gebhart/patrepeval huggingface dataset:
WP1066, a potent inhibitor of Jak2/STAT3 pathway inhibits pancreatic tumor growth both in vitro and in vivo (2007)

2393 Background: Pancreatic cancer is now the fourth leading cause of cancer-related mortality in United States. Its intransigence to current chemotherapy regimens stimulated our interest to explore novel targets for therapeutic development. Constitutive activation of Signal Transducer and Activator of Transcription-3 (STAT3) in pancreatic cancer cells is associated with VEGF expression, and when suppressed, leads to inhibition of VEGF expression, angiogenesis, tumor growth, and subsequent metastasis in vivo. In addition to VEGF expression, STAT3 activation also promotes tumor cell proliferation and survival pathways in vivo. EGF and IL-6 mediated mitogenic signaling pathways can also induce Jak2/STAT3 phosphorylation in pancreatic cancer. Thus, JAK2/STAT3 proteins are potential novel therapeutic targets in pancreatic cancer. Currently available Jak2/STAT3 pathway inhibitors including AG490 can block STAT3 phosphorylation at concentrations of 50-100 µM but are not active in vivo. The striking similarity of AG490 to the natural products of the caffeic acid family, and our comparison of caffeic acid benzyl ester to AG490, showing no additional benefit for AG490 in vitro led us to the design of novel potent inhibitors. We have discovered a new class of compounds that inhibits IL-6 induced Jak2 and STAT3 phosphorylation and suppression of related downstream signaling pathways. Next, we selected compound WP1066 for more detailed evaluation in pancreatic cancer. Aim: Determine the effects of novel Jak2/STAT3 inhibitor WP1066 on pancreatic cancer cells both in vitro and in vivo. Methods and Results: WP1066 significantly inhibited proliferation and induced apoptosis of pancreatic cancer cells including Colo357FG and MIA PaCa-2 with IC50 of 2.5 μM. WP1066 potently blocked constitutive and IL-6 induced STAT3 phosphorylation in Colo357FG cells in a dose-dependent manner with maximal effects noted at 5 μM. WP1066 (5 μM) also suppressed expression of STAT3 dependent antiapoptotic proteins including Bcl-xL and survivin. Next, we evaluated in vivo effects of WP1066 in athymic nu/nu murine subcutaneous xenograft model for pancreatic cancer. WP1066 was injected intraperitoneally thrice weekly for 4 weeks at 40 mg/kg per mouse. WP1066 was well tolerated and no adverse events were noted. WP1066 significantly inhibited Colo357FG tumor growth by 4 fold after 4 weeks of treatment (p Conclusion: Our studies show that targeting Jak2/STAT3 pathway with novel drugs including WP1066 significantly blocked pancreatic cancer cell proliferation in vitro and tumor growth in vivo. Thus drugs including WP1066 should be potentially considered as one of the future strategies for treatment of pancreatic cancer.
Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule (2010)

ABSTRACT Klotho has profound effects on phosphate metabolism, but the mechanisms of how Klotho affects phosphate homeostasis is unknown. We detected Klotho in the proximal tubule cell, brush border, and urinary lumen, where phosphate homeostasis resides. Increasing Klotho in the kidney and urine chronically by transgenic overexpression or acutely by intravenous infusion caused hypophosphatemia, phosphaturia from decreased proximal phosphate reabsorption, and decreased activity and protein of the principal renal phosphate transporter NaPi‐2a. The phosphaturic effect was present in FGF23‐null mice, indicating a direct action distinct from Klotho's known role as a coreceptor for FGF23. Direct inhibition of NaPi‐2a by Klotho was confirmed in cultured cells and in cell‐free membrane vesicles characterized by acute inhibition of transport activity followed by decreased cell surface protein. Transport inhibition can be mimicked by recombinant β‐glucuronidase and is associated with proteolytic degradation and reduced surface NaPi‐2a. The inhibitory effect of Klotho on NaPi‐2a was blocked by β‐glucuronidase inhibitor but not by protease inhibitor. Klotho is a novel phosphaturic substance that acts as an enzyme in the proximal tubule urinary lumen by modifying glycans, which cause decreased transporter activity, followed by proteolytic degradation and possibly internalization of NaPi‐2a from the apical membrane.—Hu, M. C., Shi, M., Zhang, J., Pastor, J., Nakatani, T., Lanske, B., Shawkat Razzaque, M., Rosenblatt, K. P., Baum, M. G., Kuro‐o, M., Moe, O. W. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J . 24, 3438–3450 (2010). www.fasebj.org
Differences between the Sugar Moieties of Liver- and Bone-Type Alkaline Phosphatases: A Re-Evaluation (1994)

We re-evaluated the differences between the sugar moieties of liver and bone alkaline phosphatases (ALPs). Sialic acid was added to ALP sugar moieties by alpha 2,3- or 2,6-sialyltransferase treatment of the asialo-form ALP (neuraminidase-treated ALP). Asialo-bone ALP was converted to a liver-like ALP by the 2,6-sialyltransferase treatment. The resulting liver-like ALP was less susceptible to neuraminidase than non-treated bone ALP, but was still labile to heat exposure at 56 degrees C like non-treated bone ALP. However, after the O-linked sugar moiety had been released by additional treatment with O-glycanase the liver-like ALP became more heat stable at 56 degrees C, like non-treated liver ALP. Non-treated liver ALP reacted specifically with anti-liver ALP monoclonal antibody, and non-treated bone ALP reacted with both anti-liver and anti-bone ALP antibodies. The asialo-bone ALP still reacted with anti-bone ALP antibody, whereas the asialo-form liver ALP showed little, if any, reaction with anti-liver and anti-bone ALP antibodies. Neuraminidase and O-glycanase-treated bone ALP reacted less with anti-bone ALP antibody. After O-glycanase treatment, bone ALP molecules deprived of an O-linked sugar moiety had a molecular size and heat stability similar to liver ALP. The difference between liver and bone ALP molecules may be due not only to their manner of sialic acid linkage but also to the attachment of the O-linked sugar moiety.
Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells (2001)

A key function of the proximal tubule is retrieval of most of the vast quantities of NaCl and water filtered by the kidney. Physiological studies using brush border vesicles and perfused tubules have indicated that a major fraction of Cl(-) reabsorption across the apical membrane of proximal tubule cells occurs via Cl(-)-formate exchange. The molecular identity of the transporter responsible for renal brush border Cl(-)-formate exchange has yet to be elucidated. As a strategy to identify one or more anion exchangers responsible for mediating Cl(-) reabsorption in the proximal tubule, we screened the expressed sequence tag database for homologs of pendrin, a transporter previously shown to mediate Cl(-)-formate exchange. We now report the cDNA cloning of CFEX, a mouse pendrin homolog with expression in the kidney by Northern analysis. Sequence analysis indicated that CFEX very likely represents the mouse ortholog of human SLC26A6. Immunolocalization studies detected expression of CFEX, but not pendrin, on the brush border membrane of proximal tubule cells. Functional expression studies in Xenopus oocytes demonstrated that CFEX mediates Cl(-)-formate exchange. Taken together, these observations identify CFEX as a prime candidate to mediate Cl(-)-formate exchange in the proximal tubule and thereby to contribute importantly to renal NaCl reabsorption. Given its wide tissue distribution, CFEX also may contribute to transcellular Cl(-) transport in additional epithelia such as the pancreas and contribute to transmembrane Cl(-) transport in nonepithelial tissues such as the heart.
Dependency-Based Construction of Semantic Space Models (2007)

Traditionally, vector-based semantic space models use word co-occurrence counts from large corpora to represent lexical meaning. In this article we present a novel framework for constructing semantic spaces that takes syntactic relations into account. We introduce a formalization for this class of models, which allows linguistic knowledge to guide the construction process. We evaluate our framework on a range of tasks relevant for cognitive science and natural language processing: semantic priming, synonymy detection, and word sense disambiguation. In all cases, our framework obtains results that are comparable or superior to the state of the art.
Mechanical improvements to reinforced porous silk scaffolds (2011)

Load-bearing porous biodegradable scaffolds are required to engineer functional tissues such as bone. Mechanical improvements to porogen leached scaffolds prepared from silk proteins were systematically studied through the addition of silk particles in combination with silk solution concentration, exploiting interfacial compatibility between the two components. Solvent solutions of silk up to 32 w/v % were successfully prepared in hexafluoroisopropanol (HFIP) for the study. The mechanical properties of the reinforced silk scaffolds correlated to the material density and matched by a power law relationship, independent of the ratio of silk particles to matrix. These results were similar to the relationships previously shown for cancellous bone. From these data we conclude that the increased mechanical properties were due to a densification effect and not due to the inclusion of stiffer silk particles into the softer silk matrix. A continuous interface between the silk matrix and the silk particles, as well as homogeneous distribution of the silk particles within the matrix was observed. Furthermore, we note that the roughness of the pore walls was controllable by varying the ratio of the particles matrix, providing a route to control topography. The rate of proteolytic hydrolysis of the scaffolds decreased with increase in mass of silk used in the matrix and with increasing silk particle content.
ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma (2009)

ECRG4 is silenced via promoter hypermethylation in different types of human cancer cells. Its gene product may act as inhibitor of cell proliferation in colorectal carcinoma cells and may play a role as extracellular signaling molecule.
Frataxin and Mitochondrial FeS Cluster Biogenesis (2010)

Friedreich ataxia is an inherited neurodegenerative disease caused by frataxin deficiency. Frataxin is a conserved mitochondrial protein that plays a role in FeS cluster assembly in mitochondria. FeS clusters are modular cofactors that perform essential functions throughout the cell. They are synthesized by a multistep and multisubunit mitochondrial machinery that includes the scaffold protein Isu for assembling a protein-bound FeS cluster intermediate. Frataxin interacts with Isu, iron, and the cysteine desulfurase Nfs1, which supplies sulfide, thus placing it at the center of mitochondrial FeS cluster biosynthesis.
THE COMPARATIVE RADIATION GENETICS OF HUMANS AND MICE (1990)

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ...Read More
A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts (2005)

Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. A resveratrol derivative 3,4,5,4'-tetrahydroxystilbene (R-4) exhibits potent growth inhibitory effect against transformed human cells. Here we report that 3,4,5,4'-tetramethoxystilbene (MR-4), converted from R-4, was more potent against cancer cell lines (WI38VA, IMR-90SV, HeLa, LNCaP, HT-29, and HepG2), but had almost no inhibitory effect on the growth of normal cells (WI38, IMR-90, BJ-T) at the concentrations tested. The IC50 value of MR-4 on the growth inhibition of transformed WI38VA human cells was 0.5 microM, as compared to the value of greater than 50 microM for the normal WI38 cells. Resveratrol, however, did not exhibit such clear differential effect and the IC50 value of R-3 for WI38VA cells was about 50 microM. The growth inhibitory effect of MR-4 correlated with the induction of apoptosis in the transformed cells. When normal WI38 cells and transformed WI38VA cells were compared, MR-4 induced increases of the Bax/Bcl-2 mRNA ratio, p53 and Bax protein level, activation of caspases, and DNA fragmentation in transformed, but not in normal cells. Further analysis revealed that MR-4 caused a rapid appearance of perinuclear aggregation of mitochondria in WI38VA but not in WI38 cells, suggesting that the mitochondria could serve as an early target of MR-4. R-3 also induced apoptosis and mitochondrial clustering but only at a much higher concentration, close to 500 microM. Taken together, the specific activation of the mitochondria-mediated apoptotic pathway could be a major reason for the striking differential growth inhibitory effect of MR-4.
A New Synthesis of Cyclopropanes1 (1959)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA New Synthesis of Cyclopropanes1Howard E. Simmons and Ronald D. SmithCite this: J. Am. Chem. Soc. 1959, 81, 16, 4256–4264Publication Date (Print):August 1, 1959Publication History Published online1 May 2002Published inissue 1 August 1959https://doi.org/10.1021/ja01525a036RIGHTS & PERMISSIONSArticle Views4082Altmetric-Citations608LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alerts Get e-Alerts
Efficient Non-Maximum Suppression (2006)

In this work we scrutinize a low level computer vision task - non-maximum suppression (NMS) - which is a crucial preprocessing step in many computer vision applications. Especially in real time scenarios, efficient algorithms for such preprocessing algorithms, which operate on the full image resolution, are important. In the case of NMS, it seems that merely the straightforward implementation or slight improvements are known. We show that these are far from being optimal, and derive several algorithms ranging from easy-to-implement to highly-efficient
Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. (1998)

Amyloid beta-protein (Abeta) is the major component of senile plaques that emerge in the cortex during aging and appear most abundantly in Alzheimer's disease. In the course of our immunocytochemical study on a large number of autopsy cases, we noticed, in many aged nondemented cases, the presence of unique diffuse plaques in the cortex distinct from ordinary diffuse plaques by immunocytochemistry. The former were amorphous, very faintly Abeta-immunoreactive plaques resembling diffuse plaques, but they stained for Abeta40 and were associated with small cells containing Abeta-positive granules. A panel of amino- and carboxyl-terminal-specific Abeta antibodies showed that such Abeta40-positive diffuse plaques and cell-associated granules were composed exclusively of amino-terminally deleted Abeta terminating at Abeta40, -42, and -43. Double immunostaining also showed that those Abeta-immunoreactive granules are located in astrocytes and not in microglia or neurons. Immunoelectron microscopy revealed that nonfibrillar Abeta immunoreactivity was located within lipofuscin-like granules in somewhat swollen astrocytes. These findings raise the possibility that astrocytes take up Abeta and attempt to degrade it in lysosomes in the aged brain.
Preclinical Diagnosis of Familial Hypertrophic Cardiomyopathy by Genetic Analysis of Blood Lymphocytes (1991)

Transcripts of beta cardiac myosin heavy-chain gene can be detected in blood lymphocytes and used to screen for mutations that cause familial hypertrophic cardiomyopathy. This approach makes practical the identification of mutations responsible for this disorder and may be applicable to other diseases in which direct analysis is difficult because the mutated gene is expressed only in certain tissues. Preclinical or prenatal screening in an affected family will make it possible to study the disease longitudinally and to develop preventive interventions.
SiGe-based dual-wavelength demultiplexers and polarization splitters (1999)

The simulation and performance of dual-wavelength demultiplexers fabricated in SiGe are presented. The device design is a symmetric directional coupler optimized for 1.3/1.55 micrometer demultiplexing. Modeling results using the Beam Propagation Method are presented as a means of examining the fabrication tolerances and design considerations of the devices. Initially the duplexers were fabricated with a Si<SUB>.97</SUB>Ge<SUB>.03</SUB> core using chemical etching, and displayed crosstalk of -19 dB and -15 dB in the 1.3 and 1.55 micrometer wavelength channels, respectively. This performance was enhanced by thermal tuning, resulting in isolation of -21 dB and -18 dB. The high degree of strain in pseudomorphic SiGe layers results in highly birefringent waveguides. This characteristic restricts effective duplexer operation to a single polarization, but suggests that the same devices can be modified to act as polarization splitters for a chosen wavelength. Modeling of the devices in this configuration is also presented. The simple device design used for demultiplexers and splitters was chosen to evaluate the potential for fabrication of SiGe-based optoelectronic devices using standard VLSI processing relying on the local oxidation of silicon (LOCOS). A second set of devices was successfully fabricated using LOCOS and effectively separated 1.15 and 1.3 micrometer wavelength signals. This performance is compared to similar devices that were wet-etched.
Fetal cells in the maternal circulation. (1992)

The analysis of fetal cells from the maternal circulation would be the least invasive method of prenatal diagnosis. Potential fetal cell types to enter the maternal circulation are lymphocytes, trophoblast cells and nucleated erythrocytes. With conventional methods, such as cytology and interphase or metaphase cytogenetics, the ratio of fetal to maternal cells was overestimated in the past. Currently most groups use polymerase chain reaction-based Y-sequence analysis for the detection of fetal cells in pregnancies with male fetuses, either with or without prior enrichment of fetal cells. For fetal cell separation, fluorescence-activated cell sorting and immunomagnetic beads have been applied, and recently our group has used discontinuous density gradient centrifugation for this purpose. We have shown that the transferrin receptor antigen alone is not sufficient for enrichment of fetal nucleated erythrocytes. Despite some initial promising results with fluorescence in situ hybridization, the reproducibility and reliability of the techniques are still limited, mainly due to the lack of very specific cell markers and the very low and variable concentrations of fetal cells among numerous maternal cells.
Activities of the Microtubule-stabilizing Agents Epothilones A and B with Purified Tubulin and in Cells Resistant to Paclitaxel (Taxol®) (1997)

Epothilones A and B, natural products with minimal structural analogy to taxoids, have effects similar to those of paclitaxel (Taxol(R)) in cultured cells and on microtubule protein, but differ from paclitaxel in retaining activity in multidrug-resistant cells. We examined interactions of the epothilones with purified tubulin and additional cell lines, including a paclitaxel-resistant ovarian carcinoma line with an altered beta-tubulin. The epothilones, like paclitaxel, induced tubulin to form microtubules at low temperatures and without GTP and/or microtubule-associated proteins. The epothilones are competitive inhibitors of the binding of [3H]paclitaxel to tubulin polymers. The apparent Ki values for epothilones A and B were 1.4 and 0.7 microM by Hanes analysis and 0.6 and 0.4 microM by Dixon analysis. In the paclitaxel-sensitive human cell lines we examined, epothilone B had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel. A multidrug-resistant colon carcinoma line and the paclitaxel-resistant ovarian line retained sensitivity to the epothilones. With Potorous tridactylis kidney epithelial (PtK2) cells examined by indirect immunofluorescence, microtubule bundles appeared more rapidly following epothilone B treatment, and there were different proportions of various mitotic aberrations following treatment with different drugs.
Pyrrolidino-4-iodotamoxifen and 4-iodotamoxifen, new analogues of the antiestrogen tamoxifen for the treatment of breast cancer. (1991)

New tamoxifen analogues were tested for their antiproliferative activity both in vitro and in vivo. Binding studies showed that both 4-iodotamoxifen and pyrrolidino-4-iodotamoxifen and 2.5-fold higher affinities for the estrogen receptor compared with tamoxifen. Pyrrolidino-4-iodotamoxifen was also 1.5-fold more effective in causing inhibition of estrogen-induced growth of MCF-7 cells compared with tamoxifen at 10(-6) M. The 4-iodotamoxifen analogue was similar to tamoxifen in its inhibitory action at 10(-6) M. Antiproliferative activities of these drugs were tested using the nitrosomethylurea-induced rat mammary tumor model. Pyrrolidino-4-iodotamoxifen caused regression in 92% of rats, whereas tamoxifen caused regression in 75% of rats. The agonist activity of the analogues was determined using the immature rat and mouse uterotrophic assays. Both tamoxifen and 4-iodotamoxifen had similar partial agonist activity, and this was greater than that seen with pyrrolidino-4-iodotamoxifen. Furthermore, pyrrolidino-4-iodotamoxifen caused a dose-dependent inhibition of estrogen-induced vaginal cornification, whereas tamoxifen and 4-iodotamoxifen did not. These studies demonstrate that pyrrolidino-4-iodotamoxifen is more effective than tamoxifen in inhibiting tumor regression and that its reduced uterotrophic activity and increased estrogen receptor binding may give it significant clinical advantages over the parent compound.
Comparison of racecadotril and loperamide in adults with acute diarrhoea (1999)

The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor, loperamide, were similarly and rapidly effective in resolving the symptoms and associated signs of diarrhoea.
Impulse radio: how it works (1998)

Impulse radio, a form of ultra-wide bandwidth (UWB) spread-spectrum signaling, has properties that make it a viable candidate for short-range communications in dense multipath environments. This paper describes the characteristics of impulse radio using a modulation format that can be supported by currently available impulse signal technology and gives analytical estimates of its multiple-access capability under ideal multiple-access channel conditions.