gebhart/patrepeval huggingface dataset:
Abstract PL02-01: Targeting the PI3K pathway in cancer (2009)

Abstract The role of PI3K activation in transformation was first brought to light by virtue of its association with the transforming oncoprotein Middle T antigen of the Polyoma virus. Subsequently, the discovery of the PTEN tumor suppressor gene and its characterization as a lipid phosphatase with preference for PI-3,4-P2 and PI-3,4,5-P3 brought therapeutic targeting of the PI3K pathway back to the fore. Following the discovery of PTEN direct oncogenic activation of PI3K was found to occur through gene amplification and through the acquisition of activating point mutations in PIK3CA (the gene encoding the catalytic subunit p110α) in a diverse set of malignancies. Lastly, activated oncogenic receptor tyrosine kinases including HER2 and EGFR mediated their transforming activity, at least in part, through PI3K-dependent signaling. Thus, we can envision at least 3 prevalent cancer-genetic states that may elicit a dependence on PI3K, namely, loss-of-function of PTEN, gain-of-function of PIK3CA and oncogenic mutation in receptor tyrosine kinases. The mTOR kinase is a key regulator of cell growth downstream of PI3K. mTOR activity in cancer states is more specifically deregulated in the absence of the normal function of the Tuberous Sclerosis Complex genes (TSC1 and 2). Similarly mutations in LKB1 and PTEN may elicit dependence on mTOR activity. In addition, mTOR activity is a critical regulator of hypoxia signaling. mTOR inhibitors have shown promising clinical activity in states predicated on these pre-clinical discoveries. These observations/discoveries have motivated and set the stage for the development of therapeutic molecules targeting key pathway components. These include the aformentioned allosteric inhibitors of mTOR already registered as oncology therapeutics, and the more recent entrance of PI3K and AKT inhibitors into the clinic. These events herald the opportunity to answer critical therapy based questions in man. The data emerging from the pre-clinical and clinical development of a series of distinct pathway inhibitors targeting mTOR and PI3K will be discussed with a focus on understanding pathway dependence pre-clinically and the role of relevant biomarker data emerging from the clinic and their potential relationship to efficacious dosing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL02-01.
Characterization of novel mRNAs encoding enzymes involved in peptide alpha-amidation (1991)

The COOH-terminal alpha-amidation of bioactive peptides is a 2-step process catalyzed by two separable enzymatic activities both derived from the peptidylglycine alpha-amidating monooxygenase (PAM) precursor. Two forms of PAM mRNA (rPAM-1 and -2), differing by the presence or absence of optional Exon A, were previously characterized; both encode precursors predicted to have an NH2-terminal signal sequence, an intragranular domain containing both enzymatic activities, and a single transmembrane domain followed by a short, cytoplasmic COOH-terminal domain. In this report, two novel types of PAM mRNA were identified in adult rat atrium. A cDNA of each type was sequenced, and the results indicate that rPAM-3 and -4 could be related to each other and to the previously characterized rat PAM cDNAs by alternative mRNA splicing. Deletion of a 258-nucleotide segment (optional Exon B) encoding the transmembrane domain from rPAM-3 and the presence of a novel 3'-exon in rPAM-4 mean that both rPAM-3 and -4 mRNAs encode precursor proteins that have an NH2-terminal signal peptide but lack a transmembrane domain. The rPAM-4 precursor protein lacks the region of the PAM precursor catalyzing the second step in the alpha-amidation reaction. Low levels of rPAM-3 and -4 type mRNA were detected in atrium. Utilizing the polymerase chain reaction, two major patterns of distribution of forms of PAM mRNA were found. In the heart and central nervous system, PAM mRNAs both containing and lacking optional Exon A were prevalent and almost all of the PAM mRNAs detected contained optional Exon B. In the pituitary and submaxillary glands, PAM mRNAs lacking optimal Exon A were prevalent, as were PAM mRNAs lacking all or part of optional Exon B. Since the distribution of PAM activity between soluble and membrane fractions is tissue-specific and developmentally regulated and since rPAM-4 lacks an enzymatic portion of the PAM precursor, the tissue-specific expression of these forms of rat PAM mRNA is expected to be of functional significance.
Butyrate producing colonic Clostridiales metabolise human milk oligosaccharides and cross feed on mucin via conserved pathways (2020)

The early life human gut microbiota exerts life-long health effects on the host, but the mechanisms underpinning its assembly remain elusive. Particularly, the early colonization of Clostridiales from the Roseburia-Eubacterium group, associated with protection from colorectal cancer, immune- and metabolic disorders is enigmatic. Here, we describe catabolic pathways that support the growth of Roseburia and Eubacterium members on distinct human milk oligosaccharides (HMOs). The HMO pathways, which include enzymes with a previously unknown structural fold and specificity, were upregulated together with additional glycan-utilization loci during growth on selected HMOs and in co-cultures with Akkermansia muciniphila on mucin, suggesting an additional role in enabling cross-feeding and access to mucin O-glycans. Analyses of 4599 Roseburia genomes underscored the preponderance and diversity of the HMO utilization loci within the genus. The catabolism of HMOs by butyrate-producing Clostridiales may contribute to the competitiveness of this group during the weaning-triggered maturation of the microbiota.
Reagent-Loaded Cartridges for Valveless and Automated Fluid Delivery in Microfluidic Devices (2004)

An important problem in the life sciences and in health care is simple and rapid detection of biomarkers. Although microfluidic devices are potentially useful in addressing this problem, current techniques for automating fluid delivery--which include valves and electroosmosis--require sophisticated microfabrication of the chip, bulky instrumentation, or both. In this paper, we describe a simple and reliable technique for storing and delivering a sequence of reagents to a microfluidic device. The technique is low-cost, requires minimal user intervention, and can be performed in resource-poor settings (e.g., outside of a laboratory) in the absence of electricity and computer-controlled equipment. In this method, cartridges made of commercially available tubing are filled by sequentially injecting plugs of reagents separated by air spacers. The air spacers prevent the reagents from mixing with each other during cartridge preparation, storage, and usage. As an example, we used this "plug-in cartridge" technology to complete a solid-phase immunoassay in a microchannel in 2 min with low-nanomolar sensitivity and demonstrate the diagnosis of HIV in 13 min.
Glucagon-Like Peptide-1 Functionalized PEG Hydrogels Promote Survival and Function of Encapsulated Pancreatic β-Cells (2009)

Encapsulating pancreatic islets in a semipermeable poly(ethylene glycol) (PEG) hydrogel membrane holds potential as an immuno-isolation barrier for the treatment of type 1 diabetes mellitus. The semipermeable PEG hydrogel not only permits free diffusion of nutrients, metabolic waste, and insulin produced from the encapsulated beta-cells, but also provides a size-exclusion effect to prevent direct contact of entrapped islets to host immune cells and antibodies. However, the use of unmodified PEG hydrogels for islet encapsulation is not ideal, as there is no bioactive cue to promote the long-term survival and function of the encapsulated cells. Herein, we report the synthesis and characterization of a bioactive glucagon-like peptide 1 (GLP-1) analog, namely, GLP-1-cysteine or GLP-1C, and the fabrication of functional GLP-1 immobilized PEG hydrogels via a facile thiol-acrylate photopolymerization. The immobilization of bioactive GLP-1C within PEG hydrogels is efficient and does not alter the bulk hydrogel properties. Further, the GLP-1 immobilized PEG hydrogels enhance the survival and insulin secretion of encapsulated islets. Overall, this study demonstrates a strategy to modify PEG hydrogels with bioactive peptide moieties that can significantly enhance the efficacy of islet encapsulation.
Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats. (1991)

The multitude of biological effects of the vitamin A metabolite, retinoic acid, are mediated by nuclear retinoic acid receptors (RARs), which are members of the steroid/thyroid hormone receptor superfamily. RAR-alpha, -beta, and -gamma are encoded by three genes from which multiple isoforms can be generated. Recent studies suggest that the expression of at least some RAR isoforms can be regulated by retinoic acid in certain cell lines. Here we examined regulation of RAR expression in the adult animal. RARs were analyzed by Northern blots from lung, liver, and testes of retinol-deficient rats. Retinol deficiency caused a 65-70% decrease in the mRNA levels of lung and liver RAR-beta, whereas no change was observed in RAR-alpha and -gamma mRNA levels in these organs. In the testes of retinol-deficient animals, two transcripts, RAR-alpha 1 (3.7 kb) and RAR-alpha 2 (2.8 kb), were detected as compared with one RAR-alpha 1 (3.7 kb) transcript in retinol-sufficient testes. When retinol-deficient rats were orally administered 1 dose of retinoic acid (100 micrograms per rat), lung RAR-beta mRNA levels started to increase after 1 hr and reached a 16-fold higher level after 4 hr; after 4 hr these retinoic acid-fed rats also showed a 7-fold increase in liver RAR-beta mRNA levels as compared with levels in the retinol-deficient rats. In contrast, liver, lung, and testes RAR-alpha transcripts remained either unchanged or showed only a slight increase in response to retinoic acid. RAR-gamma was constitutively expressed in lung, and its mRNA levels were induced 2-fold by retinoic acid. These results show tissue diversity in the rapid induction of RAR-beta and RAR-gamma by retinoic acid in the adult animal and suggest distinct roles for the various receptor isoforms in the control of the retinoid response.
Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo (2000)

Dentinal repair in the postnatal organism occurs through the activity of specialized cells, odontoblasts, that are thought to be maintained by an as yet undefined precursor population associated with pulp tissue. In this study, we isolated a clonogenic, rapidly proliferative population of cells from adult human dental pulp. These DPSCs were then compared with human bone marrow stromal cells (BMSCs), known precursors of osteoblasts. Although they share a similar immunophenotype in vitro, functional studies showed that DPSCs produced only sporadic, but densely calcified nodules, and did not form adipocytes, whereas BMSCs routinely calcified throughout the adherent cell layer with clusters of lipid-laden adipocytes. When DPSCs were transplanted into immunocompromised mice, they generated a dentin-like structure lined with human odontoblast-like cells that surrounded a pulp-like interstitial tissue. In contrast, BMSCs formed lamellar bone containing osteocytes and surface-lining osteoblasts, surrounding a fibrous vascular tissue with active hematopoiesis and adipocytes. This study isolates postnatal human DPSCs that have the ability to form a dentin/pulp-like complex.
Preparation of monodisperse emulsions by hydrodynamic size fractionation (2009)

We describe a microfluidic system allowing fast and efficient size-dependent separation of droplets using hydrodynamics. This system allows efficient fractionation of droplets with a difference in volume as small as 2.33-fold (corresponding to a 1.33-fold difference in diameter of spherical droplets) at &amp;gt;4.5 kHz frequencies. To demonstrate the utility of the system we combined the size-fractionation module with a passive droplet fusion module to create an integrated microfluidic platform allowing the preparation of highly monodisperse emulsions composed of &amp;gt;99% pairwise fused droplets. This type of microfluidic platform should be useful for many droplet-based lab-on-a-chip applications.
A Survey of Unstructured Mesh Generation Technology. (1998)

A brief survey of some of the fundamental algorithms in unstructured mesh generation is presented. Included is a discussion and categorization of triangle, tetrahedral, quadrilateral and hexahedral mesh generation methods currently in use in academia and industry. Also included is a brief discussion of smoothing, cleanup and refinement algorithms. An informal survey of currently available mesh generation software is also provided comparing some of their main features.
Risk factors of adverse drug reaction from non-steroidal anti-inflammatory drugs in Shanghai patients with arthropathy. (2004)

A retrospective epidemiological survey was useful in detecting the risk factors for ADRs caused by NSAIDs. The study found that different NSAIDs might have different risk factors and that there is no single risk factor universally applicable to all NSAIDs.
Regulation of tryptase from human lung mast cells by heparin. Stabilization of the active tetramer. (1986)

Tryptase was shown to be stabilized as an enzymatically active tetramer by association with heparin and dissociated to inactive monomers in the absence of heparin at 37 degrees C in physiologic buffer and in plasma. There was a 50% loss of tryptase activity at 37 degrees C by 6-8 min in both physiologic buffer and plasma. When heparin glycosaminoglycan was present, tryptase retained nearly full activity for 2 h in buffer and in plasma. Tryptase activity also decayed under standard assay conditions in the presence of synthetic ester and peptide substrates unless bound to heparin. That tryptase is bound to heparin at the pH and physiologic NaCl concentrations employed was shown by chromatography of tryptase on heparin-agarose, gel filtration, and velocity sedimentation. Elution of tryptase from heparin-agarose occurred at 0.8 M NaCl. Maximal stabilization of tryptase by heparin occurred at a weight ratio to tryptase that was equal to or greater than unity. Kcat/Km ratios for tryptase-heparin at 0.15 M NaCl and 37 degrees C were 0.9 X 10(6) s-1 M-1 for tosyl-L-Gly-Pro-Lys-p-nitroanilide and 1.7 X 10(6) s-1 M-1 for p-tosyl-L-arginine methyl ester and are among the highest reported for tryptic enzymes. The mechanism of heparin-dependent stabilization of tryptase was not due to indirect ion binding properties of heparin and was analyzed by Superose 12 high performance liquid chromatography. Active enzyme eluted with an apparent Mr of 132,000 +/- 10,000 (n = 3, +/- S.D.), whereas tryptase inactivated by incubation without heparin eluted with an apparent Mr of 34,000. The tetrameric structure of diisopropyl fluorophosphate-inhibited tryptase was also preserved after incubation with heparin at 37 degrees C but was reduced to monomeric subunits after incubation without heparin. That no appreciable degradation of tryptase occurs under conditions that cause dissociation of subunits was directly shown by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. Two different subunits of 34,000 and 33,000 Mr (after reduction) present in the intact enzyme (calculated to be 134,000 Mr) were also detected unchanged after inactivation of tryptase by dissociation of its subunits. Thus, the selective localization and association of heparin and tryptase in the human mast cell secretory granule most likely plays a major role in the regulation of tryptase after secretion.
Plantar Lateral Dislocation of the Medial Cuneiform: A Case Report (1998)

This case report describes an isolated plantar lateral dislocation of the medial cuneiform. We were able to find only one other similar case reported in the literature. That case had a delayed diagnosis of 5 months and with an associated an avulsion fracture of the second metatarsal base. Dines et al. reported an isolated dorsomedial dislocation at the medial cuneonavicular joint. An irreducible dorsomedial dislocation with the anterior tibialis tendon being trapped between the medial cuneiform and the navicular has been reported. A distal and lateral dislocation of the medial cuneiform was reported in association with displacement of the second to fourth metatarsal and medial fractures of the navicular and cuneiform. The current report differs from previous cases. There was not an associated fracture; the direction of the dislocation was unique and could be reduced closed.
Why do chronic subdural hematomas continue to grow slowly and not coagulate? Role of thrombomodulin in the mechanism (2002)

The thrombomodulin is expressed on the sinusoidal vessels, and the blood coagulation system is inhibited in the hematoma. These findings indicate that these vessels are continuously injured and fail to heal. As a result, the bleeding from the sinusoidal vessels may persist, and the hematoma may grow slowly and fail to coagulate. It is suspected that transmitted pulsation variations in the hematoma cavity generate sinusoidal vessel injury.
A patient‐to‐computed‐tomography image registration method based on digitally reconstructed radiographs (1994)

An automatic method for the accurate registration of computed tomography (CT) data with two camera‐calibrated radiographs is presented. The registration is based on the skull as visualized both in the plain radiographs and in radiographs digitally reconstructed from CT. A reference coordinate system is established based on the radiographic projection parameters obtained using an angiographic stereotactic localizer. The CT‐derived reconstructed radiographs are aligned iteratively at multiple resolutions until a best match is found by adjusting the position and orientation of the CT data set relative to the reference coordinate system. The results of experiments with a skull phantom performed under stereotactic control which show that reliable registration is possible with an accuracy better than 1 mm are presented. Possible applications include intraoperative patient‐to‐CT frameless registration and registration of radiographic data with frameless CT for depth electroencephalogram electrode position confirmation.
Insulin Pharmacokinetics (1984)

Where adjustments of diet, physical activity, and dosage of insulin are well known to diabetologists and diabetic patients, present-day knowledge of factors of importance to the pharmacokinetics of insulin is frequently ignored. The pharmacokinetics of insulin comprise the absorption process, the distribution including binding to circulating insulin antibodies, if present, and to insulin receptors, and its ultimate degradation and excretion. The distribution and metabolism of absorbed insulin follow that of endogenous insulin. The distribution and metabolism cannot be actively changed, except in the case of circulating insulin antibodies, which in rare cases also may cause insulin resistance. The use of insulin preparation of low immunogeneity will avoid or reduce this course of variation in action. The absorption process, the detailed mechanisms of which are still unknown, is influenced by many variables where some can be controlled, thereby reducing the intrapatient variability in insulin absorption, which may reach 35%, causing a corresponding metabolic lability. Besides the known differences in timing among different preparations, the size of dose, the injected volume, and the insulin concentration are determinants of absorption role. Fortuitous injection technique contributes to variance, as do changes in blood flow of the injected tissue. This may be induced by changes in ambient temperature, exercise of injected limb, or local massage. Regional differences are also due to differences in blood flow. Serum insulin peaks may peak up to 1 h after injection of soluble insulin into the thigh versus into the abdominal wall. Local degradation of insulin seems of less importance but may, in rare cases, be the cause of high insulin "requirements." Available evidence is reviewed and the importance of implementing the consequences in the daily care of the insulin-treated patient is emphasized.
Single-Walled Carbon Nanotube Biosensors Using Aptamers as Molecular Recognition Elements (2005)

We report the real-time detection of protein using SWNT-FET-based biosensors comprising DNA aptamers as molecular recognition elements. Anti-thrombin aptamers that are highly specific to serine protein thrombin were immobilized on the sidewall of a SWNT-FET using CDI-Tween linking molecules. The binding of thrombin aptamers to SWNT-FETs causes a rightward shift of the threshold gate voltages, presumably due to the negatively charged backbone of the DNA aptamers. While the addition of thrombin solution causes an abrupt decrease in the conductance of the thrombin aptamer immobilized SWNT-FET, no noticeable change was observed with elastase.
Bicyclic Organo‐Peptides as Selective Carbohydrate Receptors: Design, Solid‐phase Synthesis, and on‐bead Binding Capability (2004)

Abstract Selective recognition of monosaccharides in polar media by conformationally restricted bicyclic peptides containing an aromatic surface to facilitate the initial interaction has been examined. Molecular modeling assisted design of these peptidic receptors has been employed to optimize guest fitting in the peptide cavity. Different solid‐phase synthetic approaches to the target structures are discussed in order to develop a flexible methodology suitable for a combinatorial approach. A series of putative receptors, differing in the aromatic spacer as well as the peptide ring size, has been synthesized and characterized by HPLC and HR‐MS. They have been subjected to FRET‐based screening for binding to mono and disaccharides. This indicates that binding properties are strongly dependent on the size and rigidity of the receptors, detecting β‐glucoside selectivity in the case of a naphthyl‐bridged cyclic dodecapeptide. In addition, an ES‐MS/MS‐based method that allows structural elucidation of single bead samples with no need of encoding techniques has been devised, which will be useful for structure elucidation in libraries of cyclic peptides.
The crucial role of macrophages in lymphangiogenesis (2005)

Lymphangiogenesis is associated with pathological processes such as the metastatic spread of carcinoma cells and organization of immunologically active lymphocytic infiltrates following organ transplantation. It has not yet been established whether expansion of the lymphatic vascular meshwork is driven by incorporation of progenitor cells or by local endothelial cell division. In this issue of the JCI, Maruyama et al. provide evidence that after mouse corneal transplant, CD11b+ macrophages infiltrate the corneal stroma and transdifferentiate into lymphatic endothelial cell clusters that join existing lymphatic vessels. In complementary in vitro experiments, murine peritoneal macrophages expressed lymphatic endothelial markers and formed vessel-like protrusions. These findings add yet another facet to the plasticity of macrophages, which are already known to transform from naive monocytes into VEGF-C-producing cells. Thus, macrophages support lymphangiogenesis in 2 different ways, either by transdifferentiating and directly incorporating into the endothelial layer or by stimulating division of preexistent local lymphatic endothelial cells.