Miracle-dz/UniFAR-FTUs huggingface dataset:
Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.

PURPOSE In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. METHODS Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. RESULTS Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. CONCLUSION The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.
The Genetic Structure of Marijuana and Hemp

Despite its cultivation as a source of food, fibre and medicine, and its global status as the most used illicit drug, the genus Cannabis has an inconclusive taxonomic organization and evolutionary history. Drug types of Cannabis (marijuana), which contain high amounts of the psychoactive cannabinoid Δ 9-tetrahydrocannabinol (THC), are used for medical purposes and as a recreational drug. Hemp types are grown for the production of seed and fibre, and contain low amounts of THC. Two species or gene pools (C. sativa and C. indica) are widely used in describing the pedigree or appearance of cultivated Cannabis plants. Using 14,031 single-nucleotide polymorphisms (SNPs) genotyped in 81 marijuana and 43 hemp samples, we show that marijuana and hemp are significantly differentiated at a genome-wide level, demonstrating that the distinction between these populations is not limited to genes underlying THC production. We find a moderate correlation between the genetic structure of marijuana strains and their reported C. sativa and C. indica ancestry and show that marijuana strain names often do not reflect a meaningful genetic identity. We also provide evidence that hemp is genetically more similar to C. indica type marijuana than to C. sativa strains.
Hyperbaric oxygen therapy reduces renal lactate production

Intrarenal hypoxia is an acknowledged factor contributing to the development of diabetic nephropathy. Hyperbaric oxygen (HBO) therapy is a well‐known adjuvant treatment for several medical conditions, such as decompression sickness, infections, and wound healing. The underlying metabolic response of HBO is largely unknown. In this study, we investigated the effect of HBO on the intrarenal metabolic alteration in diabetes. Hyperpolarized [1‐13C]pyruvate MRI was performed to assess intrarenal energy metabolism in normoglycemic controls and short‐term (2 weeks) streptozotocin‐induced diabetic rats with and without HBO for five consecutive days. HBO therapy blunted intrarenal lactate production, 3 days after the therapy, in both normoglycemic controls and diabetic rats without affecting either lactate dehydrogenase mRNA expression or activity. HBO therapy reduced lactate formation in both normoglycemic and hyperglycemic rats. These findings support hyperpolarized [1‐13C]pyruvate MRI as a novel method for monitoring HBO therapy via the pyruvate to lactate conversion.
High-Temperature Operation of AlGaN/GaN HEMTs Direct-Coupled FET Logic (DCFL) Integrated Circuits

This letter presents the high-temperature performance of AlGaN/GaN HEMT direct-coupled FET logic (DCFL) integrated circuits. At 375 degC, enhancement-mode (E-mode) AlGaN/GaN HEMTs which are used as drivers in DCFL circuits exhibit proper E-mode operation with a threshold voltage (VTH) of 0.24 V and a peak current density of 56 mA/mm. The monolithically integrated E/D-mode AlGaN/GaN HEMTs DCFL circuits deliver stable operations at 375 degC: An E/D-HEMT inverter with a drive/load ratio of 10 exhibits 0.1 V for logic-low noise margin (NML) and 0.3 V for logic-high-noise margin (NMH) at a supply voltage (VDD) of 3.0 V; a 17-stage ring oscillator exhibits a maximum oscillation frequency of 66 MHz, corresponding to a minimum propagation delay ( taupd) of 446 ps/stage at VDD of 3.0 V
AGI-1067: A Multifunctional Phenolic Antioxidant, Lipid Modulator, Anti-Inflammatory and Antiatherosclerotic Agent

To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-α-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC 50values = 6, 10, and 25 μM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.
Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis

Treatment with interferon (IFN)-β1a has been associated with decreased disease activity in patients with multiple sclerosis (MS). In several biological systems, type I IFNs and retinoids have been demonstrated to have synergistic effects. In these studies, we measured blood and cerebrospinal fluid (CSF) retinol levels and naïve and memory T-helper cell subset percentages in samples from a group of patients with MS. We also examined retinol receptor expression in peripheral blood cells from MS patients with or without a history of prior treatment with IFN-β1a. The mean plasma retinol level for untreated relapsing-remitting (RR) MS patients was lower than for patients with noninflammatory neurological disease. Among IFN-β1a-treated RR patients, mean levels were slightly higher than for RR patients not on treatment. Lower plasma retinol levels among the MS patients studied were associated with higher CSF retinol index measurements - a measure that was calculated to correct for nonspecific leakage of retinol from blood into CSF. For the MS samples examined, there was a borderline statistically significant direct correlation between CSF retinol index measurements and CSF memory T-helper cell percentages. Examination of peripheral blood from untreated RR patients for retinoid receptor mRNA expression revealed the expression of the retinoic acid receptor (RAR)-α, RAR-γ, and retinoic X receptor (RXR)-α receptor subtypes. For RR patients on IFN-β1a therapy, expression of the same RAR subtypes was noted as well as expression of RXR-βand RXR-γ. These studies suggest an association between plasma retinol levels and clinical disease activity in patients with MS and that treatment with IFN-β1a may be associated with activation of specific retinoid receptor subtypes.
Focal application of low-dose-rate brachytherapy for prostate cancer: a pilot study

Purpose To evaluate the feasibility and to report the early outcomes of focal treatment of prostate cancer using low-dose-rate brachytherapy (LDR-PB). Material and methods Seventeen patients were screened with multi-parametric magnetic resonance imaging (mpMRI), 14 of whom proceeded to receive trans-perineal template mapping biopsy (TTMB). Focal LDR-PB was performed on five eligible patients using dual air kerma strength treatment plans based on planning target volumes derived from cancer locations and determined by TTMB. Patient follow-up includes prostate specific antigen (PSA) measurements, urinary and sexual function questionnaires, repeated imaging and TTMB at specific intervals post-treatment. Results Feasibility of focal LDR-PB was shown and short-term outcomes are promising. While the detection rate of tumors, a majority of which were low grade GS 3 + 3, was found to be low on mpMRI (sensitivity of 37.5%), our results suggest the potential of mpMRI in detecting the presence of higher grade (GS ≥ 3 + 4), and bilateral disease indicating its usefulness as a screening tool for focal LDR-PB. Conclusions Low-dose-rate brachytherapy is a favorable ablation option for focal treatment of prostate cancer, requiring minimal modification to the standard (whole gland) LDR-PB treatment, and appears to have a more favorable side effect profile. Further investigation, in the form of a larger study, is needed to assess the methods used and the long-term outcomes of focal LDR-PB.
Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings

Objective: To understand the role of epilepsy surgery in children with generalized or bilateral findings on preoperative scalp EEG. Methods: From our pediatric epilepsy surgery series, we identified 50 patients in whom 30 to 100% of preoperative epileptiform discharges (ictal, interictal, or both) were generalized or contralateral to the side of surgery. Results: All patients had severe refractory epilepsy and an epileptogenic lesion on brain MRI. Ninety percent of the lesions were congenital, perinatal, or acquired during infancy, predominantly malformations of cortical development (44%) or cystic encephalomalacia (40%). Age at surgery was 0.2 to 24 (median 7.7) years. Surgeries were hemispherectomy (64%) or lobar or multilobar resection. At last follow-up (median 24.0 months), 72% of patients were seizure-free, 16% had marked improvement with only brief episodes of staring or tonic stiffening, and 12% were not improved. The rate of seizure-free outcome was not significantly associated with age at seizure onset or surgery, presence of hemiparesis or focal clinical features during seizures, type of lesion, or surgery type. Postoperative seizure-free rate did not differ from that in a comparison group of similar patients who matched the study group except for their high percentage (70 to 100%) of ipsilateral ictal and interictal epileptiform discharges on preoperative EEG. Conclusions: Epilepsy surgery may be successful for selected children and adolescents with a congenital or early-acquired brain lesion, despite abundant generalized or bilateral epileptiform discharges on EEG. The diffuse EEG expression may be due to an interaction between the early lesion and the developing brain.
Efficacy and safety of telbivudine therapy in liver failure patients with chronic hepatitis B virus infection

The objective of this study was to evaluate the short‐term efficacy and safety of telbivudine therapy as compared to lamivudine therapy in liver failure patients with chronic hepatitis B virus (HBV) infection. These data were collected from 38 liver failure patients with chronic HBV infection who were randomly enrolled to one of the two treatments. All patients received comprehensive treatments; 20 patients were treated with telbivudine, and the other 18 patients were treated with lamivudine. The serum levels of HBV DNA, alanine aminotransferase, total bilirubin, prothrombin time activity, and creatine kinase were determined every 7 days for 8 weeks. The results showed that the serum HBV DNA levels in patients treated with either telbivudine or with lamivudine declined gradually after the 2nd week of treatment. However, HBV DNA levels in the telbivudine group fell to the lower limit of detection (<5 + E2 copies/ml) after the 5th week, which was more rapid than in the lamivudine group. In addition, the total bilirubin and prothrombin time activity of the patients with telbivudine treatment showed a more significant improvement as compared to the patients treated with lamivudine from the start of the 5th week. All patients tolerated telbivudine or lamivudine treatment well. The patients treated with telbivudine did not have elevated serum creatine kinase or myopathic symptoms during the 8‐week treatment period. Thus, telbivudine treatment is superior to lamivudine treatment in improving the condition of patients with liver failure as a result of chronic HBV infection in the short term. J Med. Virol. 85:1907–1912, 2013. © 2013 Wiley Periodicals, Inc.
The Guanine Nucleotide Exchange Factor Vav2 Is a Negative Regulator of Parathyroid Hormone Receptor/Gq Signaling

The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase Cβ-, adenylyl cyclase-, mitogen-activated protein kinase-, and β-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we identified vav2, a guanine nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR-interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated Gαq but not with Gαs subunits, and it competed with PTHR for coupling to Gαq. Consistent with its specific interaction with Gαq, vav2 impaired Gq-mediated inositol phosphate generation but not Gs-mediated cAMP generation. This inhibition of Gq signaling was specific for PTHR signaling, compared with other Gq-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of Na+/H+-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity.
Novel Hyperactive Transposons for Genetic Modification of Induced Pluripotent and Adult Stem Cells: A Nonviral Paradigm for Coaxed Differentiation

Adult stem cells and induced pluripotent stem cells (iPS) hold great promise for regenerative medicine. The development of robust nonviral approaches for stem cell gene transfer would facilitate functional studies and potential clinical applications. We have previously generated hyperactive transposases derived from Sleeping Beauty, using an in vitro molecular evolution and selection paradigm. We now demonstrate that these hyperactive transposases resulted in superior gene transfer efficiencies and expression in mesenchymal and muscle stem/progenitor cells, consistent with higher expression levels of therapeutically relevant proteins including coagulation factor IX. Their differentiation potential and karyotype was not affected. Moreover, stable transposition could also be achieved in iPS, which retained their ability to differentiate along neuronal, cardiac, and hepatic lineages without causing cytogenetic abnormalities. Most importantly, transposon‐mediated delivery of the myogenic PAX3 transcription factor into iPS coaxed their differentiation into MYOD+ myogenic progenitors and multinucleated myofibers, suggesting that PAX3 may serve as a myogenic “molecular switch” in iPS. Hence, this hyperactive transposon system represents an attractive nonviral gene transfer platform with broad implications for regenerative medicine, cell and gene therapy. STEM CELLS 2010;28:1760–1771
Statistical monitoring of nonlinear product and process quality profiles

In many quality control applications, use of a single (or several distinct) quality characteristic(s) is insufficient to characterize the quality of a produced item. In an increasing number of cases, a response curve (profile) is required. Such profiles can frequently be modeled using linear or nonlinear regression models. In recent research others have developed multivariate T2 control charts and other methods for monitoring the coefficients in a simple linear regression model of a profile. However, little work has been done to address the monitoring of profiles that can be represented by a parametric nonlinear regression model. Here we extend the use of the T2 control chart to monitor the coefficients resulting from a parametric nonlinear regression model fit to profile data. We give three general approaches to the formulation of the T2 statistics and determination of the associated upper control limits for Phase I applications. We also consider the use of non‐parametric regression methods and the use of metrics to measure deviations from a baseline profile. These approaches are illustrated using the vertical board density profile data presented in Walker and Wright (Comparing curves using additive models. Journal of Quality Technology 2002; 34:118–129). Copyright © 2007 John Wiley & Sons, Ltd.
On Expressing Lexical Generalizations in HPSG

This paper investigates the status of the lexicon and the possibilities for expressing lexical generalizations in the paradigm of Head-Driven Phrase Structure Grammar (HPSG). We illustrate that the architecture readily supports the use of implicational principles to express generalizations over a class of word objects. A second kind of lexical generalizations expressing relations between classes of words is often expressed in terms of lexical rules. We show how lexical rules can be integrated into the formal setup for HPSG developed by King (1989, 1994), investigate a lexical rule specification language allowing the linguist to only specify those properties which are supposed to differ between the related classes, and define how this lexical rule specification language is interpreted. We thereby provide a formalization of lexical rules as used in HPSG.
Environmental Scanning Electron Microscopy Technique to Identify Asbestos Phases Inside Ferruginous Bodies

Abstract Ferruginous bodies observed in lungs of patients affected by mesothelioma, asbestosis, and pulmonary carcinoma are important to relate the illness to exposure, environmental or occupational, to asbestos. Identification of the inorganic phase constituting the core of the ferruginous bodies, formed around asbestos but also around phases different from asbestos, is essential for legal purposes. Environmental scanning electron microscopy/energy dispersive spectroscopy was used to identify the fibrous mineral phase in the core of ferruginous bodies observed directly in thin sections of tissue, without digestion of the biological matrix. Spectra were taken with sequential analyses along a line crossing the core of the ferruginous bodies. By comparing the spectra taken near to and far from the core, the chemical elements that make up the core could be identified.
Classify or Select: Neural Architectures for Extractive Document Summarization

We present two novel and contrasting Recurrent Neural Network (RNN) based architectures for extractive summarization of documents. The Classifier based architecture sequentially accepts or rejects each sentence in the original document order for its membership in the summary. The Selector architecture, on the other hand, is free to pick one sentence at a time in any arbitrary order to generate the extractive summary. Our models under both architectures jointly capture the notions of salience and redundancy of sentences. In addition, these models have the advantage of being very interpretable, since they allow visualization of their predictions broken up by abstract features such as information content, salience and redundancy. We show that our models reach or outperform state-of-the-art supervised models on two different corpora. We also recommend the conditions under which one architecture is superior to the other based on experimental evidence.
ERK, Akt, and STAT5 are Differentially Activated by the Two Growth Hormone Receptor Subtypes of a Teleost Fish (Oncorhynchus Mykiss)

Previously, we found that the teleost fish, rainbow trout, possesses two growth hormone receptor (GHR) subtypes that display distinct ligand-binding and agonist-induced regulation features. In this study, we used Chinese hamster ovary-K1 cells stably transfected individually with the two trout GHR subtypes, GHR1 and GHR2, to elucidate receptor–effector pathway linkages. Growth hormone (GH) stimulated rapid (5–10 min) phosphorylation of ERK, Akt, JAk2, and STAT5 in both GHR1- and GHR2-expressing cells; however; STAT5 was activated to a greater extent through GHR1 than through GHR2, whereas ERK and Akt were activated to a greater through GHR2 than through GHR1. Although blockade of the ERK pathway had no effect on the activation of Akt, inhibition of PI3K–Akt partially prevented activation of ERK, suggesting cross-talk between the ERK and PI3K–Akt pathways. JAK2 inhibition completely blocked activation of ERK, Akt, and STAT5, suggesting that all of these pathways link to GHR1 and GHR2 via JAK2. These findings establish important receptor–effector pathway linkages and suggest that the GHR subtypes of teleost fish may be functionally distinct.
Networks and Reform in American Education

Educational reform networks are becoming increasingly important as alternative forms of teacher and school development in this time of unprecedented reform of schools. These networks appear to be a way of engaging school-based educators in better directing their own learning; allowing them to sidestep the limitations of institutional roles, hierarchies, and geographic locations; and encouraging them to work with many different kinds of people. In a study of sixteen educational reform networks, we found that they shared organizational themes relating to: (1) purposes and direction; (2) building collaboration, consensus, and commitment; (3) activities and relationships as important building blocks; (4) leadership as cross-cultural brokering and facilitating; and (5) dealing with the funding problem. Regardless of their differences, the sixteen networks we studied appear to have in common agendas more often challenging than prescriptive; learning that is more indirect than direct; formats more collaborative than individualistic; work that is intentionally more integrated than fragmented; leadership more facilitative than directive; thinking that encourages more multiple perspectives; values that are both context-specific and generalized; and structures more movement-like than organization- like.