gebhart/patrepeval huggingface dataset:
Reduction of Electrical Interaction in Auditory Prostheses (1987)

The spread of current in multichannel implants results in excitation of largely identical neural populations regardless of which electrode is stimulated. This severely reduces the number of independent channels of information conveyed with monopolar or even bipolar stimulation. A method based on the thresholds of multiple electrode stimuli was developed to calculate accurately the mapping from electrode current levels to excitation levels at each neural site. For the implant subjects tested, this technique accurately predicted thresholds for arbitrary patterns of stimulation. Inverting this mapping matrix produced patterns, of stimulation that selectively stimulated only one neural site with a minimum of interaction, while satisfying current limit constraints. These sharpened stimuli exhibited lower interaction and were pitch ranked with greater consistency than either monopolar or bipolar stimuli.
Bacterial Adhesion at Synthetic Surfaces (1999)

A systematic investigation into the effect of surface chemistry on bacterial adhesion was carried out. In particular, a number of physicochemical factors important in defining the surface at the molecular level were assessed for their effect on the adhesion of Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli. The primary experiments involved the grafting of groups varying in hydrophilicity, hydrophobicity, chain length, and chemical functionality onto glass substrates such that the surfaces were homogeneous and densely packed with functional groups. All of the surfaces were found to be chemically well defined, and their measured surface energies varied from 15 to 41 mJ. m(-2). Protein adsorption experiments were performed with (3)H-labelled bovine serum albumin and cytochrome c prior to bacterial attachment studies. Hydrophilic uncharged surfaces showed the greatest resistance to protein adsorption; however, our studies also showed that the effectiveness of poly(ethyleneoxide) (PEO) polymers was not simply a result of its hydrophilicity and molecular weight alone. The adsorption of the two proteins approximately correlated with short-term cell adhesion, and bacterial attachment for L. monocytogenes and E. coli also correlated with the chemistry of the underlying substrate. However, for S. aureus and S. typhimurium a different pattern of attachment occurred, suggesting a dissimilar mechanism of cell attachment, although high-molecular-weight PEO was still the least-cell-adsorbing surface. The implications of this for in vivo attachment of cells suggest that hydrophilic passivating groups may be the best method for preventing cell adsorption to synthetic substrates provided they can be grafted uniformly and in sufficient density at the surface.
ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. (2014)

The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.
Influence of orange juice over the genotoxicity induced by alkylating agents: an in vivo analysis (2005)

There is considerable epidemiological evidence indicating an association between diets rich in fresh fruit and vegetables and a decreased incidence of cancers. Methyl methanesulfonate (MMS) and cyclophosphamide (CP) are alkylating agents that differ in their mode of action. MMS is a directly-acting, monofunctional agent, while CP is a bifunctional agent that requires metabolic activation to a reactive metabolite. To evaluate if orange juice could reduce DNA damage induced by these alkylating agents, mice were treated orally (by gavage) with MMS and CP, prior to and after treatment with orange juice. DNA damage was evaluated by the comet assay in peripheral white blood cells. Under these experimental conditions, orange juice reduced the extent of DNA damage caused by both mutagens. For MMS, the antigenotoxic effect of the orange juice was both protective (orange juice pre-treatment) and reparative (orange juice post-treatment); for CP, the effect was reparative only. The components of orange juice can have several biological effects, including acting as targets of toxicants and modulating metabolization/detoxification routes. Considering the different mechanisms of the action of the two drugs, different protective effects are suggested. These results demonstated the ability of the in vivo comet assay to detect in vivo modulation of MMS and CP mutagenicity by orange juice.
Translation initiation by using various N-acylaminoacyl tRNAs (2006)

Bioactive peptides isolated from natural sources have diverse acyl groups on the N-terminus. It is difficult to synthesize these peptides in vitro translation system because ribosomal peptide synthesis generally limits the N-terminal group to be N-formylmethionine (fMet). To overcome this restriction, we developed a novel methodology for the ribosomal synthesis of peptides having various terminal N-acyl groups with desired amino acids. In this methodology, two technologies, Flexizyme system consisting of artificial ribozymes and a reconstitute E. coli cell-free translation system (PURE system), were used. First, an amino acid carrying a desired N-acyl group was charged onto an initiation tRNA by the Flexizyme system. The addition of this N-acyl-aminoacyl-tRNA (N-acyl-aa-tRNA) to the PURE system allowed us to initiate the peptide synthesis with the designated N-acyl-amino acid. By means of this methodology, the translation was exclusively initiated by various N-terminal acyl groups as well as amino acids without contamination of N-formylmethionine.
Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts (2006)

Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-gamma1 and PKCepsilon.
Enzyme‐resistant isomalto‐oligosaccharides produced from Leuconostoc mesenteroides NRRL B‐1426 dextran hydrolysis for functional food application (2015)

The extracellular dextransucrase from Leuconostoc mesenteroides NRRL B-1426 was produced and purified using polyethylene glycol fractionation. In our earlier study, it was reported that L. mesenteroides dextransucrase synthesizes a high-molecular mass dextran (>2 × 10(6) Da) with ∼85.5% α-(1→6) linear and ∼14.5% α-(1→3) branched linkages. Isomalto-oligosaccharides (IMOs) were synthesized through depolymerization of dextran by the action of dextranase. The degree of polymerization of IMOs was 2-10 as confirmed by mass spectrometry. The nuclear magnetic resonance spectroscopic analysis revealed the presence of α-(1→3) linkages in the synthesized IMOs. The IMOs were resistant to dextranase, α-glucosidase, and α-amylase, and therefore can have potential application as food additives in the functional foods.
Protodioscin isolated from fenugreek (Trigonella foenumgraecum L.) induces cell death and morphological change indicative of apoptosis in leukemic cell line H-60, but not in gastric cancer cell line KATO III (2003)

Protodioscin (PD) was purified from fenugreek (Trigonella foenumgraecum L.) and identified by Mass, and 1H- and 13C-NMR. The effects of PD on cell viability in human leukemia HL-60 and human stomach cancer KATO III cells were investigated. PD displayed strong growth inhibitory effect against HL-60 cells, but weak growth inhibitory effect on KATO III cells. Morphological change showing apoptotic bodies was observed in the HL-60 cells treated with PD, but not in KATO III cells treated with PD. Flow cytometric analysis showed that the hypodiploid nuclei of HL-60 cells were increased to 75.2, 96.3, and 100% after a 3-day treatment with 2.5, 5, and 10 microM PD, respectively. The fragmentation by PD of DNA to oligonucleosomal-sized fragments, that is a characteristic of apoptosis, was observed to be both concentration- and time-dependent in the HL-60 cells. These findings suggest that growth inhibition by PD of HL-60 cells results from the induction of apoptosis by this compound in HL-60 cells.
A Family of Telomere-Associated Autonomously Replicating Sequences and Their Functions in Targeted Recombination in Hansenula polymorpha DL-1 (1999)

A family of multiple autonomously replicating sequences (ARSs) which are located at several chromosomal ends of Hansenula polymorpha DL-1 has been identified and characterized. Genomic Southern blotting with an ARS, HARS36, originating from the end of a chromosome, as a probe showed several homologues in the genome of H. polymorpha. Nucleotide sequences of the three fragments obtained by a selective cloning for chromosomal ends were nearly identical to that of HARS36. All three fragments harbored an ARS motif and ended with 18 to 23 identical repetitions of 5'-GGGTGGCG-3' which resemble the telomeric repeat sequence in other eukaryotes. Transformation of H. polymorpha with nonlinearized plasmids containing the newly obtained telomeric ARSs almost exclusively resulted in the targeted integration of a single copy or multiple tandem copies of the plasmid into the chromosomes. The sensitivity to exonuclease Bal31 digestion of the common DNA fragment in all integrants confirmed the telomeric origin of HARS36 homologues, suggesting that several chromosomal ends, if not all of them, consisted of the same ARS motif and highly conserved sequences observed in HARS36. Even though the frequencies of targeted recombination were varied among the ends of the chromosomes, the overall frequency was over 96%. The results suggested that the integration of the plasmids containing telemeric ARSs occurred largely through homologous recombination at the telomeric repeats, which serve as high-frequency recombination targets.
Active site of Pseudomonas aeruginosa exotoxin A. Glutamic acid 553 is photolabeled by NAD and shows functional homology with glutamic acid 148 of diphtheria toxin. (1987)

Photoaffinity labeling with native NAD, a method employed earlier with diphtheria toxin (DT), was used to identify an active site residue of Pseudomonas aeruginosa exotoxin A (ETA). An enzymically active fragment (Mr 27,000), derived by partial digestion of ETA with thermolysin, was irradiated with ultraviolet light (254 nm) in the presence of various radiolabeled preparations of NAD. Label from the nicotinamide moiety was efficiently transferred to the protein (maximally 0.79 mol/mol), and the label was exclusively located at position 553. This position, like that photolabeled in DT (position 148), corresponds to glutamic acid in the native protein. Chromatographically identical photo-products were generated at these positions in the two toxins. Glu-553 lies in a cleft in domain III that is believed to represent the active site of ETA, and other evidence supports the notion that Glu-553 of ETA and Glu-148 of DT are directly involved in catalysis. When Glu-553 of ETA was aligned with Glu-148 of DT, we found similarities of local primary structure not detected earlier. These results suggest that the catalytically active domains of ETA and DT may be evolutionarily related, and they provide information that should prove useful for preparing vaccines against ETA by recombinant DNA methods.
The Roles of CD4+T Cells in Tumor Immunity (2011)

Activation of CD8 + cytotoxic T cells has long been regarded as a major antitumor mechanism of the immune system. Emerging evidence suggests that CD4 + T cells are required for the generation and maintenance of effective CD8 + cytotoxic and memory T cells, a phenomenon known as CD4 + T-cell help. CD4 + T-cell help facilitates the optimal expansion, trafficking, and effector function of CD8 + T cells, thereby enhancing tumor destruction. In addition, a specialized subset of CD4 + T cells, CD4 + CD25 + regulatory T cells (T Regs ), effectively hampers anti-tumor immune responses, which has been proposed to be one of the major tumor immune evasion mechanisms. Here, we review recent advances in deciphering how anti-tumor immune responses are orchestrated by CD4 + T cells. We will also discuss the immunotherapeutic potential of CD4 + T-cell manipulation in anti-tumor immune response.
Uptake of Long-Circulating Immunoliposomes, Directed Against Colon Adenocarcinoma Cells, by Liver Metastases of Colon Cancer (2000)

Radiolabeled ([3H]cholesteryloleyl ether) immunoliposomes directed against rat colon adenocarcinoma CC531 cells were prepared by random coupling of a tumor cell-specific antibody, CC52, via a thio ether bond. In vitro binding experiments demonstrated a saturable and specific interaction of CC52-immunoliposomes, which could be inhibited by free non-coupled CC52 but not by irrelevant antibodies. The in vivo targeting potential of CC52-immunoliposomes, which were pegylated to achieve prolonged circulation times, was tested in an established rat liver CC531 metastasis model. Twenty-four hours after injection of the liposomes, 25% of the CC52-immunoliposomes were still present in the blood, which was comparable with the control liposomes (either with or without antibody). Liposomes were mainly taken up from the blood by the liver and the spleen, although hepatic uptake of the immunoliposomes was higher and splenic uptake was lower as compared to liposomes without antibody. Within the metastatic tumor nodules in the liver, uptake of both the CC52-immunoliposomes and non-specific immunoliposomes was significantly higher than that of control liposomes without antibody. Visualization of fluorescently or gold labeled CC52-immunoliposomes revealed that, although targeting to liver metastases was achieved, the immunoliposomes were mostly not associated with tumor cells but rather localized in tumor associated cells, probably macrophages.
A Microchip Approach for Practical Label-Free CD4+ T-Cell Counting of HIV-Infected Subjects in Resource-Poor Settings (2007)

Simple affordable CD4 cell counting is urgently needed to stage and monitor HIV-infected patients in resource-limited settings. To address the limitations of current approaches, we designed a simple, label-free, and cost-effective CD4 cell counting device using microfluidic technology. We previously described the fabrication of a microfluidic system for high-efficiency isolation of pure populations of CD4+ T cells based on cell affinity chromatography operated under controlled flow. Here, we compare the performance of a microfluidic CD4 cell counting device against standard flow cytometry in 49 HIV-positive subjects over a wide range of absolute CD4 cell counts. We observed a close correlation between CD4 cell counts from the microchip device and measurements by flow cytometry, using unprocessed whole blood from HIV-positive adult subjects. Sensitivities for distinguishing clinically relevant thresholds of 200, 350, and 500 cells/microL are 0.86, 0.90, and 0.97, respectively. Specificity is 0.94 or higher at all thresholds. This device can serve as a functional cartridge for fast, accurate, affordable, and simple CD4 cell counting in resource-limited settings.
PTC299 Is a Novel DHODH Inhibitor That Modulates VEGFA mRNA Translation and Inhibits Proliferation of a Broad Range of Leukemia Cells (2017)

PTC299 was identified in a phenotypic high through put screen as an inhibitor of VEGFA mRNA translation and had been in clinical development for solid tumors. Here we demonstrate that PTC299 inhibits dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis. Our results demonstrate an unexpected role for pyrimidine nucleotide levels in the regulation of VEGF mRNA translation. Pyrimidine nucleotides can be generated either by de novo synthesis or the salvage pathway in which pyrimidine nucleotides are obtained from the diet. Resting cells typically acquire adequate levels of pyrimidine nucleotides from the salvage pathway. Rapidly proliferating cells, however, are dependent on the de novo synthesis of pyrimidine nucleotides. To identify cancer cell types that are sensitive to PTC299, a panel of 240 tumor cell lines was tested against which the concentration of compound required to reduce cell viability by 50% (CC50) was determined. Overall, the viability of 18% of cells from solid tumor(34/184) and ~57% of cells from hematologic malignancies (32/56) was reduced with a CC50 of 2 µM or less. Fresh blood from AML patients was treated ex vivo with PTC299 and analyzed by flow cytometry. In these samples, AML cells differentiated as shown by increased monocyte markers (e.g. CD14) or showed reduced viability as shown by a reduction in the blast population. PTC299 reduced the growth of leukemia cells in mouse models using human cell lines or patient-derived xenografts (PDX models). In combination, PTC299 enhanced the activity of various cytotoxic agents in animal models of solid tumor and leukemia. Consistent with the activity of PTC299 as a DHODH inhibitor, patients treated with PTC299 in clinical studies showed increased levels of dihydroorotate, the substrate of DHODH, were observed in serum samples from PTC299-treated patients In summary, we describe an unanticipated link between the inhibition of DHODH by PTC299 and subsequent translation of the mRNA for VEGFA, a key stress-induced regulator of angiogenesis. The integration between biological pathways such as pyrimidine nucleotide synthesis and protein translation contributes to the basic understanding of the strategies by which leukemia cells sustain rapid proliferation. Importantly, its favorable pharmaceutical properties together with its extensive PH1/2 clinical experience make PTC299 a promising agent for treatment of leukemia Disclosures Cao: PTC Therapeutics: Employment. Branstrom: PTC Therapeutics: Employment. Baird: PTC Therapeutics: Employment. Trotta: PTC Therapeutics: Employment. Colacino: PTC Therapeutics: Employment. Santaguida: Notable Laboratories: Consultancy. Heiser: Notable Laboratories: Consultancy. Ma: PTC Therapeutics: Employment. Peltz: PTC Therapeutics: Employment. O9Mara: PTC Therapeutics: Employment. Spiegel: PTC Therapeutics: Consultancy. Weetall: PTC Therapeutics: Employment.
Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy (2001)

Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB.
Emulating a Complex Instruction Set Computer with a Reduced Instruction Set Computer (1987)

GaAs now allows up to 30K transistors per chip. With such a limitation, can you build a 32-bit CISC on a single GaAs chip? Yes, if you build a reduced instruction set computer and emulate the 32-bit CISC on it.
The Unity of Software and the Power of Roundtrip Engineering (1999)

Part of the initial progress in developing an engineering basis for software development was to identify the specific tasks at hand and highlight their differences. Although that step was probably inevitable, it has led to a somewhat skewed view of software engineering, which ignores the fundamental unity of software construction, and leads to unnecessary gaps, detrimental to quality and productivity. It is more fruitful to take advantage of the fundamental invariants of software development and view system engineering as a continuous, seamless and reversible process. The talk will show how that full roundtrip engineering is possible in practice, leading to far higher quality of both process and product.
Swedish Two-County Trial: Impact of Mammographic Screening on Breast Cancer Mortality during 3 Decades (2011)

Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up.
The Formation of Various Cross Linkages in Wool and Their Effect on the Supercontraction Properties of the Fibers (1967)

Various solvent systems have been investigated for obtaining maximum alkylation of cysteine residues in reduced wool to dimethylene-S,S'-dicysteine residue. These and related amino acid residues were determined in wool hydrolyzates by means of an automatic amino acid analyzer. Cystine residues in wool were converted to both lanthionine and lysinoalanine residues by treating the wool with potassium carbonate solutions, whereas treatment with potassium cyanide solutions produced lanthionine resi dues without forming significant amounts of lysinoalanine residues in the wool. On a molar basis, lanthionine and dimethylene-S,S'-dicysteine residues had similar restrictive effects on the extent of total supercontraction in 8M LiBr, whereas one lysinoalanine residue was equivalent to about five lanthionine residues in its effect on the extent of supercontraction. The conversion of cystine to lanthionine or dimethylene-S-S'-dicysteine residues retarded the first stage of supercontraction in 4 M LiBr at pH 8.3, whereas in 6 M LiBr, only the second stage of supercontraction was retarded. Similarly, the addition of free bromine to the lithium bromide solutions retarded the first stage of supercontraction of unmodified wool fibers in 4 M LiBr but did not affect the initial rate of contraction in 6 M LiBr. It is suggested that the matrix protein molecules are unfolded in 6M LiBr, thereby obviating the need for thiol-disulfide interchange reactions in the deformation of the matrix which must accompany the contraction of the micro- fibrils. The presence of lanthionine or dimethylene-S,S'-dicysteine residues in the wool did not decrease the rate or extent of supercontraction in 4 M LiBr-N HCl at 98.5°C.