gebhart/patrepeval huggingface dataset:
Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation (2009)

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.
Integrin β 1 -focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs (2009)

The development of metastases is an extended and inefficient process involving multiple steps. The last of these involves the growth of micrometastases into macroscopic tumors. We show here that intravenously injected, nonmetastatic cancer cells cease proliferating after extravasating into the parenchyma of the lungs; this response is attributable to the cells inability to trigger adhesion-related signaling events when they are scattered sparsely within the extracellular matrix (ECM) of the parenchyma. We recapitulate this situation by culturing these nonmetastatic cells at low seeding density in ECM-derived gels in vitro, in which they undergo cell-cycle arrest resulting, in part, from insufficient activation of focal adhesion kinase (FAK). Metastatic cancer cells, in contrast, show sufficient FAK activation to enable their proliferation within ECM gels in vitro and continue cell-cycle progression within the lung parenchyma in vivo. Activation of FAK in these metastatic cells depends on expression of the beta(1) subunit of integrins, and proliferation of these cells after extravasation in the lungs is diminished by knocking down the expression of either FAK or integrin beta(1). These results demonstrate the critical role of integrin beta(1)-FAK signaling axis in controlling the initial proliferation of micrometastatic cancer cells disseminated in the lungs.
Cellular re- and de-programming by microenvironmental memory: why short TGF-β1 pulses can have long effects (2013)

We demonstrated that short TGF-β1 pulses can exert long-lasting effects on fibroblasts by changing their microenvironment, thus leaving an imprint and creating a reciprocal feed-back loop. Therefore, the ECM might act as mid-term memory for pathobiochemical events. We would expect this microenvironmental memory to be dependent on matrix turnover and, as such, to be erasable. Our findings contribute to the current understanding of fibroblast induction and maintenance, and have bearing on the development of antifibrotic drugs.
Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer (2009)

Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer.
Deep Inside Convolutional Networks: Visualising Image Classification Models and Saliency Maps (2013)

This paper addresses the visualisation of image classification models, learnt using deep Convolutional Networks (ConvNets). We consider two visualisation techniques, based on computing the gradient of the class score with respect to the input image. The first one generates an image, which maximises the class score [Erhan et al., 2009], thus visualising the notion of the class, captured by a ConvNet. The second technique computes a class saliency map, specific to a given image and class. We show that such maps can be employed for weakly supervised object segmentation using classification ConvNets. Finally, we establish the connection between the gradient-based ConvNet visualisation methods and deconvolutional networks [Zeiler et al., 2013].
Columbia Open Health Data, clinical concept prevalence and co-occurrence from electronic health records (2018)

Columbia Open Health Data (COHD) is a publicly accessible database of electronic health record (EHR) prevalence and co-occurrence frequencies between conditions, drugs, procedures, and demographics. COHD was derived from Columbia University Irving Medical Center's Observational Health Data Sciences and Informatics (OHDSI) database. The lifetime dataset, derived from all records, contains 36,578 single concepts (11,952 conditions, 12,334 drugs, and 10,816 procedures) and 32,788,901 concept pairs from 5,364,781 patients. The 5-year dataset, derived from records from 2013-2017, contains 29,964 single concepts (10,159 conditions, 10,264 drugs, and 8,270 procedures) and 15,927,195 concept pairs from 1,790,431 patients. Exclusion of rare concepts (count ≤ 10) and Poisson randomization enable data sharing by eliminating risks to patient privacy. EHR prevalences are informative of healthcare consumption rates. Analysis of co-occurrence frequencies via relative frequency analysis and observed-expected frequency ratio are informative of associations between clinical concepts, useful for biomedical research tasks such as drug repurposing and pharmacovigilance. COHD is publicly accessible through a web application-programming interface (API) and downloadable from the Figshare repository. The code is available on GitHub.
Humoral Response after Administration of E1-Deleted Adenoviruses: Immune Privilege of the Subretinal Space (1996)

An important limitation of E1-deleted recombinant adenoviruses in gene therapy is the immune response that they engender and that rapidly destroys transduced cells. Transduced cells of the outer retina appear to be an exception. To determine whether differences in immune sequestration of the outer retina contribute to the increased stability of transgene expression in this tissue, we examined the systemic humoral response to an E1-deleted adenovirus injected into the subretinal space. Subretinal injection of Ad.CMVlacZ in mature immunocompetent mice resulted in minimal circulating antibody production. In contrast, subcutaneous administration of equivalent doses of Ad.CMVlacZ resulted in high-titer antibody production against adenoviral proteins. Circulating antibodies in systemically immunized animals had minimal effect on retinal transgene expression patterns measured 2 weeks after subretinal injection of Ad.CMVlacZ. Histologic examination showed minimal retinal toxicity attributable to subretinal adenovirus in naive or immunized mice, although 3/18 (14%) of eyes from the latter set contained a localized granulomatous infiltrate at the ocular injection site. The data demonstrate that the subretinal space is an immune-privileged site regarding humoral immunity. Further, short-term transduction efficiency is not affected by the presence of anti-adenoviral antibodies. The retina may be a favorable environment for replication-defective virus-mediated genetic therapy.
Conceptual data modeling of multimedia database applications (2002)

Presents a conceptual data model for multimedia database applications based on the ExIFO/sub 2/ (Extraction of Information from Fuzzy Object-Oriented data) model. This data model is chosen as the conceptual model since it handles both complex objects along with their uncertain and imprecise properties. We enhanced this conceptual model in order to meet the multimedia data requirements. In addition to uncertain and imprecise information, we present a way of handling relationships among objects of multimedia database applications. Events that might be extracted from video or audio are also considered in this study. Finally, the conceptual model is mapped to a logical model-the fuzzy object-oriented data (FOOD) model-for storing and manipulating the multimedia objects. This mapping is done in a way that it preserves most of the information represented at the conceptual level.
Copepoda parasitic on Australian fishes, XIII: family Hatschekiidae (1991)

This paper deals with parasitic copepods (Copepoda: Siphonostomatoida) of the family Hatschekiidae, found on the gills of teleost fishes in Australian waters. Prohatschekia awatati, a new record for Australia, is re-described. Ten new species of the genus Hatschekia (H. bicaudata, H. clava, H. crenulata, H. difficilis, H. elegans, H. hemigymni, H. megacephala, H. papillifera, H. rohdei and H. squamigera) are described. Five others add three new host records and three new records for Australian fauna. The morphology and systematics of the genus Hatschekia are discussed.
Aptamer-Enabled Efficient Isolation of Cancer Cells from Whole Blood Using a Microfluidic Device (2012)

Circulating tumor cells (CTC) in the peripheral blood could provide important information for diagnosis of cancer metastasis and monitoring treatment progress. However, CTC are extremely rare in the bloodstream, making their detection and characterization technically challenging. We report here the development of an aptamer-mediated, micropillar-based microfluidic device that is able to efficiently isolate tumor cells from unprocessed whole blood. High-affinity aptamers were used as an alternative to antibodies for cancer cell isolation. The microscope-slide-sized device consists of >59,000 micropillars, which enhanced the probability of the interactions between aptamers and target cancer cells. The device geometry and the flow rate were investigated and optimized by studying their effects on the isolation of target leukemia cells from a cell mixture. The device yielded a capture efficiency of ~95% with purity of ~81% at the optimum flow rate of 600 nL/s. Further, we exploited the device for isolating colorectal tumor cells from unprocessed whole blood; as few as 10 tumor cells were captured from 1 mL of whole blood. We also addressed the question of low throughput of a typical microfluidic device by processing 1 mL of blood within 28 min. In addition, we found that ~93% of the captured cells were viable, making them suitable for subsequent molecular and cellular studies.
Re-configurable fluid circuits by PDMS elastomer micromachining (1999)

We report on a microfabrication technique for realizing re-configurable micro fluidics devices using polymethylsiloxane material (PDMS). The mechanical characteristics of the material, including the Young's modulus and the adhesion energy have been determined experimentally. The magnitude of Young's modulus ranges from 8.7/spl times/10/sup 5/ Pa to 3.6/spl times/10/sup 5/ Pa. The adhesion energy is a function of the PDMS composition as well as chemical treatment. A method for efficiently developing flow interconnects has been demonstrated.
The Diagnostic Value of Anti-CCP and Rheumatoid Factor for Patients with Refractory Rheumatoid Arthritis (RA) and RA in Remission (2006)

To compare the diagnostic value of antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) for patients with refractory rheumatoid arthritis (RA) and RA in remission. Methods. A total of one hundred and forty three participants were enrolled: fifty one patients with RA refractory to standard methotrexate therapy, group I (Gr I, refractory RA); forty three RA patients in complete remission status for at least 3 months, group II (Gr II, RA in remission); and forty nine community-based healthy controls, group III (Gr III). Levels of anti-CCP and RF were measured for all of the subjects. The sensitivity and specificity of both tests were determined via these subjects. The receiver operating characteristic (ROC) analysis was used to display the pairs of sensitivity and specificity for different cut off points of anti-CCP and RF. False negative rate and the complementary diagnostic effect of both assays were also calculated and compared. Results. The sensitivity of anti-CCP and RF for Gr I were 84% and 78%, and 74% and 67% for Gr II, respectively. The specificity of anti-CCP and RF was 98% and 92% respectively. The ROC analysis disclosed that anti-CCP, compared to RF, provided the best combination of sensitivity and specificity for detecting either groups of RA. In addition, anti-CCP provided better complementary diagnostic effect for our RA patients when the results of opposite tests were negative (33% vs 11% in Gr I, and 29% vs 9% in Gr II) (p＜0.001). Conclusion. The detection of anti-CCP in the diagnosis of patients with refractory RA and RA in remission showed higher sensitivity and specificity than RF assay.
Oral Administration of Recombinant Lactococcus lactis Expressing HSP65 and Tandemly Repeated P277 Reduces the Incidence of Type I Diabetes in Non-Obese Diabetic Mice (2014)

Diabetes mellitus type 1 (DM1) is an autoimmune disease that gradually destroys insulin-producing beta-cells. We have previously reported that mucosal administration of fusion protein of HSP65 with tandem repeats of P277 (HSP65-6P277) can reduce the onset of DM1 in non-obese diabetic (NOD) mice. To deliver large amounts of the fusion protein and to enhance long-term immune tolerance effects, in the present study, we investigated the efficacy of using orally administrated L. lactis expressing HSP65-6P277 to reduce the incidence of DM1 in NOD mice. L. lactis strain NZ9000 was engineered to express HSP65-6P277 either constitutively or by nisin induction. After immunization via gavage with the recombinant L. lactis strains to groups of 4-week old female NOD mice for 36 weeks, we observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis. Immunologic analysis showed that treatment with recombinant L. lactis induced HSP65- and P277- specific T cell immuno-tolerance, as well as antigen-specific proliferation of splenocytes. The results revealed that the DM1-preventing function was in part caused by a reduction in the pro-inflammatory cytokine IFN-γ and an increase in the anti-inflammatory cytokine IL-10. Orally administered recombinant L. lactis delivering HSP65-6P277 may be an effective therapeutic approach in preventing DM1.
Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. (2001)

The proangiogenic activity of hepatocyte growth factor (HGF)/scatter factor has been closely associated with its ability to stimulate endothelial cell chemotaxis, migration, proliferation, and capillary formation. However, the potential of HGF as a paracrine factor in regulating the expression of angiogenesis factors by tumor cells is not widely appreciated. We observed that increased HGF was correlated with higher levels of angiogenesis factors interleukin (IL)-8 and vascular endothelial growth factor (VEGF) in serum of patients with head and neck squamous cell carcinoma (HNSCC) as compared with that in normal volunteers and hypothesized that HGF may regulate angiogenesis factor production by tumor cells through the activation of its receptor c-Met, which is expressed by HNSCC cells. To test this hypothesis, we examined the effect of HGF treatment on IL-8 and VEGF expression by a panel of primary keratinocytes and HNSCC lines. HGF induced a significant dose-dependent increase in IL-8 and/or VEGF cytokine production in eight HNSCC lines tested, which is not observed in normal keratinocytes. In addition, HGF increased mRNA expression of IL-8 in 3 of 6 and VEGF in 5 of 6 HNSCC lines. The increase in induction of these factors by HGF corresponded to an increase in phosphorylation of c-Met in HNSCC. HGF-induced phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) pathway substrate p42/p44(erk) and phosphatidylinositol 3'-kinase (PI3K) pathway substrate Akt provided evidence for downstream activation of MEK and PI3K pathways in HNSCC. Inhibitors of MEK (U0126) and PI3K (LY294002) blocked p42/p44(erk) and Akt, respectively, and partially blocked HGF-induced production of IL-8 and VEGF, whereas the combination of U0126 and LY294002 completely inhibited expression of IL-8 and VEGF by UMSCC-11A. Our results demonstrate that HGF can promote expression of angiogenesis factors in tumor cells through both MEK- and PI3K-dependent pathways. Understanding HGF/Met paracrine regulatory mechanisms between tumor and host cells may provide critical information for targeting of therapies against angiogenesis.
Extension of the angular spectrum method to calculate pressure from a spherically curved acoustic source (2011)

The angular spectrum method is an accurate and computationally efficient method for modeling acoustic wave propagation. The use of the typical 2D fast Fourier transform algorithm makes this a fast technique but it requires that the source pressure (or velocity) be specified on a plane. Here the angular spectrum method is extended to calculate pressure from a spherical transducer-as used extensively in applications such as magnetic resonance-guided focused ultrasound surgery-to a plane. The approach, called the Ring-Bessel technique, decomposes the curved source into circular rings of increasing radii, each ring a different distance from the intermediate plane, and calculates the angular spectrum of each ring using a Fourier series. Each angular spectrum is then propagated to the intermediate plane where all the propagated angular spectra are summed to obtain the pressure on the plane; subsequent plane-to-plane propagation can be achieved using the traditional angular spectrum method. Since the Ring-Bessel calculations are carried out in the frequency domain, it reduces calculation times by a factor of approximately 24 compared to the Rayleigh-Sommerfeld method and about 82 compared to the Field II technique, while maintaining accuracies of better than 96% as judged by those methods for cases of both solid and phased-array transducers.
Aromatic fluoroalkoxylation via direct aromatic nucleophilic substitution (1983)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAromatic fluoroalkoxylation via direct aromatic nucleophilic substitutionJohn P. Idoux, John T. Gupton, Cynthia K. McCurry, A. Donald Crews, Cindy D. Jurss, Cesar Colon, and Richard C. RampiCite this: J. Org. Chem. 1983, 48, 21, 3771–3773Publication Date (Print):October 1, 1983Publication History Published online1 May 2002Published inissue 1 October 1983https://pubs.acs.org/doi/10.1021/jo00169a033https://doi.org/10.1021/jo00169a033research-articleACS PublicationsRequest reuse permissionsArticle Views501Altmetric-Citations51LEARN 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 InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Detection and separation of two serum factors responsible for depression of lymphocyte activity in pregnancy. (1978)

Studies using the rosette inhibition test have demonstrated a depression of lymphocyte activity in pregnant mice which occurs as early as 6 hr after fertilization and persists until just before delivery. This depression of lymphocyte activity is induced by two serum factors, the relative contributions of which vary with the time of gestation. The first, a high molecular weight early pregnancy factor, appears within hours of fertilization and then slowly declines in activity as gestation proceeds. The second, a lower molecular weight substance which cross-reacts with antiserum to human chorionic gonadotrophin, appears after the formation of the trophoblast at 4--5 days and persists until parturition.
Anaesthetic carrier gases (1985)

The effects of three different anaesthetic carrier gases on middle-ear pressure in the operative and postoperative periods was assessed. Patients receiving oxygen and oxygen-enriched air did not have significant changes in middle-ear pressure. The changes associated with the use of nitrous oxide as the carrier gas were reversed with return of pharyngeal reflexes or after prolonged inhalation of 100% oxygen. In patients undergoing middle-ear surgery or those with pre-existing middle-ear disease, we suggest that oxygen-enriched air is the anaesthetic carrier gas of choice.
Ni-Catalyzed Reductive Coupling of Alkyl Acids with UnactivatedTertiaryAlkyl and Glycosyl Halides (2014)

This work highlights Ni-catalyzed reductive coupling of alkyl acids with alkyl halides, particularly sterically hindered unactivated tertiary alkyl bromides for the production of all carbon quaternary ketones. The reductive strategy is applicable to α-selective synthesis of saturated, fully oxygenated C-acyl glycosides through easy manipulations of the readily available sugar bromides and alkyl acids, avoiding otherwise difficult multistep conversions. Initial mechanistic studies suggest that a radical chain mechanism (cycle B, Scheme 1) may be plausible, wherein MgCl2 promotes the reduction of Ni(II) complexes.
SNAP‐23 is located in the basolateral plasma membrane of rat pancreatic acinar cells (1997)

The SNARE hypothesis proposes that specificity of exocytosis is regulated by the appropriate interactions between the vesicle (v-) SNARE and the target membrane (t-) SNAREs. We show here that pancreatic acinar cells express the SNAP-25 t-SNARE homolog SNAP-23, and find that this t-SNARE is most highly concentrated on the basolateral plasma membrane while being expressed below detectable levels in endocrine islets within the same tissue. This is the first localization of SNAP-23 within a polarized tissue and suggests that this t-SNAREs may interact with syntaxin-4 to mediate basolateral secretion.
Bornyl diphosphate synthase: Structure and strategy for carbocation manipulation by a terpenoid cyclase (2002)

The x-ray crystal structure of dimeric (+)-bornyl diphosphate synthase, a metal-requiring monoterpene cyclase from Salvia officinalis, is reported at 2.0-A resolution. Each monomer contains two alpha-helical domains: the C-terminal domain catalyzes the cyclization of geranyl diphosphate, orienting and stabilizing multiple reactive carbocation intermediates; the N-terminal domain has no clearly defined function, although its N terminus caps the active site in the C-terminal domain during catalysis. Structures of complexes with aza analogues of substrate and carbocation intermediates, as well as complexes with pyrophosphate and bornyl diphosphate, provide "snapshots" of the terpene cyclization cascade.