gebhart/patrepeval huggingface dataset:
Metformin: Multi-faceted protection against cancer (2011)

The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.
Heteroligated Supramolecular Coordination Complexes Formed via the Halide-Induced Ligand Rearrangement Reaction (2008)

Supramolecular coordination chemistry allows researchers to synthesize higher-order structures that approach the nanoscale dimensions of small enzymes. Frequently, such structures have highly symmetric macrocyclic square or cage shapes. To build functional structures that mimic the complex recognition, catalytic, and allosteric properties of enzymes, researchers must do more than synthesize highly symmetric nanoscale structures. They must also simultaneously incorporate different functionalities into these structures and learn how to regulate their relative arrangement with respect to each other. Designing such heteroligated coordination complexes remains a significant challenge for supramolecular chemists. This Account focuses on the discovery and development of a novel supramolecular reaction known as the halide-induced ligand rearrangement (HILR) reaction. Two hemilabile ligands with different binding strengths combine with d(8) transition metal precursors that contain halide ions. The reaction spontaneously results in heteroligated complexes and is highly modular and general. Indeed, it not only can be used to prepare tweezer complexes but also allows for the rapid and quantitative formation of heteroligated macrocyclic triple-decker/step and rectangular box complexes from a variety of different ligands and transition metal ions. The relative arrangement between functional groups A and B in these structures can be regulated in situ using small ancillary ligands such as halides, CO, and nitriles. Based on this reaction, zinc- and magnesium-porphyrin moieties can be incorporated into heteroligated macrocyclic or tweezer scaffolds. These examples demonstrate the convergent and cofacial assembly of functional sites that are known to be involved in numerous processes in enzymes. They also show how the relative spatial and lateral distances of these sites can be varied, in many cases reversibly. Researchers can use such complexes to study a wide range of enzymatic processes, including catalysis, molecular recognition, electron transfer, and allosteric signal transfer.
Patterned wafer inspection using laser holography and spatial frequency filtering (1988)

An automatic patterned wafer inspection system for use in integrated circuit fabrication is described. The system is based on the techniques of optical spatial frequency filtering and laser holography. The system can locate defects as small as 0.5 μm over a 150 mm patterned silicon wafer in ∼30 min. The wafer under inspection is placed in front of a lens and is flood illuminated through beam splitting optics with a collimated laser beam. The light reflected and diffracted from the wafer is collected by the lens through the beam splitter. In the back focal plane of the lens, the Fourier transform (spatial frequency) pattern of the wafer circuit is formed. A spatial filter placed in this plane effectively blocks the transmission of the light from the repetitive circuit features of all dies of the wafer. The wave front transmitted through the filter is then recorded in a hologram. The conjugate to the recorded wave front is later reconstructed from the hologram. The reconstructed wave front thus reverse ray traces the filter and the lens, forming a real image of the wafer. In this image, the defects are greatly intensified relative to the filtered circuit features. An analysis of the optical wave fronts in the system is provided. The defect information is obtained by scanning a two-dimensional photodetector array through the holographic image and recording the size and location of each point of light above a predetermined threshold. Test wafers containing electron beam programmed defects in a trilevel resist structure were prepared and inspected. Performance results are described.
Improved detectability and signal strength for rotating phase fluorescence immunoassays through image processing (2010)

Fluorescence immunoassays based on rotating solid phase have shown promise of lowered detection limits, among other advantages. However, intrinsic background distortion effects have limited their utility. Here, novel image processing strategies are used to minimize these effects and improve the estimate of concentration and lower the detection limit. This initial demonstration of a new processing capability is performed on data for a protein, myoglobin, which is a biomarker for acute myocardial infarction. For these data, compared with published results, the detection limit is improved by a factor of approximately one hundred (to 700 fM), which is competitive with or better than other immunoassay strategies (ELISA, for example) that are fully developed. This work suggests that image and video processing technologies can provide a valuable alternative approach to biochemical detection and concentration estimation.
Retinoid-dependent pathways suppress myocardial cell hypertrophy. (1995)

Utilizing an in vitro model system of cardiac muscle cell hypertrophy, we have identified a retinoic acid (RA)-mediated pathway that suppresses the acquisition of specific features of the hypertrophic phenotype after exposure to the alpha-adrenergic receptor agonist phenylephrine. RA at physiological concentrations suppresses the increase in cell size and induction of a genetic marker for hypertrophy, the atrial natriuretic factor (ANF) gene. RA also suppresses endothelin 1 pathways for cardiac muscle cell hypertrophy, but it does not affect the increase in cell size and ANF expression induced by serum stimulation. A trans-activation analysis using a transient transfection assay reveals that neonatal rat ventricular myocardial cells express functional RA receptors of both the retinoic acid receptor and retinoid X receptor (RAR and RXR) subtypes. Using synthetic agonists of RA, which selectively bind to RXR or RAR, our data indicate that RAR/RXR heterodimers mediate suppression of alpha-adrenergic receptor-dependent hypertrophy. These results suggest the possibility that a pathway for suppression of hypertrophy may exist in vivo, which may have potential therapeutic value.
Mechanism of antitumor activity of E7080, a selective VEGFR and FGFR tyrosine kinase inhibitor (TKI), in combination with selective mutant BRAF inhibition. (2011)

8567 Background: E7080 is a TKI targeting VEGFR1-3, FGFR1-4, KIT, RET and PDGFR. Anti-tumor activity has been observed in melanoma patients in phase I. The objective of this study was to examine the effect of E7080 alone and in combination with PLX-4032 on tumor response, gene expression and tumor microvasculature in BRAFmu melanoma. Methods: BRAF mutant (mu) cell lines were created by transfection of BRAF V600E constructs into BRAF wild type (wt) cell lines. Anti-tumor activity of E7080 alone or in combination with the selective BRAF inhibitor PLX-4032 was examined in xenografted models bearing mock and BRAFmu transfectants. Results: The ratio of ANGPT1/2 expression was significantly higher in BRAFmu/ PTENwt compared to BRAFwt/PTENwt and BRAFmu/PTENmu among 14 melanoma cell lines. ANGPT1 expression was up-regulated in BRAFmu by 330%, and ANGPT2 in PTENmu by 290% compared to wt. PLX-4032 decreased ANGPT1 expression and pericyte coverage of tumor vessels in BRAFmu/PTENwt A375 melanoma. Similarly, overexpression of BRAF V600E in BRAFwt SK-MEL-2 melanoma resulted in increased ANGPT1 expression along with increased pericyte coverage. E7080 at 3, 10, 30 to 100 mg/kg showed significant anti-tumor activity against mock transfectants, but only at 100 mg/kg against BRAF V600E transfectants. Combination of E7080 at 10 mg/kg with PLX-4032 at 100 mg/kg showed synergistic anti-tumor activity against A375 melanoma and caused tumor regression, not observed by either single agent E7080 or PLX-4032. E7080 alone increased pericyte coverage of tumor vessels, but in combination with PLX-4032 resulted in marked decreased in pericyte coverage and microvessel density. Conclusions: The BRAFmu/ PTENwt melanomas studied demonstrate high pericyte coverage and resistance to E7080. Combination of E7080 with PLX-4032 achieves synergistic antitumor effect with enhanced reduction of pericyte coverage. These data provide a mechanistic basis for clinical study of BRAF inhibitors in combination with VEGFR and FGFR targeted agents.
CD47-blocking therapies stimulate macrophage cytokine secretion and are effective in a model of peritoneal carcinomatosis (2015)

Meeting abstracts Peritoneal carcinomatosis is an advanced state of malignancy often arising from gastrointestinal or ovarian cancers. It is characterized by dissemination of tumors throughout the peritoneal cavity and is associated with 5-year survival rates less than 25%. Since the peritoneal
Primary structures of the wild-type and mutant alleles encoding the phosphatidylglycerophosphate synthase of Escherichia coli (1994)

The nucleotide sequence of the Escherichia coli pgsA gene, encoding phosphatidylglycerophosphate synthase, is revised to code for an enzyme of 182 amino acid residues, instead of the 216 of a previous work (A. S. Gopalakrishnan, Y.-C. Chen, M. Temkin, and W. Dowhan, J. Biol. Chem. 261:1329-1338, 1986). The revised structure now explains the properties of the enzyme. Three pgsA mutants of different phenotypes were also analyzed: pgsA3, pgsA36, and pgsA10 have single-base replacements in codons 60 (Thr-->Pro), 1 (ATG-->ATA), and 92 (Thr-->Ile), respectively.
Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow (2005)

Long-lived plasma cells, residing primarily in the bone marrow, continuously secrete antibody and provide an important component of humoral memory. However, when such cells secrete autoantibodies or become transformed, they can be pathogenic. We have shown recently that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) is required for the formation of plasma cells. To determine what role Blimp-1 might play in maintenance of plasma cells, we generated mice in which the gene encoding Blimp-1 could be deleted in an inducible manner. Deletion of Blimp-1 either in vitro or in vivo leads to loss of previously formed B220LOCD138HI plasma cells. Using BrdU incorporation, we confirmed that Blimp-1 is required for the maintenance of nondividing, long-lived plasma cells in the bone marrow. Blimp-1 is also required for long-term maintenance of antigen-specific immunoglobulin in serum. Thus Blimp-1 is required not only for the formation but also for the maintenance of long-lived plasma cells. This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity.
Enterohaemorrhagic and enteropathogenic Escherichia coli use a different Tir‐based mechanism for pedestal formation (2001)

Enterohaemorrhagic Escherichia coli (EHEC) adheres to the host intestinal epithelium, resulting in the formation of actin pedestals beneath adhering bacteria. EHEC and a related pathogen, enteropathogenic E. coli (EPEC), insert a bacterial receptor, Tir, into the host plasma membrane, which is required for pedestal formation. An important difference between EPEC and EHEC Tir is that EPEC but not EHEC Tir is tyrosine phosphorylated once delivered into the host. In this study, we assessed the role of Tir tyrosine phosphorylation in pedestal formation by EPEC and EHEC. In EPEC, pedestal formation is absolutely dependent on Tir tyrosine phosphorylation and is not complemented by EHEC Tir. The protein sequence surrounding EPEC Tir tyrosine 474 is critical for Tir tyrosine phosphorylation and pedestal formation by EPEC. In contrast, Tir tyrosine phosphorylation is not required for pedestal formation by EHEC. EHEC forms pedestals with both wild-type EPEC Tir and the non-tyrosine-phosphorylatable EPEC Tir Y474F. Pedestal formation by EHEC requires the type III delivery of additional EHEC factors into the host cell. These findings highlight differences in the mechanisms of pedestal formation by these closely related pathogens and indicate that EPEC and EHEC modulate different signalling pathways to affect the host actin cytoskeleton.
On the possibility of using Coanda Effect for Unmanned Aerial Vehicles – a numerical investigation (2014)

Abstract In this paper we present numerical results of conceptual design study of an UAV which uses Coanda Effect for lift production. Results indicate the ability of manuveuring by creating asymmetric flow patterns which lead to uneven lift production and resulting force with horizontal component necessary for establishing forward flight conditions. (© 2014 Wiley‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Advanced Glycosylation End Products Up-Regulate Connective Tissue Growth Factor (Insulin-Like Growth Factor-Binding Protein-Related Protein 2) in Human Fibroblasts: A Potential Mechanism for Expansion of Extracellular Matrix in Diabetes Mellitus* (2001)

Expansion of extracellular matrix with fibrosis occurs in many tissues as part of the end-organ complications in diabetes, and advanced glycosylation end products (AGE) are implicated as one causative factor in diabetic tissue fibrosis. Connective tissue growth factor (CTGF), also known as insulin-like growth factor-binding protein-related protein-2 (IGFBP-rP2), is a potent inducer of extracellular matrix synthesis and angiogenesis and is increased in tissues from rodent models of diabetes. The aim of this study was to determine whether CTGF is up-regulated by AGE in vitro and to explore the cellular mechanisms involved. AGE treatment of primary cultures of nonfetal human dermal fibroblasts in confluent monolayer increased CTGF steady state messenger RNA (mRNA) levels in a time- and dose-dependent manner. In contrast, mRNAs for other IGFBP superfamily members, IGFBP-rP1 (mac 25) and IGFBP-3, were not up-regulated by AGE. The effect of the AGE BSA reagent on CTGF mRNA was due to nonenzymatic glycosylation of BSA and, using neutralizing antisera to AGE and to the receptor for AGE, termed RAGE, was seen to be due to late products of nonenzymatic glycosylation and was partly mediated by RAGE. Reactive oxygen species as well as endogenous transforming growth factor-beta1 could not explain the AGE effect on CTGF mRNA. AGE also increased CTGF protein in the conditioned medium and cell-associated CTGF. Thus, AGE up-regulates the profibrotic and proangiogenic protein CTGF (IGFBP-rP2), a finding that may have significance in the development of diabetic complications.
Minimization of diffraction peaks of spatial light modulators using Voronoi diagrams (2010)

It is possible to reduce the diffraction peaks of a Spatial Light Modulator (SLM) by breaking the periodicity of the pixels shape. We propose a theoretical investigation of a SLM that would be based on a Voronoi diagram, obtained by deforming a regular grid, and show that for a specific deformation parameter the diffraction peaks disappear and are replaced with a speckle-like diffraction halo. We also develop a simple model to determine the shape and the level of this halo.
2-Aroylbenzoyl Serine Proteases:  Photoreversible Inhibition or Photoaffinity Labeling? (1999)

Phenyl esters of 2-benzoylbenzoates were determined to be inhibitors of the serine protease enzymes chymotrypsin and thrombin. Thus, p-guanidinophenyl 2-benzoylbenzoate (1b) inhibited thrombin while the corresponding p-nitrophenyl ester (1a) inhibited chymotrypsin activity. Other p-nitrophenyl esters were prepared that display activity as chymotrypsin inhibitors, three having methoxy group substitution on the benzoyl ring: 2-methoxy (2a), 2,5-dimethoxy (3a), and 2,4,5-trimethoxybenzoyl (4). After incubation with 1b, an acyl thrombin was isolated that showed no lytic activity but which slowly regained activity in pH 7.4 buffer. Irradiation of this acyl enzyme with 366 nm light led to an enzyme that showed no gain of lytic activity over time. Incubation of chymotrypsin with 1a−3a and 4 led to acyl enzymes which showed no activity but which regained activity slowly. Irradiation of these inactive acyl enzymes with 366 nm light led to a rapid increase in enzyme activity. The formation of acylchymotrypsins that can be photochemically deacylated is suggested by these data. Experiments that relate to the mechanism of enzyme acylation and the subsequent photochemistry of the acylenzymes are reported.
Reactivity of 2‐methyl‐4‐(1‐pyrrolidinyl)‐2H‐1,2‐benzothiazine 1,1‐dioxide towards p‐toluenesulphonyl azide (1990)

Abstract The 2‐methyl‐2 H ‐1,2‐benzothiazin‐4‐(3 H )‐one 1,1 dioxide ( 2 ), obtained according to a new, one‐pot method, is transformed into the pyrrolidino enamine 3 . Reaction of p ‐toluenesulphonyl azide with 3 gives, via an unstable triazoline adduct which loses nitrogen, the two isomeric tosylamino derivatives 4 and 5 . The structures have been assigned by exhaustive nmr analysis and some aspects on their formation and chemical behaviour are discussed.
Self-Assembled Monolayers of an Oligo(ethylene oxide) Disulfide and Its Corresponding Thiol Assembled from Water:  Characterization and Protein Resistance (2008)

Self-assembled monolayers (SAMs) of the disulfide [S(CH2CH2O)6CH3]2 ([S(EO)6]2) on Au from 95% ethanol and from 100% water are described. Spectroscopic ellipsometry and reflection-absorption infrared spectroscopy indicate that the [S(EO)6]2 films are similar to the disordered films of HS(CH2CH2O)6CH3 ((EO)6) and HS(CH2)3O(CH2CH2O)5CH3 (C3EO5) at their protein adsorption minima. The [S(EO)6]2 SAMs exhibit constant film thickness (d) of 1.2 +/- 0.2 nm over long immersion times (up to 20 days) and do not attain the highly ordered, 7/2 helical structure of the (EO)6 and C3EO5 SAMs (d = 2.0 nm). Exposure of these self-limiting [S(EO)6]2 SAMs to bovine serum albumin show high resistance to protein adsorption.
AUTOTRANSPLANTS IN ACUTE LEUKAEMIA (1991)

The data we review indicate that in adults with ALL in first remission intensive chemotherapy and radiation given before a transplant is more effective in eradicating leukaemia than current chemotherapy. This is not so in adults with AML in first remission where more intensive therapy does not reduce the likelihood of relapse. Furthermore, leukaemia relapse because of re-infused leukaemia cells is an important issue in autotransplants for ALL. Whether re-infusing leukaemia cells would be important in AML were more effective pretransplant therapy developed is unknown. Presently, there appears to be little sense to test in vitro approaches to remove leukaemia cells in autotransplants for AML because efficacy cannot be evaluated. (A randomized trial is an exception but would not be expected to show a difference.) Another conclusion is that attempts to induce GVHD in autotransplant recipients, such as by using cyclosporine post-transplant (Jones et al, 1989), are more likely to succeed in AML than ALL since the impact of GVHD is substantially greater (Horowitz et al, 1990). However, the GVHD-related antileukaemia effect in AML is associated with chronic GVHD whereas cyclosporine treatment of autotransplant recipients results in acute GVHD. Also, attempts to separate clinical and antileukaemia effects of GVHD were unsuccessful (Sullivan et al, 1989). Another caution is that in AML we detected an immune antileukaemia effect distinct from GVHD (termed GVL) only after HLA-identical sibling transplants. Since GVL was absent in twins it is unlikely to operate after autotransplants. In summary, there is sense in studying autotransplants in adults with acute leukaemia in first remission. However, there are currently no convincing data that autotransplants are superior to current therapy. More intensive treatment seems effective in ALL; the focus should be on increasing the antileukaemia efficacy of pretransplant therapy and on attempts to remove leukaemia cells from the graft. In AML, there is no evidence that more intensive therapy is more effective. This problem needs resolution before evaluating attempts to remove leukaemia cells from the graft. The best place to test new pretransplant regimens is in twins and recipients of HLA-identical sibling transplants without GVHD. The data and ideas we review and discuss should be useful in planning clinical trials.