obtained from patients with pulmonary tuberculosis compared to normal controls. In addition, Northern blots demonstrated striking up-regulation of IL-8 mRNA in macrophages from these patients. M. tuberculosis and its cell wall components lipoarabinomannan (LAM), lipomannan (LM), and phosphoinositolmannoside (PIM) stimulated IL-8 protein release and mRNA expression in vitro from alveolar macrophages, but deacylated LAM did not. Neutralizing antibodies to TNF-alpha and/or IL-1-alpha and beta blocked 83% of the stimulation. IL-8 synthesis and release is an early response of macrophages after phagocytosis of M. tuberculosis. Its production serves to attract both acute and chronic inflammatory cells of active infection and thus participates in the process of containment of the pathogen.