gebhart/patrepeval huggingface dataset:
Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin–Ran Protein Complex (2012)

Abstract Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR.
Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates (1997)

Leucine-rich nuclear export signals (NESs) are recognized by the NES receptor exportin 1 and are central to the export of multiple shuttling proteins and RNAs. The export of messenger RNA in vertebrates was, however, thought to occur by a different pathway, because inhibition by injection of a synthetic Rev NES conjugate could not be demonstrated. Here we find that peptide conjugates composed of the NES of either protein kinase A inhibitor protein (PKI) or the HIV-1 Rev protein, when coupled to human serum albumin, are potent inhibitors of mRNA and small nuclear RNA export. These results provide direct evidence that mRNA export in vertebrates depends on interactions between an NES and its cognate NES receptors. PKI NES conjugates are significantly more efficient at inhibiting RNA export than are REV NES conjugates, indicating that different NESs may have different abilities to promote protein and RNA export. Surprisingly, an expected control conjugate containing the mutant Rev NES sequence M10 strongly inhibited the export of intronless dihydrofolate reductase mRNA. Nuclear injection of NES peptide conjugates led to mislocalization to the nucleus of 10-20% of the cytoplasmic Ran GTPase-binding protein (RanBP1) indicating that RanBP1 shuttles between the nucleus and the cytoplasm via an NES pathway. These results demonstrate that in vertebrates the export of mRNA, like that of small nuclear RNA, 5S rRNA, and transport factors such as RanBP1, employs NES-mediated molecular machinery.
Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. (1994)

GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. Human GMP synthetase has been purified to homogeneity, and a cDNA encoding the enzyme has been isolated from the T-lymphoblastoma cell line, A3.01. The open reading frame encodes a protein of 693 amino acids with a predicted molecular weight of 76,725. The cDNA complements a guaA mutant of Escherichia coli, which lacks a functional GMP synthetase and extracts from the transformed E. coli exhibit GMP synthetase activity, which is absent in the parental strain. RNA hybridization analysis shows that human GMP synthetase is encoded by a single 2.4-kilobase message. DNA hybridization analysis suggests that the human GMP synthetase is encoded by one gene. In several human cell lines, the level of mRNA expression is substantially higher in proliferating, transformed cells than in nontransformed cells. In two transformed cell lines, treatment with phorbol ester inhibits proliferation and results in a dramatic down-regulation in the levels of GMP synthetase mRNA and protein.
Protamine-Induced Hypocalcemia (1970)

Protamine, administered intravenouslyin doses of 5–10 mg/kg, induced hypocalcemia and hypophosphatemia in intact and nephrectomized rats, and hypocalcemia in thyroparathyroidectomized rats. Protamine inhibited parathyroid hormone-induced bone resorption in cultured calvariae of newborn mice, and both acute and long-term studies using 46Ca in the intact rat suggested that protamine also inhibited bone resorption in vivo. Whereas protamine appeared to mimic the action of thyrocalcitonin in the above respects, the mechanism of protamine-induced hypocalcemia probably differs from that of thyrocalcitonin. The dose-response curves for hypocalcemia induced by protamine and by thyrocalcitonin were not parallel. The hypercalcemic effect of dibutyryl cyclic AMP was blocked by protamine, and protamine produced hypocalcemia in the presence of theophylline, suggesting that 3′,5′-cyclic AMP may not be involved. Protamine was apparently cleared from blood, or bound to some fraction of blood, very rapidly; heparin administered 5 min before protamine prevented hypocalcemia, but was ineffective when given 5 min after protamine. The experimental evidence suggests that protamine produces hypocalcemia and hypophosphatemia by direct inhibition of bone resorption. (Endocrinology87:1211, 1970)
TEMPERATURE TUNING OF AN ORGANIC DYE LASER (1968)

The wavelength spectrum of an organic dye laser (DTTC in ethanol) pumped by a Q-switched ruby laser has been measured as a function of temperature (−117°C to +78°C) for several dye concentrations. Absorption and fluorescence spectra were also obtained. The results are in qualitative agreement with the model of a vibrationally broadened two-level system, each of which is separately thermalized.
Use of Nanoparticles for Cerebral Cancer (2008)

Nanoparticles made of poly(butyl cyanoacrylate) (PBCA) or poly(lactic-co-glycolic acid) (PLGA) coated with polysorbate 80 or poloxamer 188 enable the transport of cytostatics such as doxorubicin across the blood-brain barrier (BBB). Following intravenous injection to rats bearing intracranially the very aggressive glioblastoma 101/8 these particles loaded with doxorubicin significantly increased the survival times and led to a complete tumor remission in 20-40% of the animals. Moreover, these particles considerably reduced the dose-limiting cardiotoxicity and also the testicular toxicity of this drug. The drug transport across the BBB by nanoparticles appears to be due to a receptor-mediated interaction with the brain capillary endothelial cells, which is facilitated by certain plasma apolipoproteins adsorbed by nanoparticles in the blood.
A comparison of the metabolic complications and hospital course of severe anorexia nervosa by binge-purge and restricting subtypes (2017)

This study examines adult patients with severe, life-threatening anorexia nervosa who were admitted to an inpatient, medical stabilization unit between October 1, 2008 and December 31, 2014. Specifically, the study compares anorexia nervosa, binge purge subtype (AN-BP) and anorexia nervosa, restricting subtype (AN-R) on admission measures, hospital course, and outcomes. Of the 232 patients, 46% (N = 108) had AN-BP. Patients with AN-R manifested a higher frequency of underweight-mediated medical complications, including bone marrow dysfunction, hepatic dysfunction, and hypoglycemia. Understanding the pathophysiologic differences between severe AN-R and AN-BP is essential to understanding the abnormalities seen on clinical presentation, guiding appropriate clinical treatment, and predicting medical complications during refeeding.
Improved detectability in low signal‐to‐noise ratio magnetic resonance images by means of a phase‐corrected real reconstruction (1989)

We show that for magnetic resonance (MR) images with signal-to-noise ratio (SNR) less than 2 it is advantageous to use a phase-corrected real reconstruction, rather than the more usual magnitude reconstruction. We discuss the results of the phase correction algorithm used to experimentally verify the result. We supplement the existing literature by presenting closed form expressions (in an MR context) for the probability distribution and first moments of the signal resulting from a magnitude reconstruction.
The Treatment of Cancer with Activated Cytotoxic Leukocyte Subsets (1988)

Cancer biotherapy focuses on stimulating natural defense mechanisms designed to control or eradicate cancer. Many distinct cancer biotherapy strategies have been formulated over the past two decades; one of the most promising involves the removal of cytotoxic leukocyte subsets from cancer patients, augmenting the cytotoxic function of these cells ex vivo and re-administering these activated cells with additional function-enhancing biologicals. This approach is termed adoptive cellular immunotherapy and is best represented at present by the activated killer monocyte and the lymphokinc activated killer cell therapies. The activation of cytotoxic monocytes with gamma interferon and the activation of cytotoxic lymphocytes with interleukin-2 are prototypic examples of adoptive immunotherapy research activity which is likely to expand in the near future.
Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors (2013)

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications (2002)

Microelectronic arrays have been developed for DNA hybridization analysis of point mutations, single nucleotide polymorphisms, short tandem repeats and gene expression. In addition to a variety of molecular biology and genomic research applications, such devices will also be used for infectious disease detection, genetic and cancer diagnostics, and pharmacogenomic applications. These microelectronic array devices are able to produce defined electric fields on their surfaces that allow charged molecules and other entities to be transported to or from any test site or micro-location on the planar surface of the device. These molecules and entities include DNA, RNA, proteins, enzymes, antibodies and cells. Electronic-based molecule addressing and hybridization can then be carried out, where the electric field is now used to greatly accelerate the hybridization reactions that occur on the selected test sites. When reversed, the electric field can be used to provide an additional parameter for improved hybridization. Special low-conductance buffers have been developed that provide for the rapid transport of the DNA molecules and facilitate the electronic hybridization reactions under conditions that do not support hybridization. Important to the device function is the permeation layer that overcoats the underlying microelectrodes. Generally composed of a porous hydrogel material impregnated with attachment chemistry, this permeation layer prevents the destruction of analytes at the active microelectrode surface, ameliorates the adverse effects of electrolysis products on the sensitive hybridization and affinity reactions, and serves as a support structure for attaching DNA probes and other molecules to the array. The microelectronic chip or array device is incorporated into a cartridge package (NanoChip trade mark cartridge) that provides the electronic, optical, and fluidic interfacing. A complete instrument system (NanoChip trade mark Molecular Biology Workstation) provides a chip loader, fluorescent reader, computer control interface and data display screen. The probe loader component allows DNA probes or target molecules (polymerase chain reactions amplicons, genomic DNA, RNA, etc.) to be selectively addressed to the array test sites, providing the end-user with 'make your own chip' capabilities. The electronic hybridization can then be carried out and the chip analyzed using a fluorescent detector system. In addition to carrying out rapid, accurate and highly reliable genotyping (point mutations, single nucleotide polymorphisms, short tandem repeats), other future applications include gene expression analysis, or on-chip amplification, immunoassays and cell separation and selection. Smaller and more compact systems are also being designed for portable sample to answer and point of care diagnostics.
Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels (2003)

Recently, cationic liposomes have been shown to preferentially target the angiogenic endothelium of tumors. It was the aim of our study to investigate the influence of liposomal surface charge on the uptake and kinetics of liposomes into solid tumors and tumor vasculature. Experiments were performed in the amelanotic hamster melanoma A-Mel-3 growing in the dorsal skinfold chamber preparation of male Syrian golden hamsters. Fluorescently labeled liposomes with different surface charge were prepared. Accumulation of i.v. injected liposomes was assessed by quantitative intravital fluorescence microscopy of tumor and surrounding host tissue. The histological distribution of liposomes was analyzed by double-fluorescence microscopy 20 min after application of fluorescently labeled lectin as a vascular marker. After i.v. application of anionic and neutral liposomes, we observed an almost homogeneous distribution of liposome-induced fluorescence throughout the chamber preparation without specific targeting to tumor tissue. In contrast, cationic liposomes exhibited a significantly enhanced accumulation in tumor tissue and tumor vasculature up to 3-fold compared to surrounding tissue (p<0.05). The histological distribution of neutral and anionic liposomes revealed extravasation 20 min after i.v. injection, while cationic liposomes displayed a highly selective accumulation on the vascular endothelium. In conclusion, cationic liposomes exhibited a preferential uptake in angiogenic tumor vessels and therefore may provide an efficient tool for the selective delivery of diagnostic or therapeutic agents to angiogenic blood vessels of solid tumors. On the other hand, anionic and neutral liposomes may be used as carriers of drugs to the extravascular compartment of tumors due to their extravasation.
A dual-targeting nanocarrier based on modified chitosan micelles for tumor imaging and therapy (2014)

Conventional chemotherapy suffers from non-specificity, lack of aqueous solubility and multidrug resistance. Tumor-targeting nanotherapeutics exhibit unique advantages in the delivery of drugs specifically into tumors. Here, folic acid (FA), methionine (Met) and a near infrared (NIR) fluorescence probe (cypate, ICG derivative) were all bio-conjugated to succinyl-chitosan (SC) micelles. An anti-cancer drug (paclitaxel, PTX) was loaded into the hydrophobic cores of the formed FA–Met–SC–ICG derivative (FMSCI) micelles, which were under 200 nm in size. In comparison with micelles containing a single targeting moiety (FA or Met), FA and Met co-mediated micelles presented excellent biocompatibility, much higher affinity for cancer cells and excellent tumor-specific distribution in tumor-bearing mice. In vivo anti-tumor activity demonstrated that PTX-loaded FMSCI provided favourable therapeutic efficacy for tumors. In this research, novel nanotherapeutics based on FMSCI loaded with an anti-cancer drug provide a promising nanocomposite for combined tumor-targeting imaging and therapy.
Optical waveguides in single layers of Ga1−xAlx As grown on GaAs substrates (1973)

Efficient low-loss optical waveguides have been made with the growth of only a single epilayer of Ga1−xAlx on GaAs substrates. The AlAs concentration gradient which is grown by liquid-phase epitaxy using thin gallium melts is the cause of the guiding.
Cobalt-Catalyzed Intramolecular C−H Amination with Arylsulfonyl Azides (2007)

Cobalt complexes of porphyrins are effective catalysts for intramolecular C-H amination with arylsulfonyl azides. The cobalt-catalyzed process can proceed efficiently under mild and neutral conditions in low catalyst loading without the need of other reagents or additives, generating nitrogen gas as the only byproduct. The catalytic system can be applied to primary, secondary, and tertiary C-H bonds and is suitable for a broad range of arylsulfonyl azides, leading to high-yielding syntheses of various benzosultams.
Cesarean Delivery Is Associated With Celiac Disease but Not Inflammatory Bowel Disease in Children (2010)

The mode of delivery and associated alterations in the development of the enteric homeostasis during the neonatal period might influence the incidence of celiac disease.
Oligonucleotide therapeutics: 25 years agrowing. (2004)

The year 2003 saw the 25th anniversary of the first publication of research using antisense oligonucleotides in cells. Oligonucleotides complementary to RNA use a variety of mechanisms to provide a direct link from genomics to gene function, drug target validation and new lead therapeutics. Other applications use oligonucleotides that bind to DNA or proteins to serve similar purposes. In this review, recent advances in mechanisms, chemical modifications and uses of oligonucleotides are discussed, and a broad overview of progress, mainly concerning RNA inhibition, is provided.
Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90 (2009)

Although therapeutically targeting a single signaling pathway that drives tumor development and/or progression has been effective for a number of cancers, in many cases this approach has not been successful. Targeting networks of signaling pathways, instead of isolated pathways, may overcome this problem, which is probably due to the extreme heterogeneity of human tumors. However, the possibility that such networks may be spatially arranged in specialized subcellular compartments is not often considered in pathway-oriented drug discovery and may influence the design of new agents. Hsp90 is a chaperone protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression. Here, we report the synthesis and properties of Gamitrinibs, a class of small molecules designed to selectively target Hsp90 in human tumor mitochondria. Gamitrinibs were shown to accumulate in the mitochondria of human tumor cell lines and to inhibit Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic" mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria. Therefore, combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific subcellular compartments, may generate effective anticancer drugs with novel mechanisms of action.
Digital spectra of nonuniformly sampled signals: a robust sampling time offset estimation algorithm for ultra high-speed waveform digitizers using interleaving (1990)

The author presents an algorithm for estimating the sampling time offsets encountered at the parallel sampling paths of an ultra-high-speed waveform digitizing system which is realized by interleaving many sample-hold and A/D (analog/digital) converter modules. One obvious application of this algorithm is to feed these estimates back to adjustable delay units in all the sampling paths to compensate the sampling-time offsets. Simulation results indicate that with an 8-bit quantizer the residual timing error can be reduced to just about 0.05% of the sampling period.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The Role of Cancer-Derived Exosomes in Tumorigenicity & Epithelial-to-Mesenchymal Transition (2017)

Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells lose their basement membrane interaction and acquire a more migratory, mesenchymal phenotype. EMT has been implicated in cancer cell progression, as cells transform and increase motility and invasiveness, induce angiogenesis, and metastasize. Exosomes are 30-100 nm membrane-bound vesicles that are formed and excreted by all cell types and released into the extracellular environment. Exosomal contents include DNA, mRNA, miRNA, as well as transmembrane- and membrane-bound proteins derived from their host cell contents. Exosomes are involved in intercellular signaling, both by membrane fusion to recipient cells with deposition of exosomal contents into the cytoplasm and by the binding of recipient cell membrane receptors. Recent work has implicated cancer-derived exosomes as an important mediator of intercellular signaling and EMT, with resultant transformation of cancer cells to a more aggressive phenotype, as well as the tropism of metastatic disease in specific cancer types with the establishment of the pre-metastatic niche.