gebhart/patrepeval huggingface dataset:
Modulation of Notch Signaling by Antibodies Specific for the Extracellular Negative Regulatory Region of NOTCH3 (2008)

The Notch pathway regulates the development of many tissues and cell types and is involved in a variety of human diseases, making it an attractive potential therapeutic target. This promise has been limited by the absence of potent inhibitors or agonists that are specific for individual human Notch receptors (NOTCH1-4). Using an unbiased functional screening, we identified monoclonal antibodies that specifically inhibit or induce activating proteolytic cleavages in NOTCH3. Remarkably, the most potent inhibitory and activating antibodies bind to overlapping epitopes within a juxtamembrane negative regulatory region that protects NOTCH3 from proteolysis and activation in its resting autoinhibited state. The inhibitory antibodies revert phenotypes conveyed on 293T cells by NOTCH3 signaling, such as increased cellular proliferation, survival, and motility, whereas the activating antibody mimics some of the effects of ligand-induced Notch activation. These findings provide insights into the mechanisms of Notch autoinhibition and activation and pave the way for the further development of specific antibody-based modulators of the Notch receptors, which are likely to be of utility in a wide range of experimental and therapeutic settings.
Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells (2006)

The molecular and cellular mechanism of the development of pancreatic cancer is under constant and intensive study, and yet the cure is still out of reach. While surgical treatment is optional, conventional chemotherapy or chemo-radiotherapy remains the best choice. Among others, paclitaxel is proven to be a popular and, to a certain extent, effective chemotherapy agent. We proposed that the combination of paclitaxel and membrane permeable ceramide would enhance the fatality of cancer cells, and reported that the combination increased cell death of both head and neck and leukemic cancer cells. In this study, we treated pancreatic cancer cells (L3.6 cells) with paclitaxel and ceramide at the concentrations of clinical relevance, and treatment was then followed up with an investigation of the molecular mechanism of the synergism of paclitaxel and ceramide. The results of Western blot analysis indicated that the combo synergistically induced ERK and JNK phosphorylation, but not p38 and Akt phosphorylation. We also found that the combination (combo) induced EGFR phosphorylation in a synergistic manner. Furthermore, we observed that paclitaxel, ceramide, or combo-induced EGFR phosphorylation was inhibited by EGFR inhibitor, PD153035, while paclitaxel, ceramide, or combo-induced JNK and ERK phosphorylation was blocked by EGFR inhibitor, PD153035 and ERK inhibitor, U126. Taken together, our results demonstrated that the combination of paclitaxel and ceramide synergistically induced pancreatic cancer cell death through differential activation of EGFR-mediated MAP kinases. EGFR and ERK inhibitors may further enhance the paclitaxel and ceramide effect.
PSMA-Targeted Stably Linked “Dendrimer-Glutamate Urea-Methotrexate” as a Prostate Cancer Therapeutic (2014)

One of the important criteria for achieving efficient nanoparticle-based targeted drug delivery is that the drug is not prematurely released at off-target sites. Here we report the preclinical evaluation of a serum-stable dendrimer-based drug conjugate capable of actively targeting into prostate cancer (PC) cells, delivered through the prostate-specific membrane antigen (PSMA). Multiple molecules of PSMA-binding small molecule glutamate urea (GLA; targeting agent) and the drug methotrexate (MTX) were conjugated to generation 5 PAMAM dendrimer (G5) through Cu-free "click" chemistry. The GLA was conjugated through a stable amide bond, and the MTX was conjugated either through ester (Es)- or amide (Am)-coupling, to generate G5-GLA(m)-(Es)MTX(n) and G5-GLA(m)-(Am)MTX(n), respectively. In serum-containing medium, free MTX was slowly released from "G5-GLA(m)-(Es)MTX(n)", with ~8% MTX released from the dendrimer in 72 h, whereas the MTX on G5-GLA(m)-(Am)MTX(n) was completely stable. The G5-GLA(m)-(Am)MTX(n) bound and internalized into PSMA-expressing LNCaP cells, but not into PSMA-negative PC3 cells. The conjugate-inhibited recombinant dihydrofolate reductase and induced potent cytotoxicity in the LNCaP cells, but not in the PC3 cells. Similar to the action of free GLA, stable amide-linked dendrimer-GLA was capable of inhibiting the enzyme N-acetylated α-linked acidic dipeptidase (NAALADase) activity of PSMA. The G5-GLA(m)-MTX(n) may serve as a serum-stable nanoparticle conjugate to specifically and effectively target and treat PSMA-overexpressing prostate tumors.
Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes (2014)

Islet cell transplantation has therapeutic potential to treat type 1 diabetes, which is characterized by autoimmune destruction of insulin-producing pancreatic islet β cells. It represents a minimal invasive approach for β cell replacement, but long-term blood control is still largely unachievable. This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia. Moreover, graft failures continue to occur because of immunological rejection, despite the use of potent immunosuppressive agents. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection. In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.
Clonal Architecture of Secondary Acute Myeloid Leukemia (2012)

Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
Oral Drug Absorption: Prediction and Assessment (2000)

Gastrointestinal Variables Gastrointestinal Transit and Drug Absorption Clive G. Wilson Permeability in the Gastrointestinal Tract Lars Knutson, F. Knutson, and T. Knutson Gastrointestinal Disease and Dosage Form Performance Vladan Milovic and Jurgen Stein Membrane Permeability Intestinal Permeability: Prediction from Theory Han van de Waterbeemd In Vitro Methods for the Assessment of Permeability Josef J. Tukker Animal Perfusion Studies Hans Lennernas Human Perfusion Studies Hans Lennernas The Role of Permeability Studies in Preclinical Evaluation Philip L. Smith Solubility and Drug Dissolution Solubility as a Limiting Factor to Drug Absorption Raimar Loebenberg, Michael Vieira, and Gordon L. Amidon Dissolution Testing of Immediate-Release Products and Its Application to Forecasting In Vivo Performance Jennifer B. Dressman Dissolution Tests for Extended-Release Products Barbara Sievert and Martin Siewert Dissolution Testing in the Development of Oral Drug Products Bertil Abrahamsson In Vivo-In Vitro Correlations Analysis of Drug Dissolution Data Christos Reppas and Eleftheria Nicolaides Convolution and Deconvolution Methods Richard Suverkrup The Correlation of In Vitro and In Vivo Drug Dissolution Dierk Brockmeier IVIVC: A Perspective from the Workbench Johannes Kramer
Reactivity of 3H‐pyrimido[5,4‐c] [1,2,5]oxadiazin‐3‐one towards carbanions: Synthesis of pteridine‐2,4‐diones (1986)

Abstract The reaction of 3 H ‐pyrimido[5,4‐ c ] [1,2,5]oxadiazin‐3‐one ( 5 ) with carbanions prepared in situ from compounds containing an activated methylene group afforded 6,7‐disubstituted pteridine‐2,4‐diones 7a‐m in good yields. The reaction mechanism, involving the initial attack by carbanion at oxadiazinone nitrogen atom bonded to oxygen, is proposed and discussed.
Water-Insoluble Drug Formulation (2000)

Delivering drugs in a water-insoluble formulation is a critical matter in therapeutic drug development. However, because a drug molecule has to be water soluble to be readily delivered to the cellular membrane while retaining its hydrophobic properties, issues surrounding water insolubility can postpone - or completely derail - important new drug d
Inverse scattering series and seismic exploration (2003)

This paper presents an overview and a detailed description of the key logic steps and mathematical-physics framework behind the development of practical algorithms for seismic exploration derived from the inverse scattering series.
Comparative efficacy of avinew (VG/GA strain) and BCRDV (F strain) vaccines against Newcastle disease in broiler chickens (1970)

A study was conducted for the detection of persistence of maternal antibody as well as the comparative efficacy of Avinew (VG/GA Strain) and BCRDV (F Strain) vaccines against Newcastle disease during the period from January to April 2006 using 100 day-old broiler chicks divided into three groups namely A, B and C. Birds of groups A and B consisting each of 40 were primarily vaccinated intraocularly (IO) with Avinew and BCRDV respectively at the age of day three (3) and secondarily with the same vaccines, as the cases were, on day 20. Sera samples were obtained from 10 randomly selected birds on each occasion of day 1, 10, 17, 27, 30, 34 and 44 of age of birds. Birds of group C were maintained as unvaccinated control for the determination of existence of maternal antibody parallel to the day of vaccination and challenge. It was observed that following primary vaccination in case of group A, the HI titres with a mean Â± SD on day 10 and 17 were 121.6 Â± 19.2 and 60.8 Â± 9.60 respectively as against at mean titres Â± SD of 57.6 Â± 12.8 and 30.4 Â± 4.80 in case group B respectively. On the other hand, subsequent to secondary vaccination, sera samples obtained from group A on day 27 had a mean Â± SD of HI titres 128 Â± 0 and in case of group B, the performance of Avinew in respect of such titre was 57.6 Â± 12.8 on day 27. Thus it was indicated that performance of Aninew in respect of elucidation of HI antibody was comparatively better than that of BCRDV. In case of unvaccinated control birds of group C, the mean of existence of maternal antibody with Â± SD were 512 Â± 0, 54.4 Â± 14.66, 24 Â± 8, 12.8 Â± 8.54, â¤ 4, â¤ 4 and â¤ 4 at the age of day 1, 10, 17, 27, 30, 34 and 44 respectively. One half of vaccinated birds of groups A and B were subjected to challenge test with a virulent isolate of NDV on each of two occasion of day 30 and 44 of age of birds where it was observed that 100% of both the groups of A and B were refractory to each test whereas 95% and 85% of the remaining half of birds of groups A and B resisted the challenge exposure. It was found that maternal antibody against NDV in chicks persisted to a minimal until the age of day 27 and none at day 30 or 34. The analysis of HI titres by Student's t-test revealed that Avinew vaccinated group maintained significantly higher HI titres following primary and secondary vaccination as well as during first challenge than that of BCRDV vaccinated group. Key words: Avinew, BCRDV, efficacy, vaccine, broiler chicks Â DOI = 10.3329/bjvm.v5i1.1304 Bangl. J. Vet. Med. (2007). 5 (1 &amp; 2): 19-23
IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages (2007)

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage—Th17—have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.
Bacteriophage T4 DNA polymerase mutations that confer sensitivity to the PPi analog phosphonoacetic acid (1993)

Mutations that conferred sensitivity to the pyrophosphate analog phosphonoacetic acid in bacteriophage T4 DNA polymerase were identified. The mutations were loosely clustered in four regions of the gene. As found for herpes simplex virus DNA polymerase, T4 mutations that altered sensitivity to phosphonoacetic acid also altered sensitivity to nucleotide analogs. Some of the T4 DNA polymerase mutations also altered the ability of the enzyme to translocate from one template position to the next and affected DNA replication fidelity. Kornberg (A. Kornberg, Science 163:1410-1418, 1969) envisioned a DNA polymerase active center which accommodates primer terminus and template DNAs and the incoming nucleotide. Some mutations identified on the basis of sensitivity to phosphonoacetic acid may be part of such an active center because single amino acid substitutions simultaneously alter several DNA polymerase functions.
Active Specific Immunotherapy for Metastatic Colorectal Carcinoma: Phase I Study of an Allogeneic Cell Vaccine Plus Low-Dose Interleukin-1?? (1999)

A vaccine consisting of four allogeneic colon carcinoma cell lines (DLD-1, HCT116, WiDr, and T84) mixed with the adjuvant DETOX (Mycobacterium phlei cell wall and Salmonella minnesota lipid A) was administered to 25 patients with low-volume metastatic colorectal carcinoma. The first eight patients received vaccine only, given intradermally on three occasions at 3-week intervals. Subsequent patients also received subcutaneous interleukin-1 alpha (IL-1 alpha), 0.3-0.5 microgram/m2 per day for 8 days after each vaccination in an outpatient setting. Vaccine alone caused local erythema, induration, and pruritus. IL-1 caused fevers, chills, and rigors that started in 4 h and lasted 1-2 h. One patient developed a brief loss of consciousness with a rigor that resolved without sequelae. One episode of mild hypotension occurred. Fatigue occurred by day 8 of IL-1. A substantial increase in the number of patients with positive skin tests to DLD-1 and HCT116 occurred after vaccine treatment both without and with IL-1 alpha. An allogeneic cell vaccine plus subcutaneous IL-1 was administered safely to outpatients with some evidence of in vivo effect observed.
Role of tumor necrosis factor‐alpha in rheumatoid arthritis: a review (2007)

Abstract Tumor necrosis factor‐alpha (TNF‐α) is a proinflammatory cytokine that plays a pivotal role in regulating the inflammatory response in rheumatoid arthritis (RA). Although it is controversial whether TNF‐α genes are associated with RA susceptibility, they are well known to mediate RA pathogenesis. We review in depth the history, formation and biological action, TNF receptor, role in mediating pathogenesis in RA and mode of action, of anti‐TNF‐α drugs.
Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction (2014)

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons.
Nosocomial Acquisition ofClostridium difficileInfection (1989)

We studied the acquisition and transmission of Clostridium difficile infection prospectively on a general medical ward by serially culturing rectal-swab specimens from 428 patients admitted over an 11-month period. Immunoblot typing was used to differentiate individual strains of C. difficile. Seven percent of the patients (29) had positive cultures at admission. Eighty-three (21 percent) of the 399 patients with negative cultures acquired C. difficile during their hospitalizations. Of these patients, 52 (63 percent) remained asymptomatic and 31 (37 percent) had diarrhea; none had colitis. Patient-to-patient transmission of C. difficile was evidenced by time-space clustering of incident cases with identical immunoblot types and by significantly more frequent and earlier acquisition of C. difficile among patients exposed to roommates with positive cultures. Of the hospital personnel caring for patients with positive cultures, 59 percent (20) had positive cultures for C. difficile from their hands. The hospital rooms occupied by symptomatic patients (49 percent) as well as those occupied by asymptomatic patients (29 percent) were frequently contaminated. Eighty-two percent of the infected cohort still had positive cultures at hospital discharge, and such patients were significantly more likely to be discharged to a long-term care facility. We conclude that nosocomial C. difficile infection, which was associated with diarrhea in about one third of cases, is frequently transmitted among hospitalized patients and that the organism is often present on the hands of hospital personnel caring for such patients. Effective preventive measures are needed to reduce nosocomial acquisition of C. difficile.
Evaporation and skin penetration characteristics of mosquito repellent formulations. (1989)

Formulations of the mosquito repellent N,N-diethyl-3-methylbenzamide (deet) in combination with a variety of additives were developed to control repellent evaporation and percutaneous penetration. Deet was also formulated with the repellent dimethyl phthalate to study the interaction of the two compounds on the skin. The evaporation and penetration processes were evaluated on whole and split-thickness pig skin using radiolabeled repellents with an in vitro apparatus. Under essentially still air and air flow conditions, one of the deet formulations resulted in significantly reduced total evaporation and percutaneous penetration of deet as compared to unformulated repellent. When deet and dimethyl phthalate were combined, neither repellent affected the total amount of evaporation and penetration of the other compound. However, initial percutaneous penetration and evaporation rates were slightly less and decayed less rapidly than when both chemicals were tested separately at the same dose. These results indicated a degree of competition of the two compounds for the same avenues of loss.
Argentina: El Digesto Juridico Argentino: Una Obra Juridica Monumental (2005)

El 28 de agosto de 1998 publiqué en La Ley un articulo del titulo El Digesto Argentino. Una oportunidad para no perder casi siete anos después modificaría el titulo indicando que es una oportunidad para aprovechar. Semánticamente parecerá sutil la diferencia pero no lo es en los hechos. En 1988 recién aparecía la ley 24967 de creación del Digesto Jurídico Argentino y la preocupación era no perder la oportunidad de realizar una obra ciclópea que solo asustaba el enunciarla.
Deficiency of lubricating surfactant lining the articular surfaces of replaced hips and knees (1998)

While preceding papers have demonstrated that the active load-bearing agent in the boundary mode of joint lubrication is surface-active phospholipid (SAPL)--probably adsorbed as the outermost layer of articular cartilage--this study is designed to determine whether that layer is deficient in osteoarthritis (OA). This layer has been studied on 12 hips and 31 knees obtained from surgically replaced joints afflicted with OA. Measurement of the contact angle (theta) subtended by a droplet of saline clearly demonstrated a highly significant decrease in hydrophobicity, theta falling from 100 degrees for 13 bovine controls (78 degrees for five human controls) to 56 degrees for arthritic hips and 63 degrees and 68 degrees for the 'worn' and 'unworn' areas of arthritic knees, respectively. These changes were reflected in the quantities of SAPL (and proteolipid) recovered from the same articular surfaces by solvent rinsing, yields of SAPL being 36% lower in hips and 25% lower in 'worn' areas of knees, but not significantly different in 'unworn' areas. These results indicate that the outermost lubricating layer of SAPL deposited onto articular cartilage from SF is deficient in OA.
Use of Reporter Genes for Optical Measurements of Neoplastic Disease In Vivo (2000)

Revealing the cellular and molecular changes associated with cancer, as they occur in intact living animal models of human neoplastic disease, holds tremendous potential for understanding disease mechanisms and elucidating effective therapies. Since light is transmitted through mammalian tissues, at a low level, optical signatures conferred on tumor cells by expression of reporter genes encoding bioluminescent and fluorescent proteins can be detected externally using sensitive photon detection systems. Expression of reporter genes, such as the bioluminescent enzyme firefly luciferase (Luc) or variants of green fluorescent protein (GFP) in transformed cells, can effectively be used to reveal molecular and cellular features of neoplasia in vivo. Tumor cell growth and regression in response to various therapies have been evaluated non-invasively in living experimental animals using these reporter genes. Detection of Luc-labeled cells in vivo was extremely sensitive with signals over background from as few as 1000 human tumor cells distributed throughout the peritoneal cavity of a mouse with linear relationships between cell number and signal intensity over five logs. GFP offers the strength of high-resolution ex vivo analyses following in vivo localization of the tumor. The dynamic range of Luc detection allows the full disease course to be monitored since disease progression from small numbers of cells to extensive disease can be assessed. As such, therapies that target minimal disease as well as those designed for late stage disease can be readily evaluated in animal models. Real time spatiotemporal analyses of tumor cell growth can reveal the dynamics of neoplastic disease, and facilitate rapid optimization of effective treatment regimens. Thus, these methods improve the predictability of animal models of human disease as study groups can be followed over time, and can accelerate the development of therapeutic strategies.
Practical Synthesis of Chiral 9,9′‐Spirobixanthene‐1,1′‐diol. (2007)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.