gebhart/patrepeval huggingface dataset:
Inhibition of kidney lysosomal phospholipases A and C by aminoglycoside antibiotics: possible mechanism of aminoglycoside toxicity. (1982)

Nephrotoxicity is an important side effect of aminoglycoside antibiotics, which are used to control infections caused by Gram-negative bacteria. Accumulation of aminoglycosides and phospholipids in the lysosomes is a prominent and early feature of aminoglycoside nephrotoxicity and is characterized histologically by the presence of numerous multilamellar bodies in kidney proximal tubule cells. Previous studies have shown that the drug-induced phospholipid fatty liver in man and animals is due to concentration of certain cationic amphiphilic drugs in lysosomes with inhibition of lysosomal phospholipases. It seemed possible that this mechanism might also explain the elevated levels of phospholipid and increased numbers of multilamellar bodies reported in the kidney cortex in aminoglycoside nephrotoxicity. In this study, subcellular localization of acid phospholipases A and C has been shown to be lysosomal in rat kidney cortex. A soluble lysosomal protein fraction was isolated and found to contain both phospholipase A and phospholipase C activity. Streptomycin did not inhibit the release of fatty acids from [3H]dioleoylphosphatidylcholine. However, amikacin, dibekacin, gentamicin, and tobramycin inhibited both phospholipase A and phospholipase C. Our results suggest that the accumulation of phospholipids in lysosomes of kidney cortex, an early and pervasive feature of acute aminoglycoside nephrotoxicity, is due to inhibition of lysosomal phospholipases.
Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition (2014)

Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients.
A One Year Follow-Up of a Placebo Controlled Behavioural Treatment of Peripheral Vasospasm (1996)

Abstract This paper presents the outcome of a twelve months follow-up of a behavioural treatment of 12 subjects suffering from peripheral vasospasm of the type Raynaud's disease. The subjects were offered a behavioural treatment with a classical conditioning procedure. The method was intended to weaken the unconditioned link between cold and peripheral vasoconstriction. This was accomplished by having patients in a cold room (+3 °C) while their hands were immersed in warm water (+3 °C) causing vasodilation (10 trials). Six of the subjects formed a placebo group, which received the same procedure as the treatment group except for the temperature of the water. This group was later given active treatment. The objective measures of decrease in finger temperature during cold test as well as the subjective recording of number of attacks demonstrated the short-term effectiveness of the active treatment, reported earlier in this journal (Melin and Fagerström, 1981). The present paper shows that the positive effects were maintained at 12 months follow-up. However, data indicate that booster sessions are important for maintenance.
Nicosan: Phytomedicinal Treatment for Sickle Cell Disease (2009)

Nicosan (formerly called Niprisan) is a multiple herbal drug that has been approved in Nigeria for the treatment of sickle cell disease. This phytomedicinal-based drug was developed by traditional healers in Nigeria and has recently been the subject of in vitro studies and clinical trials. Nicosan is an extract mixture of four plants, Piper guineenses, Pterocarpus osun, Eugenia caryophyllum, and Sorghum bicolor, which grow wild or are cultivated in West Africa. In this chapter, we will discuss the development history of this herbal drug and its chemical properties.
Sequence specificities of human fibroblast and neutrophil collagenases. (1991)

The sequence specificities of human fibroblast and neutrophil collagenases have been investigated by measuring the rate of hydrolysis of 60 synthetic oligopeptides covering the P4 through P'5 subsites of the substrate. The choice of peptides was patterned after both known cleavage sites in noncollagenous proteins and potential cleavage sites (those containing Gly-Ile-Ala, Gly-Leu-Ala, or Gly-Ile-Leu sequences) found in types I, II, III, and IV collagens. The initial rate of hydrolysis of the P1-P'1 bond of each peptide has been measured under first-order conditions ([SO] much less than KM), and kcat/KM values have been calculated from the initial rates. The amino acids in subsites P4 through P'4 all influence the hydrolysis rates for both collagenases. However, the effects of substitutions at each site are distinctive and are consistent with the view that human fibroblast and neutrophil collagenases are homologous but nonidentical enzymes. For peptides with unblocked NH2 and COOH termini, occupancy of subsites P3 through P'3 is necessary for rapid hydrolysis. Compared with the alpha 1(I) cleavage sequence, none of the substitutions investigated at subsites P3, P2, and P'4 produces markedly improved substrates. In contrast, many substitutions at subsites P1, P'1, and P'2 improve specificity. The preferences of both collagenases for alanine in subsite P1 and tryptophan or phenylalanine in subsite P'2, is noteworthy. Human neutrophil collagenase accommodates aromatic residues in subsite P'1 much better than human fibroblast collagenase. The subsite preferences observed for human fibroblast collagenase in these studies agree well with the residues found at cleavage sites in noncollagenous substrates. However, the sequence specificities of these collagenases cannot explain the failure of these enzymes to hydrolyze many potentially cleavable but apparently protected sites in intact collagens. This represents additional support for the notion that the local structure of collagen is important in determining the location of collagenase cleavage sites.
Mechanism Underlying the Iron-dependent Nuclear Export of the Iron-responsive Transcription Factor Aft1p inSaccharomyces cerevisiae (2007)

Aft1p is an iron-responsive transcriptional activator that plays a central role in maintaining iron homeostasis in Saccharomyces cerevisiae. Aft1p is regulated primarily by iron-induced shuttling of the protein between the nucleus and cytoplasm, but its nuclear import is not regulated by iron. Here, we have shown that the nuclear export of Aft1p is promoted in the presence of iron and that Msn5p is the nuclear export receptor (exportin) for Aft1p. Msn5p recognizes Aft1p in the iron-replete condition. Phosphorylation of S210 and S224 in Aft1p, which is not iron dependent, and the iron-induced intermolecular interaction of Aft1p are both essential for its recognition by Msn5p. Mutation of Cys291 of Aft1p to Phe, which causes Aft1p to be retained in the nucleus and results in constitutive activation of Aft1-target genes, disrupts the intermolecular interaction of Aft1p. Collectively, these results suggest that iron induces a conformational change in Aft1p, in which Aft1p Cys291 plays a critical role, and that, in turn, Aft1p is recognized by Msn5p and exported into the cytoplasm in an iron-dependent manner.
Immunochemotherapy for Intracellular Leishmania donovani Infection: Interferon Plus Pentavalent Antimony (1988)

To determine if the macrophage-activating T cell lymphokine gamma interferon (IFN-gamma) can enhance the effect of conventional chemotherapy against intracellular Leishmania donovani, we treated human macrophages in vitro with both recombinant (r) IFN-gamma and sodium stibogluconate (Pentostam). After pretreatment with a nonactivating dose of rIFN-gamma (10 U/mL), ineffective concentrations of Pentostam (1 and 5 micrograms/mL) were converted to leishmanistatic concentrations, and a leishmanistatic dose (10 micrograms/mL) was converted to uptake of Pentostam. In a model of visceral leishmaniasis, infected mice were treated with ineffective concentrations of rIFN-gamma (10(4) U) plus suboptimal doses of Pentostam (10 or 50 mg/kg). With combination therapy, the doses of Pentostam required to achieve 50% inhibition or killing of visceral L. donovani were reduced by 10-fold and fourfold, respectively. These results suggest that IFN-gamma therapy may be a useful adjunct in visceral leishmaniasis and illustrate one potential role for IFN-gamma in the treatment of systemic intracellular infections.
Particle Systems—a Technique for Modeling a Class of Fuzzy Objects (1983)

This paper introduces particle systems--a method for modeling fuzzy objects such as fire, clouds, and water. Particle systems model an object as a cloud of primitive particles that define its volume. Over a period of time, particles are generated into the system, move and change form within the system, and die from the system. The resulting model is able to represent motion, changes of form, and dynamics that are not possible with classical surface-based representations. The particles can easily be motion blurred, and therefore do not exhibit temporal aliasing or strobing. Stochastic processes are used to generate and control the many particles within a particle system. The application of particle systems to the wall of fire element from the Genesis Demo sequence of the film Star Trek H: The Wrath of Khan [10] is presented.
Controlling Binding Affinities for Anions by a Photoswitchable Foldamer (2010)

A photoswitchable foldamer containing an azobenzene and phenyl-1,2,3-triazole motif was found to show photochemical/dark isomerization in a controllable and reversible manner in both the absence and presence of anions. The transformation in conformation of the foldamer leads to changes in binding affinities for anions to a certain extent that depends on the size and the geometrical shape of the anions.
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. (1992)

The inward Na+ current underlying the action potential in nerve is terminated by inactivation. The preceding report shows that deletions within the intracellular linker between domains III and IV remove inactivation, but mutation of conserved basic and paired acidic amino acids has little effect. Here we show that substitution of glutamine for three clustered hydrophobic amino acids, Ile-1488, Phe-1489, and Met-1490, completely removes fast inactivation. Substitution of Met-1490 alone slows inactivation significantly, substitution of Ile-1488 alone both slows inactivation and makes it incomplete, and substitution of Phe-1489 alone removes inactivation nearly completely. These results demonstrate an essential role of Phe-1489 in Na(+)-channel inactivation. It is proposed that the hydrophobic cluster of Ile-1488, Phe-1489, and Met-1490 serves as a hydrophobic latch that stabilizes the inactivated state in a hinged-lid mechanism of Na(+)-channel inactivation.
Periplasmic superoxide dismutase protectsSalmonellafrom products of phagocyte NADPH-oxidase and nitric oxide synthase (1997)

Superoxide dismutase (SOD) catalyzes the conversion of superoxide radical to hydrogen peroxide. Periplasmic localization of bacterial Cu,Zn-SOD has suggested a role of this enzyme in defense against extracellular phagocyte-derived reactive oxygen species. Sequence analysis of regions flanking the Salmonella typhimurium sodC gene encoding Cu,Zn-SOD demonstrates significant homology to lambda phage proteins, reflecting possible bacteriophage-mediated horizontal gene transfer of this determinant among pathogenic bacteria. Salmonella deficient in Cu,Zn-SOD has reduced survival in macrophages and attenuated virulence in mice, which can be restored by abrogation of either the phagocyte respiratory burst or inducible nitric oxide synthase. Moreover, a sodC mutant is extremely susceptible to the combination of superoxide and nitric oxide. These observations suggest that SOD protects periplasmic or inner membrane targets by diverting superoxide and limiting peroxynitrite formation, and they demonstrate the ability of the respiratory burst and nitric oxide synthase to synergistically kill microbial pathogens in vivo.
Intravenous immunoglobulin replacement prevents severe and lower respiratory tract infections, but not upper respiratory tract and non‐respiratory infections in common variable immune deficiency (2005)

Overall, these data support the use of standard-dose 400 mg/kg intravenous immunoglobulin therapy, despite the high cost, to raise trough IgG levels to 5-7 g/l, but underlines that some categories of infectious events (non-respiratory, upper respiratory) may need parallel surgical or pharmacological approaches to be optimally prevented or treated.
Sorafenib for the Treatment of Advanced Renal Cell Carcinoma (2006)

Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.
Syk Is a New Target for AML Differentiation. (2007)

Abstract One of the challenges of phenotype-based small molecule screening has been the difficulty of protein target identification for newly discovered compounds. For example, we previously performed a gene expression-based small molecule library screen, which identified gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, as an inducer of acute myeloid leukemia (AML) differentiation in cell lines and primary patient cells. Neither EGFR transcript nor protein is expressed in the tested AML cell lines, thus precluding inhibition of this kinase as the mechanism of AML differentiation. However, because multiple EGFR inhibitors induce this phenotype, we hypothesize that a shared off-target kinase is the target in AML differentiation. In order to identify candidate gefitinib targets of AML differentiation, we utilized a proteomics method: peptide immunoprecipitation-HPLC-mass spectrometry. This approach enriches for phospho-tyrosine peptides with immunoprecipitation (IP) after enzyme digestion. In contrast to IP at the protein level, the final mixture following peptide-IP contains primarily phospho-tyrosine-containing peptides. We treated the AML cell line HL-60 with gefitinib versus vehicle and then identified peptide sites with loss of phosphorylation with gefitinib treatment. Spleen tyrosine kinase (Syk) was identified as one of the only kinases with loss of phosphorylation post treatment. Syk is a nonreceptor tyrosine kinase, important in normal B-cell differentiation, and implicated in malignancies such as myelodysplastic syndrome and lymphoma. We first confirmed with IP western immunoblotting the inhibition of Syk phosphorylation with gefitinib treatment in HL-60 cells. We next confirmed with both pharmacological inhibition and genetic loss of Syk the induction of differentiation in the AML cell lines HL-60 and U937. Numerous determinants of myeloid maturation were tested: a complex differentiation gene expression signature, cellular morphology, cell surface proteins CD11b and CD14 expression, and nitro-blue tetrazolium (NBT) reduction, a functional assay for myeloid differentiation. Two reported pharmacological inhibitors of Syk scored positive on all measurements of differentiation. Furthermore, the shRNA construct inducing the most complete loss of Syk also scored the highest on all measurements of differentiation. The most convincing data that Syk is the true target of these inhibitors would be the identification of an inhibitor resistant Syk mutant, analogous to BCR-ABL or c-Kit mutants that confer imatinib resistance. To this end, a Syk random mutagenesis screen is ongoing. In summary, these data identify Syk as a strong candidate target of gefitinib, demonstrate that inhibition of Syk can induce AML differentiation, and identify Syk as a potential target for AML differentiation therapy.
Isolation and manipulation of living adherent cells by micromolded magnetic rafts (2011)

A new strategy for magnetically manipulating and isolating adherent cells with extremely high post-collection purity and viability is reported. Micromolded magnetic elements (termed microrafts) were fabricated in an array format and used as culture surfaces and carriers for living, adherent cells. A poly(styrene-co-acrylic acid) polymer containing well dispersed magnetic nanoparticles was developed for creating the microstructures by molding. Nanoparticles of γFe(2)O(3) at concentrations up to 1% wt.∕wt. could be used to fabricate microrafts that were optically transparent, highly magnetic, biocompatible, and minimally fluorescent. To prevent cellular uptake of nanoparticles from the magnetic polymer, a poly(styrene-co-acrylic acid) layer lacking γFe(2)O(3) nanoparticles was placed over the initial magnetic microraft layer to prevent cellular uptake of the γFe(2)O(3) during culture. The microraft surface geometry and physical properties were altered by varying the polymer concentration or layering different polymers during fabrication. Cells plated on the magnetic microrafts were visualized using standard imaging techniques including brightfield, epifluorescence, and confocal microscopy. Magnetic microrafts possessing cells of interest were dislodged from the array and efficiently collected with an external magnet. To demonstrate the feasibility of cell isolation using the magnetic microrafts, a mixed population of wild-type cells and cells stably transfected with a fluorescent protein was plated onto an array. Microrafts possessing single, fluorescent cells were released from the array and magnetically collected. A post-sorting single-cell cloning rate of 92% and a purity of 100% were attained.
An antiangiogenic urokinase-derived peptide combined with tamoxifen decreases tumor growth and metastasis in a syngeneic model of breast cancer. (2002)

Expression of urokinase (uPA) and its receptor (uPAR) is associated with increased tumor-cellinvasion and metastasis in several malignancies including breast cancer. An 8-mer peptide derived from the nonreceptor-binding domain of urokinase (A6) has been shown to have antiangiogenic and proapoptotic effects to block the progression of breast cancer in vivo. In the present study, we evaluated the effects of A6 and the antiestrogen tamoxifen (TAM) alone and in combination on estrogen-receptor-positive Mat B-III rat breast cancer cells in vitro and in vivo. Treatment of Mat B-III cells with A6 and TAM resulted in a dose-dependent decrease in tumor-cell invasion through Matrigel; these effects were more marked when A6 and TAM were tested in combination. In addition, treatment of Mat B-III cells with either A6 or TAM resulted in a significant reduction of vascular endothelial growth factor receptor (flk-1) expression and in transforming growth factor beta activity, effects that were significantly higher after combined treatment with A6 and TAM. For in vivo studies, female Fischer rats were inoculated with Mat B-III cells (1 x 10(6)) into the mammary fat pad. These orthotopic tumors were staged to 30-40 mm(3) in volume and then treatment was initiated with A6 (75 mg/kg/day) and TAM (3 mg/kg/day) alone or in combination. Both A6 and TAM caused a significant reduction in tumor volume; however, these antitumor effects were significantly greater in animals receiving both A6 and TAM, which demonstrated a 75% reduction in tumor growth as compared with control animals. The number of macroscopic tumor foci was significantly reduced in A6-treated animals, whereas TAM failed to exhibit any antimetastatic effects. Histological analysis of primary tumors from different groups showed a decrease in new blood-vessel density and increased tumor-cell death in A6- and TAM-treated animals, and these effects were greater in experimental animals receiving A6 and TAM in combination. Collectively, these studies demonstrate that the addition of novel antiangiogenic/antimetastatic agents like A6 to hormone therapy can enhance the antitumor effects of hormone therapy through increased inhibition of angiogenesis and induction of tumor-cell death.
Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes (1990)

Neoplastic transformation was found to have a marked effect on the expression of nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) genes. Examining three pairs of human diploid fibroblasts and their SV 40-transformed counterparts revealed that mRNAs for the nuclear-encoded ATP synthase beta and the adenine nucleotide translocator (ANT) isoform 1 and 2 genes were markedly induced, whereas the mRNA for the ANT isoform 3 gene remained unchanged. The mRNA levels for the mtDNA-encoded 12 S rRNA, ND2, ATPase6+8, COIII, ND5+6, and Cytb genes were also increased, whereas the mtDNA number declined. Similar analysis of a cervical carcinoma (HeLa), fibrosarcoma (HT1080), and an Epstein-Barr virus (EBV)-transformed lymphoblastoid line (EBV-L) revealed that all three ANT isoforms were also expressed in these cells. Hence, changes in the expression of OXPHOS genes may be a common feature of transformed cells.
A New Architecture for Offshore Wind Farms (2008)

Offshore wind farms using HVDC links can be positioned a large distance from shore, opening up new opportunities for wind generation. Conventional approaches using 60 Hz generators and transformers are not appropriate in such applications, as they are heavy and result in expensive and complex installation and maintenance issues. This paper proposes an alternative architecture for such wind farms, using permanent magnet generators, medium frequency transformers and simple power converters to realize a compact and light system. It is possible that in the long term, the proposed approach may prove attractive for land-based wind farms as well.