gebhart/patrepeval huggingface dataset:
Direct Effects of the Hypoxic Cell Sensitizer Misonidazole on Colony Formation in a Human Tumor Cloning Assay (1986)

The human tumor cloning assay as described by Hamburger and Salmon was utilized to study the direct antitumor effects of the hypoxic cell sensitizer misonidazole (MISO). Cells from 106 tumor specimens directly obtained from patients were exposed to MISO at clinically achievable drug concentrations (0.5 mM). Of 30 evaluable tumors, seven specimens (23%) showed a less than or equal to 50% decrease of TCFU's. In vitro sensitivity to MISO was noted in human breast cancer, renal cancer, non small-cell lung cancer, and adenocarcinoma of unknown primary site. A dose response relationship was demonstrated in a subset of experiments including 6 patient's tumors and one human breast cancer cell-line. An analysis relating MISO sensitivity or resistance to the results obtained with other, simultaneously tested standard anticancer drugs indicated that tumors exhibiting a less than or equal to 50% decrease of TCFU's in the presence of MISO were also likely to be sensitive to other cytotoxic drugs. In summary, our data suggest that the 'nitroimidazoles' may exert clinically significant direct antitumor effects in individual tumors. The human tumor cloning assay may have potential to evaluate these direct effects of MISO-analogues and other new radiosensitizers currently being tested in clinical trials.
Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models (2017)

<b>Purpose:</b> Estrogen receptor-positive (ER<sup>+</sup>) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER<sup>+</sup> breast cancer.<b>Experimental Design:</b> Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER<sup>+</sup> breast cancer models, including several patient-derived xenograft models.<b>Results:</b> Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER<sup>+</sup> breast cancer cell lines <i>in vitro</i> and <i>in vivo</i>, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring <i>ESR1</i> mutations.<b>Conclusions:</b> These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER<sup>+</sup> disease. <i>Clin Cancer Res; 23(16); 4793-804. ©2017 AACR</i>.
On conceptual modelling and design of role-based access control systems (2004)

While conceptual modelling has been prevail in database and information systems design & development, it also plays an important role in many other complex systems design where the relationships among components and elements are complicated and need proper modelling/understanding.In this talk, we present a formal approach for role-based access control systems design and emphasize the role of conceptual modelling of various relationships and constraints in RBAC systems. Users access control is a critical and sensitive issue in many systems and applications, especially for many web-based systems with large number of users, proper access control is a key issue for system security. Role-based access control governs users' access to the information on the basis of users' positions in the organisation (outside the organisation as well). RBAC involves individual users being associated with roles as well as roles being associated with permissions (Each permission is a pair of object set and operation set). As such, a role is used to associate users and permissions. A user in this model is a human being. A role is a job function or job title within the organization associated with authority and responsibility.The relationships between users and roles and/or between roles and permissions are complicated by the facts that roles may have hierarchical structures with role inheritance from the junior roles to senior roles, some may conflict with each other due to security reason, user' roles may change during the course, such as further roles can be granted, some roles may be revoked, etc. For example, when granting further roles to a user, the new roles together with the existing roles may enable the user to access or derive some more restricted information of higher level security than he or she is entitled. To maintain the system consistency and security, the complex relationships need to be modelled and automatic algorithms need to be in place to check the consistence when granting and updating user-role and role-permission assignments.In this work, we start with conceptual modelling of various relationship and constraints, and introduce formal algebraic notations to specify the constraints, and then develop formal algorithms and procedures to check the conflicts and help administrators to assign and allocate roles to users and permissions to roles.This work aims at two contributions, (1) develop a formal approach for RBAC system modelling and design, and (2) promote the use and role of conceptual modelling in complex system design.
UK‐2A, B, C and D, Novel Antifungal Antibiotics from Streptomyces sp. 517‐02. Part 6. Structure—Activity Relationships of UK‐2A. (2002)

Abstract For Abstract see ChemInform Abstract in Full Text.
Cyclodextrin‐Based Iminosugar Click Clusters: The First Examples of Multivalent Pharmacological Chaperones for the Treatment of Lysosomal Storage Disorders (2012)

Seven-arm chaperone: A modest μM inhibitor of glucosylceramide β-glucosidase (GCase) has been transformed into a potent low-nM inhibitor by multivalency. This iminosugar inhibitor acts as a pharmacological chaperone and increases residual GCase activity in fibroblasts from Gaucher patients. These results open the way to a new class of chaperones for the treatment of lysosomal diseases. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Novel Glucagon Receptor Antagonists with Improved Selectivity over the Glucose-Dependent Insulinotropic Polypeptide Receptor (2008)

Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.
Enabling People with Visual Impairments to Navigate Virtual Reality with a Haptic and Auditory Cane Simulation (2018)

Traditional virtual reality (VR) mainly focuses on visual feedback, which is not accessible for people with visual impairments. We created Canetroller, a haptic cane controller that simulates white cane interactions, enabling people with visual impairments to navigate a virtual environment by transferring their cane skills into the virtual world. Canetroller provides three types of feedback: (1) physical resistance generated by a wearable programmable brake mechanism that physically impedes the controller when the virtual cane comes in contact with a virtual object; (2) vibrotactile feedback that simulates the vibrations when a cane hits an object or touches and drags across various surfaces; and (3) spatial 3D auditory feedback simulating the sound of real-world cane interactions. We designed indoor and outdoor VR scenes to evaluate the effectiveness of our controller. Our study showed that Canetroller was a promising tool that enabled visually impaired participants to navigate different virtual spaces. We discuss potential applications supported by Canetroller ranging from entertainment to mobility training.
Serotonin and Migraine: Biology and Clinical Implications (2007)

Migraine is the most frequent neurological disorder in the adult population worldwide, affecting up to 12% of the general population and more frequent in women ( approximately 25%). It has a high impact on our society due to its disabling nature and, therein, reduced quality of life and increased absenteeism from work. Headache is the primary clinical manifestation and it has been associated with 'a hereditary or predisposed sensitivity of neurovascular reactions to certain stimuli or to cyclic changes in the central nervous system' (1). Amongst the many neurotransmitters in the brain, the serotonergic (serotonin, 5-HT) system from the brainstem raphe nucleus has been most convincingly implicated in migraine pathophysiology. The documented changes in 5-HT metabolism and in the processing of central 5-HT-mediated responses during and in between migraine attacks have led to the suggestion that migraine is a consequence of a central neurochemical imbalance that involves a low serotonergic disposition. Although the exact cascade of events that link abnormal serotonergic neurotransmission to the manifestation of head pain and the accompanying symptoms has yet to be fully understood, recent evidence suggests that a low 5-HT state facilitates activation of the trigeminovascular nociceptive pathway, as induced by cortical spreading depression. In this short review, we present and discuss the original and most recent findings that support a role for altered serotonergic neurotransmission in the manifestation of migraine headache.
Targeting EGFRs and Src signaling with a modified ectodomain of human EGFR (EBIP) and dasatinib in breast cancer. (2009)

Abstract Abstract #3069 It is becoming increasingly evident that many solid tumors including breast cancer show increased activation of several growth factor receptors, specifically EGFR and its family members (EGFRs) as well as c-Src, a non-receptor tyrosine kinase that promote proliferation, inhibit apoptosis and induce metastasis. The EGF-receptor (EGFR) consists of an extracellular ligand-binding domain, a hydrophobic transmembrane region, and an intracellular tyrosine kinase domain. The extracellular or ectodomain of EGFR is essential for ligand-binding and subsequent homo/heterodimerization of the receptor. This raises the possibility that the ectodomain of EGFR could be utilized to inhibit EGFR functions and in turn cellular growth. Recently, we generated an ectodomain of human EGFR (hEGFR), composed of 1-448 amino acids fragment of hEGFR and the 30 amino acid epitope (known as “U” region) of rat EGFR-Related Protein (ERRP) fused at the carboxy-terminal end. The new protein, referred to as EBIP (ErbB Inhibitory Protein), as has been observed for ERRP (Xu et al. Mol. Cancer Ther. 2005 (4): 435-42), inhibits growth of colon and breast cancer cells that express varying levels of EGFR and/or its family members. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for breast cancer. To test our hypothesis we used Dasatinib (BMS-354825; Bristol-Myers Squibb), a newly developed highly potent, ATP-competitive Src and Abl kinase inhibitor and ErbB Inhibitory Protein (EBIP). Four different breast cancer cell lines (MDA-MB-468, SKBr-3, MDA-MB-453 and MDA-MB-231) expressing different levels of EGFR and/or its family members were used. Both EBIP and dasatinib caused a dose dependent inhibition of growth in all breast cancer cells, but dasatinib was less effective compared to EBIP. However, the combination of Dasatinib and EBIP synergistically inhibited cell growth. In EGFR overexpressing MDA-MB-468 cells, the combination therapy also inhibited invasion through extracellular matrix and decreased colony formation. Induction of apoptosis could be attributed to activation of caspases -9 and -8 and by modulating phosphorylation of anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The combination of Dasatinib and EBIP produced a greater inhibition of EGFR and Src activation and their downstream signaling pathways involving Akt and p44/42 MAPK. Additionally, we observed that EGFR promoter activities as well as transactivation of NFκB in MDA-MB-468 cells were greatly reduced. In conclusion, our data suggest that combination treatment of Dasatinib and EBIP that target EGFRs and Src could be a highly effective therapy for breast cancer than mono therapy, as they are likely to impact several aspects of tumor progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3069.
Diastereomers of thymidine 3'-O-(methanephosphonothioate): synthesis, absolute configuration and reaction with 3'-methoxyacetylthymidine under conditions of triester approach to oligonucleotide synthesis. (1987)

Diastereomers of the title compound were obtained and absolute configuration was assigned by means of stereochemical correlation. Their reaction with 3'-O-methoxyacetylthymidine in the presence of triisopropylbenzenesulphonyl (4-nitro) triazole is neither chemo- nor stereo-selective and leads to diastereomeric pairs of dithymidyl (3',5')methanephosphonate and -methanephosphonothioate. Obtained results are discussed in terms of mechanism of activation of phosphodiesters under conditions known as "phosphotriester approach to oligonucleotide synthesis".
Recent Developments on Ketolides and Macrolides (2001)

Recent semi-synthetic studies of erythromycin A culminated in the discovery of two ketolide drug candidates, HMR-3647 and ABT-773, for the treatment of community-acquired bacterial infections caused by both macrolide- and beta-lactam-susceptible and -resistant S. pneumoniae, gram negative bacteria, and intracellular atypical pathogens. The discovery of ketolides has rekindled interest in macrolides, and recent efforts have also led to a novel class of 4''-carbamates with activity against macrolide-resistant organisms. This review is an account of recent developments on ketolides and macrolides in terms of both chemistry and antibacterial activity.
Replication-Deficient Ebolavirus as a Vaccine Candidate (2009)

Ebolavirus causes severe hemorrhagic fever, with case fatality rates as high as 90%. Currently, no licensed vaccine is available against Ebolavirus. We previously generated a replication-deficient, biologically contained Ebolavirus, EbolaDeltaVP30, which lacks the essential VP30 gene, grows only in cells stably expressing this gene product, and is genetically stable. Here, we evaluated the vaccine potential of EbolaDeltaVP30. First, we demonstrated its safety in STAT-1-knockout mice, a susceptible animal model for Ebolavirus infection. We then tested its protective efficacy in two animal models, mice and guinea pigs. Mice immunized twice with EbolaDeltaVP30 were protected from a lethal infection of mouse-adapted Ebolavirus. Virus titers in the serum of vaccinated mice were significantly lower than those in nonvaccinated mice. Protection of mice immunized with EbolaDeltaVP30 was associated with a high antibody response to the Ebolavirus glycoprotein and the generation of an Ebolavirus NP-specific CD8(+) T-cell response. Guinea pigs immunized twice with EbolaDeltaVP30 were also protected from a lethal infection of guinea pig-adapted Ebolavirus. Our study demonstrates the potential of the EbolaDeltaVP30 virus as a new vaccine platform.
Histone deacetylases as targets for treatment of multiple diseases (2013)

HDACs (histone deacetylases) are a group of enzymes that deacetylate histones as well as non-histone proteins. They are known as modulators of gene transcription and are associated with proliferation and differentiation of a variety of cell types and the pathogenesis of some diseases. Recently, HDACs have come to be considered crucial targets in various diseases, including cancer, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders. Pharmacological inhibitors of HDACs have been used or tested to treat those diseases. In the present review, we will examine the application of HDAC inhibitors in a variety of diseases with the focus on their effects of anti-cancer, fibrosis, anti-inflammatory, immunomodulatory activity and regulating metabolic disorders.
Immunogenic Consensus Sequence T helper Epitopes for a Pan-Burkholderia Biodefense Vaccine (2011)

Our results show it is possible to rapidly identify promiscuous T helper epitopes conserved across multiple <i>Burkholderia</i> species and test their binding to HLA ligands <i>in vitro</i>. The next step in our process will be to test the epitopes <i>ex vivo</i> using peripheral leukocytes from BC, BPM infected humans and for immunogenicity in human HLA transgenic mice. We expect that this approach will lead to development of a licensable, pan-<i>Burkholderia</i> biodefense vaccine.
Use of cyclodextrins in capillary zone electrophoresis for the separation of optical isomers: Resolution of racemic tryptophan derivatives (1992)

Abstract In this study capillary zone electrophoresis has been used for the separation of racemic tryptophan derivatives in their enantiomers. The effect of cyclodextrins with different shape, added to the background electrolyte, on the migration time of 10 compounds, including methyl tryptophan, hydroxy tryptophan, and tryptophan ester derivatives, has been studied. Furthermore, the effect of cyclodextrins with different shape and that of the composition of the background electrolyte on the enantiomer resolution are discussed. Among different cyclodextrins used α‐cyclodextrin and heptakis(2,6‐di‐O‐methyl)‐β‐cyclodextrin were found to possess the best complexing capacity and thus the resolution power toward analysed compounds.
Structure and reactivity of α,β‐unsaturated ethers. VII. Electronic effects of the β‐methyl substitution on the cationic polymerizabilities of alkyl vinyl ethers (1969)

Abstract Reactivities of propenyl alkyl ethers toward various cationic agents are summarized, and the effects of a β‐methyl group and geometrical isomerism are discussed on the basis of the extended Hückel molecular orbital theory. The reactions considered include cationic polymerization, acid‐catalyzed hydrolysis, and silver‐ion complexation. The effects of a β‐methyl substitution on the reactivity of vinyl ether are different depending on the type of the reactions. The substitution enhances the reactivity of vinyl ether in homogeneous polymerization, whereas it reduces the reactivity in hydrolysis. This contrasting effect of a β‐methyl group was found to be compatible with the results of the theoretical calculations of the electronic energy changes accompanying the formation of the relevant transition states. A π‐complex‐type transition state was concluded for the cationic polymerization. Several lines of experimental evidence in support of the conclusion are presented.
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing (2009)

Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.
Distribution of Dexamethasone and Preservation of Inner Ear Function following Intratympanic Delivery of a Gel-Based Formulation (2010)

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-μl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.