gebhart/patrepeval huggingface dataset:
Targeted delivery of methotrexate to epidermal growth factor receptor–positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates (2006)

We have constructed a drug delivery vehicle that targets the epidermal growth factor receptor (EGFR) and its mutant isoform EGFRvIII. The monoclonal antibody, cetuximab, previously known as C225, which binds to both EGFR and EGFRvIII, was covalently linked via its Fc region to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. As measured by mass spectrometry and UV/vis spectroscopy, the resulting bioconjugate, designated C225-G5-MTX, contained 12.6 molecules of methotrexate per unit of dendrimer. Specific binding and cytotoxicity of the bioconjugate was evaluated against the EGFR-expressing rat glioma cell line F98(EGFR). Using a competitive binding assay, it was shown that the bioconjugate retained its affinity for F98(EGFR) cells, with a 0.8 log unit reduction in its EC(50). Only cetuximab completely inhibited binding of the bioconjugate, which was unaffected by methotrexate or dendrimer. Cetuximab alone was not cytotoxic to F98(EGFR) cells at the concentration tested, whereas the IC(50) of the bioconjugate was 220 nmol/L, which was a 2.7 log unit decrease in toxicity over that of free methotrexate. The biodistribution of C225-G5-MTX in rats bearing i.c. implants of either F98(EGFR) or F98(WT) gliomas was determined 24 hours following convection enhanced delivery of (125)I-labeled bioconjugate. At this time, 62.9 +/- 14.7% ID/g tumor was localized in rats bearing F98(EGFR) gliomas versus 11.3 +/- 3.6% ID/g tumor in animals bearing F98(WT) gliomas, thereby showing specific molecular targeting of the tumor. The corresponding radioactivity of normal brain from the F98(EGFR) tumor-bearing right and non-tumor-bearing left cerebral hemisphere were 5.8 +/- 3.4% and 0.8 +/- 0.6% ID/g, respectively. Based on these results, therapy studies were initiated in F98(EGFR) glioma-bearing rats. Animals that received C225-G5-MTX, cetuximab, or free methotrexate had median survival times of 15, 17, and 19.5 days, respectively, which were not statistically different from each other or untreated control animals. Our results, which are both positive and negative, show that specific molecular targeting is but one of several requirements that must be fulfilled if an antibody-drug bioconjugate will be therapeutically useful.
RGC-32 Increases p34CDC2 Kinase Activity and Entry of Aortic Smooth Muscle Cells into S-phase (2002)

Proliferation of aortic smooth muscle cells contributes to atherogenesis and neointima formation. Sublytic activation of complement, particularly C5b-9, induces cell cycle progression in aortic smooth muscle cells. RGC-32 is a novel protein that may promote cell cycle progression in response to complement activation. We cloned human RGC-32 cDNA from a human fetal brain cDNA library. The human RGC-32 cDNA encodes a 117-amino acid protein with 92% similarity to the rat and mouse protein. Human RGC-32 maps to chromosome 13 and is expressed in most tissues. Sublytic complement activation enhanced RGC-32 mRNA expression in human aortic smooth muscle cells and induced nuclear translocation of the protein. RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. Overexpression of RGC-32 induced quiescent aortic smooth muscle cells to enter S-phase. These data indicate that cell cycle activation by C5b-9 may involve p34CDC2 activity through RGC-32. RGC-32 appears to be a cell cycle regulatory factor that mediates cell proliferation, both as an activator and substrate of p34CDC2.
Clonal polymorphisms of outer membrane protein OspB of Borrelia burgdorferi (1989)

The outer membrane protein OspB of Borrelia burgdorferi, the Lyme borreliosis agent, differs in relative molecular weight (Mr) among strains. To determine whether antigenic variation occurs in B. burgdorferi, a cell population of the human isolate HB19 was cloned first by being diluted in broth and then by being plated on agar medium. Several clones were obtained and characterized by polyacrylamide gel electrophoresis, in situ protease treatment, and Western (immunoblot), Southern, and Northern (RNA) blot analyses. Variants featuring OspB proteins that differed in Mrs and in reactivities with monoclonal antibodies were found. One variant made increased amounts of a 21,000-molecular-weight protein (21K protein) in addition to normal amounts of a 33K OspB protein. Another variant did not produce an OspB protein at all but did express an 18.5K protein. Both the 18.5K and 21K proteins were susceptible in situ to trypsin and were bound by a monoclonal antibody directed against the OspB of strain HB19. There were no differences in the Southern and Northern blot analyses of the different variants. The results led to the following conclusions. (i) Clonal polymorphisms in the surface protein OspB occurred in B. burgdorferi. (ii) Hitherto uncharacterized 18.5K and 21K proteins were protease susceptible, antigenically related to OspB, and apparently produced in greater amounts when an OspB either was not produced or was altered in structure. (iii) The OspB variations, including its absence from cells, were not accounted for by major DNA rearrangements or failure of transcription of the ospB gene.
Recombinant human anti–transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo‐controlled phase I/II trial of CAT‐192 (2006)

We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.
Custom built nonlinear optical crosslinking (NLO CXL) device capable of producing mechanical stiffening in ex vivo rabbit corneas (2017)

The purpose of this study was to develop and test a nonlinear optical device to photoactivate riboflavin to produce spatially controlled collagen crosslinking and mechanical stiffening within the cornea. A nonlinear optical device using a variable numerical aperture objective was built and coupled to a Chameleon femtosecond laser. Ex vivo rabbit eyes were then saturated with riboflavin and scanned with various scanning parameters over a 4 mm area in the central cornea. Effectiveness of NLO CXL was assessed by evaluating corneal collagen auto fluorescence (CAF). To determine mechanical stiffening effects, corneas were removed from the eye and subjected to indentation testing using a 1 mm diameter probe and force transducer. NLO CXL was also compared to standard UVA CXL. The NLO CXL delivery device was able to induce a significant increase in corneal stiffness, comparable to the increase produced by standard UVA CXL.
Efficient two-photon-induced fluorescence in a new organic crystal (1998)

Results are presented on the two-photon absorption and fluorescence properties of a new molecular crystal based on (E)-(E)-4-(p-N,N-dimethylaniline)-1-cyano-1-di(ethoxy)phosphinoylbuta-1,3-diene (DCP). This material shows a two-photon-induced fluorescence when excited in the infrared, in powder ∼6 times that obtained from a [2-[2-[4-dimethylaminophenyl]ethenyl]-6-methyl-4H-pyron-4-ylidene]propanedinitrile powder excited at 1.064 μm, and ∼50 times that of a 1-cm-long Rhodamine 640 solution (2 mM in methanol). Pulsed photoacoustic spectroscopy has been used to characterize the two-photon absorption band of the crystalline state. A high two-photon absorption coefficient, β=15 cm/GW, is reported, and an energy-conversion yield of 2.0% (incoherent fluorescence) was obtained in a DCP monocrystal in a single-pass beam configuration. Finally, a correlation is shown between the polarization of the excitation radiation and the crystalline structure of the material.
BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma (2008)

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.
Invariant Chain Induces B Cell Maturation by Activating a TAFII105-NF-κB-dependent Transcription Program (2001)

Early stages of B cell development occur in the bone marrow, resulting in formation of immature B cells. From there these immature cells migrate to the spleen where they differentiate to mature cells. This final maturation step is crucial for the B cells to become responsive to antigens and to participate in the immune response. Recently, invariant chain (Ii), a major histocompatibility complex class II chaperone, as well as the transcription factors c-Rel and p65/RelA, were found to play a role in the final antigen-independent differentiation stage of B cells in the spleen. In this study, we investigated a possible link between Ii-dependent B cell maturation and the NF-kappaB pathway. Our studies indicate that Ii-induced B cell maturation involves activation of transcription mediated by the NF-kappaB p65/RelA homodimer and requires the B cell-enriched coactivator TBP-associated factor (II)105.
Improved Activity of an Actin-resistant DNase I Variant on the Cystic Fibrosis Airway Secretions (2001)

In cystic fibrosis (CF), actin and DNA originating from inflammatory cells contribute to the thickness of airway secretions. Actin can bind to DNA-rich fibers and potently inhibit the enzymatic activity of rhDNase. The in vitro effects of the actin-resistant rhDNase variant (A114R) were analyzed and compared with those of the wild-type rhDNase. Frozen and thawed CF airway secretions were incubated for 30 min with different concentrations (0.1, 0.5, 1, 5, or 10 microg/ml) of either actin-resistant rhDNase or wild-type rhDNase. We observed that both the wild-type and the actin-resistant rhDNase significantly decreased (p < 0.05 and p < 0.001, respectively) the airway secretion viscosity. The decrease in airway secretion viscosity was significant even at low concentrations (0.1 microg/ml) of the actin-resistant variant. Incubation with the actin-resistant variant resulted in a significant decrease (p < 0.02) of the airway secretion contact angle and cough transport. A significantly higher (p < 0.01) increase in contact angle and cough transport of airway secretions was observed at 10 microg/ml with the actin-resistant variant as compared with the wild-type rhDNase. The present study had demonstrated that the actin-resistant rhDNase variant (A114R) has an enhanced capacity to improve the physical properties and cough transport of airway secretions from patients with cystic fibrosis.
PHOTODYNAMIC INACTIVATION OF E. COLI BY ROSE BENGAL IMMOBILIZED ON POLYSTYRENE BEADS (1978)

Abstract. The photodynamic inactivation of E. coli by visible light and O 2 was found to occur in the presence of the sensitizer rose bengal, immobilized by covalent bonding to polystyrene beads. The demonstrated absence of significant amounts of dissolved rose bengal indicated that an inactivation mechanism based on penetration of sensitizer molecules into the cell's interior could not be operating. Survival curves typically exhibited induction periods followed by rapid exponential death, with 99.99% kill requiring 1–2 h depending on conditions. A mechanism involving the participation of photo‐generated singlet excited oxygen O 2 ( 1 δ) in inactivation of E. coli is proposed. The photodynamic inactivation rate increased significantly in H 2 O compared with H 2 O, which is evidence supporting singlet oxygen as an active intermediate, since O 2 ( 1 δ) has a much longer lifetime in H 2 O than in H 2 O. H 2 O did not act as a short term poison in the absence of sensitizer.
Employing Plasmas as Gaseous Electrodes at the Free Surface of Ionic Liquids: Deposition of Nanocrystalline Silver Particles (2006)

Plasma-electrochemical deposition: Metals can be deposited on the surface of an ionic liquid by electrochemical reduction with free electrons from a low-temperature plasma (see picture). This unusual reaction represents a novel electrochemical process—leading to the reproducible growth of nanoscale products. The preparation of silver nanoparticles is presented as an experimental example.
Crystal Structures of Penicillin-Binding Protein 6 from Escherichia coli (2009)

Penicillin-binding protein 6 (PBP6) is one of the two main dd-carboxypeptidases in Escherichia coli, which are implicated in maturation of bacterial cell wall and formation of cell shape. Here, we report the first X-ray crystal structures of PBP6, capturing its apo state (2.1 Å), an acyl-enzyme intermediate with the antibiotic ampicillin (1.8 Å), and for the first time for a PBP, a preacylation complex (a “Michaelis complex”, determined at 1.8 Å) with a peptidoglycan substrate fragment containing the full pentapeptide, NAM-(l-Ala-d-isoGlu-l-Lys-d-Ala-d-Ala). These structures illuminate the molecular interactions essential for ligand recognition and catalysis by dd-carboxypeptidases, and suggest a coupling of conformational flexibility of active site loops to the reaction coordinate. The substrate fragment complex structure, in particular, provides templates for models of cell wall recognition by PBPs, as well as substantiating evidence for the molecular mimicry by β-lactam antibiotics of the peptidoglycan acyl-d-Ala-d-Ala moiety.
Sodium Channel β4, a New Disulfide-Linked Auxiliary Subunit with Similarity to β2 (2003)

The principal alpha subunit of voltage-gated sodium channels is associated with auxiliary beta subunits that modify channel function and mediate protein-protein interactions. We have identified a new beta subunit termed beta4. Like the beta1-beta3 subunits, beta4 contains a cleaved signal sequence, an extracellular Ig-like fold, a transmembrane segment, and a short intracellular C-terminal tail. Using TaqMan reverse transcription-PCR analysis, in situ hybridization, and immunocytochemistry, we show that beta4 is widely distributed in neurons in the brain, spinal cord, and some sensory neurons.beta4 is most similar to the beta2 subunit (35% identity), and, like the beta2 subunit, the Ig-like fold of beta4 contains an unpaired cysteine that may interact with the alpha subunit. Under nonreducing conditions, beta4 has a molecular mass exceeding 250 kDa because of its covalent linkage to Nav1.2a, whereas on reduction, it migrates with a molecular mass of 38 kDa, similar to the mature glycosylated forms of the other beta subunits. Coexpression of beta4 with brain Nav1.2a and skeletal muscle Nav1.4 alpha subunits in tsA-201 cells resulted in a negative shift in the voltage dependence of channel activation, which overrode the opposite effects of beta1 and beta3 subunits when they were present. This novel, disulfide-linked beta subunit is likely to affect both protein-protein interactions and physiological function of multiple sodium channel alpha subunits.
In colorectal carcinoma patients, serum vitamin D levels vary according to stage of the carcinoma (1999)

An inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage has been demonstrated for the first time, to the authors' knowledge, in colorectal carcinoma patients. Because 1,25(OH)2D3 has been shown to inhibit proliferation of colonic epithelial cells, decreased serum levels may facilitate the growth of colorectal carcinoma and influence its biologic behavior.
Anti-HIV-1 NNRT agents: Acylamino Pyrryl Aryl Sulfones (APASs) as truncated analogues of tricyclic PBTDs (2002)

Pyrryl Aryl Sulfones (PASs) bearing acylamino moieties at position 2 of the benzene ring were designed as truncated analogs of pyrrolo[1,2b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs). Acylarnino-PASs (APASs) were synthesized by reacting 1-(2-amino-5-chlorobenzenesulfonyl)-2-ethoxycarbonyl-1H-pyrrole with alkanoyl, aroyl or benzenesulfonyl halides in the presence of pyridine or sodium hydrogen carbonate. Some of test compounds were achieved by treating 1-(2-bromoacetylamino-5-chlorobenzenesulfonyl)-2-ethoxycarbonyl-1H-pyrrole with appropriate amines, heterocycles or sodium thiomethoxide. Reaction of 1-(2-acetylamino-5-chlorobenzenesulfonyl)-1H-pyrrole with acetyl chloride in the presence of boron trifluoride ethyl etherate or aluminum chloride afforded the related 2- and 3-acetyl-1H-pyrrole- isomers. The most potent derivatives 1-[2-(1-X-acetyl)amino-5-chlorobenzenesulfonyl]-2-ethoxycarbonyl-1H-pyrroles (X = CH3O, CH3S) were active at submicromolar concentrations, comparable with that of nevirapine. Various derivatives were as active as the related cyclic pyrrolobenzothiadiazepines (PBTDs). A binding mode investigation by molecular modeling and docking studies is reported for these novel NNRTIs. Furthermore, some information about the relation between hydrophobicity and anti-HIV activity were evaluated using calculated logP values.
A critical examination of the mechanics of dynamic NBTI for PMOSFETs (2004)

The physics of frequency-dependent shift in transistor parameters due to negative bias temperature instability (NBTI) is examined using numerical and analytical solutions of the reaction-diffusion model (R-D). We find that the magnitude of NBTI degradation depends on frequency through a complex interplay of reaction- and diffusion-limited trap generation processes, and that the intrinsic symmetry of the stress and relaxation phases can account for the relatively weak frequency dependence of the NBTI phenomenon. We also show that the model is consistent with the broad features of the dynamic NBTI problem and can provide an adequate framework to discuss NBTI issues.
Distribution and intensity of constraint in mammalian genomic sequence (2005)

Comparisons of orthologous genomic DNA sequences can be used to characterize regions that have been subject to purifying selection and are enriched for functional elements. We here present the results of such an analysis on an alignment of sequences from 29 mammalian species. The alignment captures approximately 3.9 neutral substitutions per site and spans approximately 1.9 Mbp of the human genome. We identify constrained elements from 3 bp to over 1 kbp in length, covering approximately 5.5% of the human locus. Our estimate for the total amount of nonexonic constraint experienced by this locus is roughly twice that for exonic constraint. Constrained elements tend to cluster, and we identify large constrained regions that correspond well with known functional elements. While constraint density inversely correlates with mobile element density, we also show the presence of unambiguously constrained elements overlapping mammalian ancestral repeats. In addition, we describe a number of elements in this region that have undergone intense purifying selection throughout mammalian evolution, and we show that these important elements are more numerous than previously thought. These results were obtained with Genomic Evolutionary Rate Profiling (GERP), a statistically rigorous and biologically transparent framework for constrained element identification. GERP identifies regions at high resolution that exhibit nucleotide substitution deficits, and measures these deficits as "rejected substitutions". Rejected substitutions reflect the intensity of past purifying selection and are used to rank and characterize constrained elements. We anticipate that GERP and the types of analyses it facilitates will provide further insights and improved annotation for the human genome as mammalian genome sequence data become richer.
Study on adaptive reference picture selection coding scheme for the NEWPRED-receiver-oriented mobile visual communication system (2002)

The NEWPRED method is effective in preventing the propagation of transmission errors in real-time video communication. Its performance depends on round-trip delay and the size of the reference picture memory. This paper presents a new method of reference picture selection that adapts to the conditions at the receiving side in a way that is controlled by that side.
Optical wavelength routing, translation, and packet/cell switched networks (1996)

We study several models for fixed-size packet/cell switching (e.g., 53 bytes for asynchronous transfer mode) in wavelength routed optical networks with an emphasis on throughput performance analysis. In particular, we examine the associated trade-offs between functionality and hardware complexity. The basic model here is a two-sided "switch" or sorter. Cells generated at user inputs destined for user outputs are allowed to reach their destinations by recirculation or multihop through a fixed wavelength routed optical network a number of times. Using algebraic techniques, we analyze the basic model and its variations that use different types of wavelength translation for their capability to achieve permutations of cells from inputs to outputs. In particular, we showed that when cell-by-cell wavelength translation functionality is allowed, the number of recirculations in the network to achieve all permutations is 3 log/sub W/ N where W is the number of wavelengths. The resultant normalized per user throughput of 1/3 log/sub W/ N is close to the conjectured optimal of 1/(2 log/sub W/ N-1) under the conditions specified in the model. Finally, using another model we show that it is possible to achieve a normalized per user throughput of 1 and we calculate the amount of extra hardware required for this purpose.
Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening (2018)

As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.