gebhart/patrepeval huggingface dataset:
Targeted drug delivery for cancer therapy: the other side of antibodies (2012)

Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients.
Isolation and characterization of a cDNA clone for the gamma subunit of bovine retinal transducin. (1984)

We have isolated and characterized a cDNA clone that encodes the gamma subunit of transducin, the guanine nucleotide binding regulatory protein found in vertebrate photoreceptors. The gamma subunit was separated from the alpha and beta subunits of transducin and purified to homogeneity by reversed-phase high performance liquid chromatography. The sequence of the first 45 amino acids at the amino terminus of this polypeptide was then determined by automated Edman degradation. Oligodeoxynucleotide probes corresponding to two nonoverlapping regions of this sequence were synthesized and then used to screen a bovine retinal cDNA library. One probe, T gamma 1, was a mixture of 32 different heptadecamers complementary to all possible mRNA sequences that could encode a portion of the T gamma sequence; the other probe, T gamma 2, was a mixture of 128 different heptadecamers. Thirteen clones that hybridized with T gamma 1 were selected. Only one of these had an insert that also hybridized with T gamma 2. The DNA sequence of this insert encodes a 73-amino acid polypeptide that corresponds to the transducin gamma subunit on the basis of amino-terminal sequence, amino acid composition, and carboxyl-terminal sequence. The molecular weight of the mature gamma subunit is 8400. It appears to be synthesized as a discrete polypeptide and not as a domain of a larger precursor polyprotein. The transducin gamma subunit is very hydrophilic and acidic; it has 19 acidic and 11 basic amino acids as well as three cysteine residues. Furthermore, significant homology was found in comparisons of the nucleic acid sequence corresponding to the carboxyl terminus of the gamma transducin transcript with the sequences corresponding to the carboxyl terminus of ras oncogene products, suggesting a possible ancestral relationship between these genes.
The Chronic Myelogenous Leukemia-Specific P210 Protein Is the Product of the bcr / abl Hybrid Gene (1986)

Chronic myelogenous leukemia (CML) is a human disease associated with a consistent chromosomal translocation that results in sequences from the c-abl locus on chromosome 9 being fused to sequences in a breakpoint cluster region (bcr) on chromosome 22. CML cells have two novel products: an 8.5-kilobase RNA transcript containing both abl and bcr and a 210-kilodalton phosphoprotein (P210) recognized by v-abl-specific antisera. To test whether the P210 is the product of the novel 8.5-kilobase bcr/abl fusion transcript, antibodies were prepared against c-abl and bcr determinants. By using these reagents and v-abl-specific antisera, it was demonstrated that the P210 in CML cells is indeed the protein product of the 8.5-kilobase transcript. By analogy to the gag/abl fusion protein of Abelson murine leukemia virus, the replacement of amino terminal c-abl sequences by bcr sequences in P210 may create a transforming protein involved in CML. A 190-kilodalton phosphoprotein that is a candidate for the normal bcr protein was identified in both HeLa and K562 cells.
Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome (2004)

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.
Characterization of genomic and complementary DNA sequence of human C-reactive protein, and comparison with the complementary DNA sequence of serum amyloid P component. (1985)

Complementary and genomic DNA clones corresponding to the human C-reactive protein (CRP) mRNA and structural gene have been analyzed and compared. Nucleotide sequencing of the coding regions of both cDNA and genomic DNA revealed an additional 19 amino acid peptide not described in the published CRP amino acid sequence. The CRP gene contains a single 278 base pair intron within the codon specifying the third residue of mature CRP. The intron contains a repetitive sequence (GT)15G(GT)3 which is similar to structures capable of adopting the Z-DNA form. A comparison of CRP coding and amino acid sequences with those of serum amyloid P component revealed striking overall homology which was not uniform: a region of limited conservation is bounded by two highly conserved regions.
Capacitance and conductance characterization of ferrocene-containing self-assembled monolayers on silicon surfaces for memory applications (2002)

Self-assembled monolayers of 4-ferrocenylbenzyl alcohol attached to silicon provided the basis for electrolyte-molecule-silicon capacitors. Characterization by conventional capacitance and conductance techniques showed very high capacitance and conductance peaks near ∼0.6 V associated with charging and discharging of electrons into and from discrete levels in the monolayer owing to the presence of the redox-active ferrocenes. The reversible charge trapping of these molecules suggest their potential application in memory devices. Due to the molecular scalability and low-power operation, molecular-silicon hybrid devices may be strong candidates for next-generation electronic devices.
Approaching capacity by equiprobable signaling on the Gaussian channel (1993)

For the additive white Gaussian noise channel, there is a gap between the channel capacity and the highest achievable rate of equiprobable uniformly spaced one-dimensional signaling. It is commonly believed that approaching channel capacity requires the constituent one-dimensional signal points to have a Gaussian probability distribution. It is shown that the channel capacity can be achieved by equiprobable signaling with geometrical, Gaussian-like signal sets. Construction of these signal constellations is explicitly given. This result implicates that it is possible to approach channel capacity without using any kind of shaping codes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease (2010)

This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).
Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. (1995)

VEGF may be one of the long anticipated factors linking retinal ischemia and intraocular angiogenesis. Irrespective of the cause of retinal ischemia, sustained overproduction of VEGF by ischemic retinal cells may promote retinal and iris neovascularization in a number of neovascular eye diseases.
Dual modality instrument for simultaneous optical coherence tomography imaging and fluorescence spectroscopy (2004)

We develop a dual-modality device that combines the anatomical imaging capabilities of optical coherence tomography (OCT) with the functional capabilities of laser-induced fluorescence (LIF) spectroscopy. OCT provides cross-sectional images of tissue structure to a depth of up to 2 mm with approximately 10-µm resolution. LIF spectroscopy provides histochemical information in the form of emission spectra from a given tissue location. The OCT subsystem utilizes a superluminescent diode with a center wavelength of 1300 nm, whereas a helium cadmium laser provides the LIF excitation source at wavelengths of 325 and 442 nm. Preliminary data are obtained on eight postmortem aorta samples, each 10 mm in length. OCT images and LIF spectra give complementary information from normal and atherosclerotic portions of aorta wall. OCT images show structures such as intima, media, internal elastic lamina, and fibrotic regions. Emission spectra ratios of 520/490 (325-nm excitation) and 595/635 (442-nm excitation) could be used to identify normal and plaque regions with 97 and 91% correct classification rates, respectively. With miniaturization of the delivery probe and improvements in system speed, this dual-modality device could provide a valuable tool for identification and characterization of atherosclerotic plaques.
The Site of the Inhibition of the Shikimate Pathway by Glyphosate (1980)

The nonselective herbicide glyphosate (n-[phosphonomethyl]glycine) inhibited the light-induced accumulation of phenylpropanoid substances (chlorogenic acid, procyanidin, rutin, anthocyanin) in etiolated buckwheat hypocotyls 90% at 1 millimolar. Structurally related compounds, such as n,n-bis[phosphonomethyl]glycine, aminomethylphosphonate, methylglycine, and iminodiacetate, had little or no inhibiting effects. Of all amino acids tested, only l-phenylalanine reversed the inhibition, and partial reversal of anthocyanin synthesis was achieved with chorismate, phenylpyruvate, trans-cinnamate, p-coumarate, and naringenin. Phenylalanine concentrations were reduced in glyphosate-treated hypocotyls, and glyphosate effectively reduced the high level of phenylalanine that was caused by the phenylalanine ammonia-lyase inhibitor l-alpha-aminooxy-beta-phenylpropionate. Glyphosate had no significant effect on the time course of phenylalanine ammonia-lyase activity in hypocotyls incubated either in the dark or in the light. Under appropriate feeding conditions, glyphosate inhibited the incorporation of [(14)C]shikimate into all three aromatic amino acids, and radioactive shikimate accumulated in the tissue. The results lead to the conclusion that glyphosate interferes with the shikimate pathway at or prior to the formation of chorismate.
A Cell Type-specific Constitutive Point Mutant of the Common β-Subunit of the Human Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Interleukin (IL)-3, and IL-5 Receptors Requires the GM-CSF Receptor α-Subunit for Activation (1999)

The high affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) consists of a cytokine-specific alpha-subunit (hGMRalpha) and a common signal-transducing beta-subunit (hbetac) that is shared with the interleukin-3 and -5 receptors. We have previously identified a constitutively active extracellular point mutant of hbetac, I374N, that can confer factor independence on murine FDC-P1 cells but not BAF-B03 or CTLL-2 cells (Jenkins, B. J., D'Andrea, R. J., and Gonda, T. J. (1995) EMBO J. 14, 4276-4287). This restricted activity suggested the involvement of cell type-specific signaling molecules in the activation of this mutant. We report here that one such molecule is the mouse GMRalpha (mGMRalpha) subunit, since introduction of mGMRalpha, but not hGMRalpha, into BAF-B03 or CTLL-2 cells expressing the I374N mutant conferred factor independence. Experiments utilizing mouse/human chimeric GMRalpha subunits indicated that the species specificity lies in the extracellular domain of GMRalpha. Importantly, the requirement for mGMRalpha correlated with the ability of I374N (but not wild-type hbetac) to constitutively associate with mGMRalpha. Expression of I374N in human factor-dependent UT7 cells also led to factor-independent proliferation, with concomitant up-regulation of hGMRalpha surface expression. Taken together, these findings suggest a critical role for association with GMRalpha in the constitutive activity of I374N.
The role of cytokines in the pathogenesis of rheumatoid arthritis. (1999)

Recombinant DNA technology has made it possible to identify the cytokines expressed in the joints of people with active rheumatoid arthritis (RA). Because a large number of cytokines are expressed in the rheumatoid synovium and many of these cytokines may have redundant biological functions, it was necessary to study cytokine regulation to identify potential therapeutic targets. The regulation of interleukin 1, a proven inducer of bone and cartilage destruction in the rheumatoid synovium, was thus studied and anti-tumour necrosis factor alpha (anti-TNF-alpha) antibody was found to reduce its synthesis markedly, as well as that of other cytokines, leading to our proposal of TNF-alpha as a therapeutic target. The further study of clinical trials in RA verified that the mechanism of action of anti-TNF-alpha includes the down-regulation of several pro-inflammatory agents, diminished leucocyte recruitment and possibly regulation of angiogenesis.
CD4+CD25highCD127low Regulatory T Cells in Peripheral Blood Are Not an Independent Factor for Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation (2012)

This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity.
Device transparency (2010)

This paper proposes a new storage model, device transparency , in which users view and manage their entire data collection from any of their devices, even from disconnected storage-limited devices holding only a subset of the entire collection.
An Efficient and Large-Scale Enantioselective Synthesis of PNP405:  A Purine Nucleoside Phosphorylase Inhibitor (2002)

An efficient and large-scale enantioselective synthesis of PNP405 (1), a purine nucleoside phosphorylase inhibitor, is described. This synthesis of 1 involved eight steps starting from o-fluorophenylacetic acid with a 21.6% overall yield and >99.5% enantiopurity. The key stereogenic center with (R)-configuration was created using Evans' asymmetric alkylation methodology. This synthesis also features the racemization-free reductive removal of the chiral auxiliary in 5 using sodium borohydride, protection of the gamma-cyano alcohol 6 as the trityl ether by a new water-assisted tritylation with trityl chloride and triethylamine or with trityl alcohol and catalytic trifluoroacetic acid, and an efficient one-pot cyclo-guanidinylation of 10 using cyanamide as the guanidinylating agent.
Perceptual models and the filtering of high-contrast achromatic images (1984)

A model based on research in the psychophysics of vision is developed for use in the design of image processing filters in order to quantify the results of image processing as perceived by a human observer. An alternate formulation of the classical frequency-domain filter design problem with both space and frequency-domain specifications is developed. New experimental results concerning the masking effect in the vicinity of edges are reported, and a structure of a model for detection of distortion in complex images is proposed. The ability of the model to predict the visibility of one-dimensional patterns in the vicinity of edges is tested. A distortion measure based on the model is introduced, and practical filter-design criteria are developed. Both FIR linear phase filters and IIR filters are used to demonstrate the applicability of the methods.
Growth Hormone Replacement in Healthy Older Men Improves Body Composition but Not Functional Ability (1996)

Physiologic doses of growth hormone given for 6 months to healthy older men with well-preserved functional abilities increased lean tissue mass and decreased fat mass. Although body composition improved with growth hormone use, functional ability did not improve. Side effects occurred frequently.
Gel-Coated Catheters as Drug Delivery Systems (1999)

Commercially available poly(ethylene oxide) [PEO] and poly (acrylic acid) [PAA] gel-coated balloon angioplasty catheters are investigated for their use as local drug delivery systems in terms of gel/solute interactions, solute loading, and release kinetics. The solutes investigated are methylene blue, methyl orange, acetaminophen, and ovalbumin which model cationic, anionic, nonionic, and protein compounds, respectively. Solute interactions with gel coatings are found to be consistent with observations with bulk gels. Oppositely charged gel coatings and solutes exhibit ion exchange. Gel coatings and solutes with the same charge demonstrate Donnan ion exclusion; exclusion is reduced upon the addition of salt to the solution. Nonionic interactions, such as size exclusion, are also seen. Loading of proteins in PEO-gel coatings can be approximately doubled with the addition of soluble dextran to the loading solution. Release of solutes from gel coatings is diffusion limited, though resistance may be due to the boundary layer as well as the gel.
Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function (2005)

Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The gamma-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.
Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor-binding protein-3 by enhancing its ubiquitin/proteasome-dependent degradation (2007)

The E7 protein encoded by the oncogenic human papillomavirus type 16 has been shown to bind and inactivate insulin-like growth factor-binding protein-3 (IGFBP-3), the pro-apoptotic product of a tumour suppressor gene; however, the molecular mechanism underlying E7-induced inactivation of IGFBP-3 remained uncertain. In this study, we map the IGFBP-3-binding domain for E7 to the nuclear localization signal in the conserved C-terminal domain of IGFBP-3. Moreover, we demonstrate that both proteins interact in the nucleus and that E7 induces polyubiquitination and proteasome-dependent proteolysis of nuclear IGFBP-3 in cervical cancer cells. This leads to a dramatic shortening of the half-life of nuclear IGFBP-3, whereas the stability of an E7-non-binding IGFBP-3 mutant is not affected by E7. Finally, we show that E7-mediated destruction of nuclear IGFBP-3 correlates with the inhibition of IGFBP-3-induced apoptotic cell death. These data are consistent with E7-induced ubiquitin/proteasome-dependent inactivation of nuclear IGFBP-3.
Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues (2005)

Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy approximately 4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.
Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor (2009)

NL63 coronavirus (NL63-CoV), a prevalent human respiratory virus, is the only group I coronavirus known to use angiotensin-converting enzyme 2 (ACE2) as its receptor. Incidentally, ACE2 is also used by group II SARS coronavirus (SARS-CoV). We investigated how different groups of coronaviruses recognize the same receptor, whereas homologous group I coronaviruses recognize different receptors. We determined the crystal structure of NL63-CoV spike protein receptor-binding domain (RBD) complexed with human ACE2. NL63-CoV RBD has a novel beta-sandwich core structure consisting of 2 layers of beta-sheets, presenting 3 discontinuous receptor-binding motifs (RBMs) to bind ACE2. NL63-CoV and SARS-CoV have no structural homology in RBD cores or RBMs; yet the 2 viruses recognize common ACE2 regions, largely because of a "virus-binding hotspot" on ACE2. Among group I coronaviruses, RBD cores are conserved but RBMs are variable, explaining how these viruses recognize different receptors. These results provide a structural basis for understanding viral evolution and virus-receptor interactions.