gebhart/patrepeval huggingface dataset:
The HLA‐DOB gene displays limited polymorphism with only one amino acid substitution (2002)

The HLA-DO molecule is a non-classical class II heterodimer composed of alpha and beta chains. We have previously recognized that all eight of the allelic variations of the HLA-DOA gene represent non-synonymous amino acid substitution. In the present study, to analyze genetic polymorphism and allelic variation of the HLA-DOB gene which may affect the efficiency of class II restricted antigen presentation thereby being involved in the susceptibility of HLA associated diseases, we conducted direct DNA sequencing of HLA-DOB in 36 HLA class II homozygous typing cells and identified six new allelic variations (DOB*0101101, *0101102, *01012, *01022, *0104101 and *0104102) including five single nucleotide polymorphisms with only one amino acid substitution. Furthermore, strong linkage disequilibrium was detected between DOB*01022 and DRB1*1502 only, with no linkage disequilibrium between the DOA and the DOB genes. The HLA-DOB gene has been identified in other mammals, and their nucleotide sequences are well conserved. These facts suggest that limited polymorphism in the DOB gene is profitable to execute their unique function as a co chaperone and so strong selective pressure is operating to prevent generic variation against the DOB molecule interacting with the DM molecule and thus maintaining the specified immunological function of regulating antigen presentation.
Cancer and Leukemia Group B 90206 (2004)

The majority of sporadic clear cell renal cell carcinoma (RCC) is characterized by loss of heterozygosity of the von Hippel-Lindau (VHL) tumor suppressor gene and somatic inactivation of the remaining VHL allele. The resulting VHL gene silencing leads to induction of hypoxia-regulated genes including vascular endothelial growth factor (VEGF). Thus, therapeutic inhibition of VEGF holds promise for treatment of this historically refractory malignancy. An antibody to VEGF (bevacizumab, Avastin) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Interferon-alpha (IFN-alpha) is a standard initial cytokine therapy in RCC with a modest response rate and a survival advantage demonstrated in randomized trials. We hypothesized that the addition of anti-VEGF therapy to IFN-alpha would prolong survival in untreated metastatic RCC patients. A Phase III trial is now being conducted randomizing untreated, metastatic clear cell RCC patients to IFN-alpha alone or IFN-alpha plus Avastin.
Effect of Bladder Outlet Obstruction on Micturition Reflex Pathways in the Rat (1988)

The effect of outlet obstruction on neural pathways to the bladder was examined six weeks after urethral ligation in rats. Ligated rats exhibited a seven-fold increase in bladder weight, a six-fold increase in volume, and significant increases (p less than 0.001) in micturition pressure, residual volume and compliance measured under urethane anesthesia. Unanesthetized ligated rats in comparison to control rats voided smaller volumes of urine more frequently (0.7 vs 1.1 voids/hr., p less than 0.001). Electrophysiological examination of vesical afferent and efferent peripheral neural pathways in the pelvic and hypogastric nerves and sympathetic chain did not reveal any differences in thresholds, axonal conduction velocities or ganglionic transmission. A significant difference (p less than 0.05) was noted in the percentage of obstructed rats (100%) exhibiting a short latency spinal reflex as compared to controls (35%). The long latency supraspinal micturition reflex was similar in both groups. These data suggest that obstruction in rats is accompanied by some degree of neural plasticity resulting in a more prominent spinal reflex that could contribute to the development of the unstable bladder following obstruction in humans and unanesthetized animals.
A phase I study of IPI-926, a novel hedgehog pathway inhibitor, in patients (pts) with advanced or metastatic solid tumors. (2011)

3014 Background: IPI-926 is a novel, selective, oral, natural- product derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, making Smo a target for treatment of a broad range of cancers. We conducted a phase I dose-escalation study to evaluate the safety, maximum tolerated dose and anti-tumor activity of IPI-926. Methods: Eligible pts had advanced or metastatic solid tumors and adequate bone marrow, hepatic and renal function. IPI-926 was administered orally, daily (QD), in 1 to 6 pt cohorts. A cycle was 28 days in length. An expanded cohort in basal cell carcinoma (BCC) was implemented. All pts were evaluated for safety, pharmacokinetics, pharmacodynamics (PD) and tumor response. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Results: As of December 2010, 79 pts had been enrolled at dose levels of IPI-926 ranging from 20-210 mg QD. 31 pts had locally-advanced (LA) or metastatic (M) BCC. The median age for all patients was 60 years (range 40-87) and median number of cycles received was 3 (range 1-22), with 3 (1 LA-BCC and 2 M-BCC) pts receiving IPI-926 for > 12 months. No grade 4/5 related adverse events (AEs) have been observed. The most common IPI-926–related AEs to date include fatigue (29% total, 2.5% grade 3), ALT increased (20%, 7.6% grade 3), AST increased (19%, 3.8% grade 3) and nausea (19%, 0% grade 3). DLTs noted to date were asymptomatic grade 2/3 increased transaminases and/or bilirubin (1 pt at 160 mg, 4 pts at > 160 mg), all of which resolved when drug was held. IPI-926 exposure generally increased with increasing dose. 41 (72%) pts demonstrated a PD effect in normal skin. 6 (27%) clinical or radiologic partial responses have been observed in the 22 pts with Hh-inhibitor naive BCC treated at doses ≥ 130 mg, with 18 of these patients still on study, with a median of 7 cycles received (1-10). 27 pts in total are currently on study. Conclusions: IPI-926, a potent and selective Smo inhibitor, was well tolerated up to 160 mg in pts with advanced or metastatic solid tumor malignancies. Evidence of clinical activity has been observed in BCC pts. The recommended dose for phase II studies will be presented.
Samarium Iodobinaphtholate: An Efficient Catalyst for Enantioselective Aza‐Michael Additions of O‐Benzylhydroxylamine to N‐Alkenoyloxazolidinones (2011)

Abstract Samarium diiodide is an efficient catalyst for the aza‐Michael addition of O ‐benzylhydroxylamine to α,β‐unsaturated N ‐acyloxazolidinones leading to mixtures of the Michael adduct and the product resulting from its amidation. Samarium iodobinaphtholate catalyzed reactions selectively afford the Michael adducts with enantiomeric excesses up to 88 %. An isoinversion effect with temperature is observed with the highest enantiomeric excess at –40 °C.
Access control for large collections (1997)

Efforts to place vast information resources at the fingertips of each individual in large user populations must be balanced by commensurate attention to information protection. For distributed systems with less-structured tasks, more-diversified information, and a heterogeneous user set, the computing system must administer enterprise-chosen access control policies. One kind of resource is a digital library that emulates massive collections of paper and other physical media for clerical, engineering, and cultural applications. This article considers the security requirements for such libraries and proposes an access control method that mimics organizational practice by combining a subject tree with ad hoc role granting that controls privileges for many operations independently, that treats (all but one) privileged roles (e.g., auditor, security officer) like every other individual authorization, and that binds access control information to objects indirectly for scaling, flexibility, and reflexive protection. We sketch a realization and show that it will perform well, generalizes many deployed proposed access control policies, and permits individual data centers to implement other models economically and without disruption.
Pulmonary Arterial Hypertension in France (2006)

This contemporary registry highlights current practice and shows that PAH is detected late in the course of the disease, with a majority of patients displaying severe functional and hemodynamic compromise.
AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models (2015)

Treated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients.
Metabolic Effects of Rosiglitazone in HIV Lipodystrophy (2004)

The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.
Assessment and Development of the Dry Horseshoe Canyon CBM Play in Canada (2005)

Abstract This paper discusses how the Horseshoe Canyon coalbed methane (CBM) play in Western Canada was converted from an under-explored, non-commercial resource to a major commercial play through the application and modification of technology and analysis techniques from other basins, and how this play is being developed today. As of December 2004, production from the Horseshoe Canyon CBM play is estimated to be over 100 MMscfd of gas, with future production expected to grow significantly. The first commercial developments were completed in 2003 and 2004, and drilling is increasing and expected to exceed 3,000 wells per year in 2005.1 The Horseshoe Canyon CBM play covers a large geographic area of 200 miles by 50 miles, and exists in a large, complex vertical section with numerous coal, sand, silt, shale and mudstone layers. In addition, the play is naturally under-pressured, and the coal beds are mostly dry. Because of these complex and unique characteristics, assessment of commercial viability and development optimization can be confusing and only applicable over small parts of the play. MGV Energy, Inc. (a wholly-owned subsidiary of Ft. Worth-based Quicksilver Resources, Inc.) and its initial joint venture (JV) partner, PanCanadian Petroleum Limited (now EnCana Corp.), discovered the techniques to achieve commerciality and pioneered many of the practices used by industry today for Horseshoe Canyon CBM development. In this paper, we discuss identification of the reservoir opportunity, including data acquisition and analysis. We describe geologic and reservoir models, and production forecasting methods. We also cover completion and production practices, spacing optimization and reserves estimation procedures.
Distinct molecular interactions mediate neuronal process outgrowth on non-neuronal cell surfaces and extracellular matrices. (1986)

We have compared neurite outgrowth on extracellular matrix (ECM) constituents to outgrowth on glial and muscle cell surfaces. Embryonic chick ciliary ganglion (CG) neurons regenerate neurites rapidly on surfaces coated with laminin (LN), fibronectin (FN), conditioned media (CM) from several non-neuronal cell types that secrete LN, and on intact extracellular matrices. Neurite outgrowth on all of these substrates is blocked by two monoclonal antibodies, CSAT and JG22, that prevent the adhesion of many cells, including neurons, to the ECM constituents LN, FN, and collagen. Neurite outgrowth is inhibited even on mixed LN/poly-D-lysine substrates where neuronal attachment is independent of LN. Therefore, neuronal process outgrowth on extracellular matrices requires the function of neuronal cell surface molecules recognized by these antibodies. The surfaces of cultured astrocytes, Schwann cells, and skeletal myotubes also promote rapid process outgrowth from CG neurons. Neurite outgrowth on these surfaces, though, is not prevented by CSAT or JG22 antibodies. In addition, antibodies to a LN/proteoglycan complex that block neurite outgrowth on several LN-containing CM factors and on an ECM extract failed to inhibit cell surface-stimulated neurite outgrowth. After extraction with a nonionic detergent, Schwann cells and myotubes continue to support rapid neurite outgrowth. However, the activity associated with the detergent insoluble residue is blocked by CSAT and JG22 antibodies. Detergent extraction of astrocytes, in contrast, removes all neurite-promoting activity. These results provide evidence for at least two types of neuronal interactions with cells that promote neurite outgrowth. One involves adhesive proteins present in the ECM and ECM receptors on neurons. The second is mediated through detergent-extractable macromolecules present on non-neuronal cell surfaces and different, uncharacterized receptor(s) on neurons. Schwann cells and skeletal myotubes appear to promote neurite outgrowth by both mechanisms.
Design and Application of Bispecific Splice-Switching Oligonucleotides (2014)

Targeting of pre-mRNA by short splice-switching oligonucleotides (SSOs) is increasingly being used as a therapeutic modality, one rationale being to disrupt splicing so as to remove exons containing premature termination codons, or to restore the translation reading frame around out-of-frame deletion mutations. The aim of this study was to investigate the effect of chemically linking individual SSOs so as to ascertain equimolar cellular uptake that would provide for more defined drug formulations. In contrast to conventional bispecific SSOs generated by conjugation in solution, here we describe a protocol for synthesis of bispecific SSOs on solid phase. These SSOs comprised of either a non-cleavable hydrocarbon linker or disulfide-based cleavable linkers. To assess the efficacy of these SSOs we have utilized splice switching to bypass a disease-causing mutation in the DMD gene concurrent with disruption of the reading frame of the myostatin gene (Mstn). The premise of this approach is that disruption of myostatin expression is known to induce muscle hypertrophy and so for Duchenne muscular dystrophy (DMD) could be expected to have a better outcome than dystrophin restoration alone. All tested SSOs mediated simultaneous robust exon removal from mature Dmd and Mstn transcripts in myotubes. Our results also demonstrate that using cleavable SSOs is preferred over the non-cleavable counterparts and that these are equally efficient at inducing exon skipping as cocktails of monospecific versions. In conclusion, we have developed a protocol for solid-phase synthesis of single molecule cleavable bispecific SSOs that can be efficiently exploited for targeting of multiple RNA transcripts.
Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease (2007)

NO produced by eNOS (endothelial nitric oxide synthase) is a key mediator of vascular homoeostasis. NO bioavailability is reduced early in vascular disease states, such as hypercholesterolaemia, diabetes and hypertension, and throughout the progression of atherosclerosis. This is a result of both reduced NO synthesis and increased NO consumption by reactive oxygen species. eNOS enzymatic activity appears to be determined by the availability of its cofactor BH4 (tetrahydrobiopterin). When BH4 levels are adequate, eNOS produces NO; when BH4 levels are limiting, eNOS becomes enzymatically uncoupled and generates superoxide, contributing to vascular oxidative stress and endothelial dysfunction. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus oxidative degradation in dysfunctional endothelium. Augmenting vascular BH4 levels by pharmacological supplementation, by enhancing the rate of de novo biosynthesis or by measures to reduce BH4 oxidation have been shown in experimental studies to enhance NO bioavailability. Thus BH4 represents a potential therapeutic target for preserving eNOS function in vascular disease.
Reductive Amination using Poly(Ethylene Glycol) Acetaldehyde Hydrate Generated in Situ: Applications to Chitosan and Lysozyme (1998)

Covalent linkage of poly(ethylene glycol) (PEG) to drug molecules results in water-soluble conjugates with altered bioavailability, pharmacokinetics, immunogenic properties, and biological activities. For drugs bearing one or more amino groups, reductive amination is a potentially useful method for conjugation to PEG. PEG acetaldehyde has been used for this purpose, but its ease of polymerization under certain conditions and its susceptibility to air oxidation have caused some problems in its application. A simple and reliable method for preparation and use in reductive amination of PEG acetaldehyde hydrate generated in situ by hydrolysis of PEG acetaldehyde diethylacetal is demonstrated. PEG acetaldehyde diethylacetal is prepared in high yield and purity by reaction of PEG with chlorodiethylacetal in dioxane in the presence of finely powdered sodium hydroxide under heterogeneous conditions. PEG acetaldehyde hydrate is generated in solution by hydrolysis in aqueous acids. Solutions of the hydrate may be used directly, in conjunction with sodium cyanoborohydride, to effect reductive amination. We demonstrate application of these methods in PEGylation of lysozyme and chitosan to form water-soluble methoxy poly(ethylene glycol) (mPEG) derivatives and PEG-chitosan hydrogels.
Performance Evaluation of Deep Neural Networks Applied to Speech Recognition: RNN, LSTM and GRU (2019)

Abstract Deep Neural Networks (DNN) are nothing but neural networks with many hidden layers. DNNs are becoming popular in automatic speech recognition tasks which combines a good acoustic with a language model. Standard feedforward neural networks cannot handle speech data well since they do not have a way to feed information from a later layer back to an earlier layer. Thus, Recurrent Neural Networks (RNNs) have been introduced to take temporal dependencies into account. However, the shortcoming of RNNs is that long-term dependencies due to the vanishing/exploding gradient problem cannot be handled. Therefore, Long Short-Term Memory (LSTM) networks were introduced, which are a special case of RNNs, that takes long-term dependencies in a speech in addition to short-term dependencies into account. Similarily, GRU (Gated Recurrent Unit) networks are an improvement of LSTM networks also taking long-term dependencies into consideration. Thus, in this paper, we evaluate RNN, LSTM, and GRU to compare their performances on a reduced TED-LIUM speech data set. The results show that LSTM achieves the best word error rates, however, the GRU optimization is faster while achieving word error rates close to LSTM.
Oxidative desulfurization–fluorination of alkanol xanthates. Control of the reaction pathway to fluorination or trifluoromethoxylation (1997)

The reagent consisting of 70% HF–py (py = pyridine) and a halonium oxidant converts R–OCS 2 Me into either R–OCF 3 (R = primary) or R–F (R = secondary, tertiary or benzylic) whereas the 50% HF–py system converts R–OCS 2 Me (R = secondary) into R–OCF 3 .
Micromotors Spontaneously Neutralize Gastric Acid for pH‐Responsive Payload Release (2017)

The highly acidic gastric environment creates a physiological barrier for using therapeutic drugs in the stomach. While proton pump inhibitors have been widely used for blocking acid-producing enzymes, this approach can cause various adverse effects. Reported herein is a new microdevice, consisting of magnesium-based micromotors which can autonomously and temporally neutralize gastric acid through efficient chemical propulsion in the gastric fluid by rapidly depleting the localized protons. Coating these micromotors with a cargo-containing pH-responsive polymer layer leads to autonomous release of the encapsulated payload upon gastric-acid neutralization by the motors. Testing in a mouse model demonstrate that these motors can safely and rapidly neutralize gastric acid and simultaneously release payload without causing noticeable acute toxicity or affecting the stomach function, and the normal stomach pH is restored within 24 h post motor administration.
Blood Substitutes Based on Modified Hemoglobin Prepared by Encapsulation or Crosslinking: an Overview (1992)

Modified hemoglobin consists of (1) encapsulated hemoglobin and (2) crosslinked hemoglobin (polyhemoglobin, intramolecularly cross-linked hemoglobin and conjugated hemoglobin). There have been new advances in all types of modified hemoglobins. Modified hemoglobins are effective in hemorrhagic shock. However, it is important to define hemorrhagic shock models and experimental designs. Important progress has been made in research on vasoactivities, organ perfusion, organ preservation, biodistribution, hematology, complement activation immunology and other areas. A preclinical screening test may bridge the gap between animal safety studies and injection into human. Potential new sources of hemoglobin included bovine hemoglobin, recombinant human hemoglobin and synthetic heme.
Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220) (2015)

More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an "Abl-like" inactive conformation with the activation loop stabilized in the "DFG-out" orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations.
In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb (2009)

Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves co-stimulation of tumor-specific CD8(+) T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8beta(+) T-cell-dependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen cross-presentation revealed that CD11c(+) cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumor-draining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein-->C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA(257-264) epitope and in the antitumor efficacy induced by anti-CD137 mAb.