gebhart/patrepeval huggingface dataset:
Growth factor balance and tumor progression (1994)

The role of balance of negative and positive autocrine growth factors in malignant progression is reviewed with an emphasis on transforming growth factor alpha (TGF-alpha) as a stimulating factor and transforming growth factor beta (TGF-beta) as an inhibiting factor. Evidence suggests that in normal cells TGF-alpha is down regulated in non-dividing or quiescent states in vitro. Tumor cells which have early stage characteristics as represented by poor clonal growth and poor tumorigenicity in athymic mice also show repression of TGF-alpha in non-dividing states. Progression of this phenotype is induced by uncontrolled low level expression of TGF-alpha by transfection with a constitutive expression vector for the polypeptide. Transfection of the unprogressed phenotype with a constitutive anti-sense vector for TGF-beta, also leads to tumor progression by repressing the autocrine negative TGF-beta activity normally expressed by these cells. Both the upregulation of TGF-alpha and the repression of TGF-beta generated in vivo progression without changing growth rates in vitro. Instead, clonality and ability to reenter the cell cycle from quiescence were increased. Thus, it is concluded that an autocrine balance of positive and negative factors is important for maintaining controlled re-entry into dividing states from non-dividing states and that disruption of this balance leads to malignant progression characterized by greater independence of the malignant cells from the control of exogenous growth factors.
Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. (1997)

Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased twofold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.
Pancreatic cancer and thromboembolic disease, 150 years after Trousseau. (2015)

The connection between pancreatic cancer and venous thrombosis has been discussed for almost 150 years. The exact pathophysiological mechanisms are still partly understood, but it is known that pancreatic cancer induces a prothrombotic and hypercoagulable state and genetic events involved in neoplastic transformation (e.g., KRAS, c-MET, p53), procoagulant factors [e.g., tissue factor (TF), platelet factor 4 (PF4), plasminogen activator inhibitor type 1 (PAI-1)], mucin production (e.g., through activation of P- and L-selectin) and pro-inflammatory factors [e.g., cytokines, cyclooxygenase-2 (COX-2)] may be implicated. Also pancreatitis, both acute and chronic, is associated with increased risk of venous thrombosis, but in this circumstance a direct inflammatory process may be more important. This article discusses the incidence, treatment and outcome of venous thromboembolism (VTE) complicating pancreatic disease, with special emphasis on new knowledge obtained during the last fifteen years.
Female Steroid Hormones and Target Cell Nuclei (1974)

The data discussed herein demonstrate the great variation in target-tissue response that can occur after administration of steroid hormones. The female sex steroids can exert regulatory effects on the synthesis, activity, and possibly even the degradation of tissue enzymes and structural proteins. Each response, nevertheless, appears to be dependent on the synthesis of nuclear RNA. In many instances, the steroid actually promotes a qualitative change in the base composition and sequence of the RNA synthesized by the target cell, implying a specific effect on gene transcription. Most important is our direct quantitative evidence that sex steroids cause a net increase in the intracellular amounts of specific mRNA molecules in target tissues. It thus appears that we are discovering a pattern of steroid hormone action which includes (Fig. 1): (i) uptake of the hormone by the target cell and binding to a specific cytoplasmic receptor protein; (ii) transport of the steroid-receptor complex to the nucleus; (iii) binding of this "active" complex to specific "acceptor" sites on the genome (chromatin DNA and acidic protein); (iv) activation of the transcriptional apparatus resulting in the appearance of new RNA species which includes specific mRNA's; (v) transport of the hormone-induced RNA to the cytoplasm resulting in synthesis of new proteins on cytoplasmic ribosomes; and (vi) the occurrence of the specific steroid-mediated "functional response" characteristic of that particular target tissue. To elucidate fully the mechanism of steroid hormone action we must study the biochemistry of the process by which information held by the steroid hormone-receptor complex is transferred to the nuclear transcription apparatus. If our assumptions are correct, we should ultimately be able to discover how this hormone-receptor complex exerts a specific regulatory effect on nuclear RNA metabolism. Such regulation might be achieved (i) by direct effects on chromatin template leading to increased gene transcription and thus RNA synthesis; (ii) by activation of the polymerase complex itself; (iii) by inhibition of RNA breakdown; or (iv) by intranuclear processing of large precursor molecules so that smaller biologically active sequences are produced, and (v) by transport of RNA from the nucleus to the cytoplasmic sites of cellular protein synthesis.
Abstract 4547: Enhanced anti-tumor effect of WNT pathway antagonists in combination with taxanes (2014)

Abstract The Wnt/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and several co-receptors, has long been implicated in cancer. We have previously demonstrated that inhibition of WNT/beta-catenin signaling by vantictumab (anti-FZD) or OMP-54F28 (FZD8-Fc) inhibits tumor growth, decreases tumorigenicity and induces differentiation in solid tumors. The anti-tumor effect of our Wnt antagonists is most evident in combination with chemotherapeutic agents. We sought to determine if the anti-tumor effect of Wnt pathway inhibitors varied with different chemotherapeutic agents. We compared the growth inhibitory effect of vantictumab and OMP-54F28 with either taxanes (paclitaxel and nab-paclitaxel) or with DNA synthesis inhibitors (gemcitabine and carboplatin) in patient-derived tumor xenografts. In a model for pancreatic ductal carcinoma, vantictumab with nab-paclitaxel was more efficacious than vantictumab with gemcitabine in inhibiting tumor growth and Wnt target gene expression (at doses of nab-paclitaxel and gemcitabine that were equivalent in their single-agent growth-inhibitory effects). Histologic analysis indicated that nab-paclitaxel increased mitotic cells and beta-catenin levels. Importantly, the addition of vantictumab to nab-paclitaxel reversed the nab-paclitaxel-induced increase in mitotic cells and beta-catenin expression. An independent experiment in a serous ovarian cancer xenograft model also showed enhanced anti-tumor activity when combining OMP-54F28 with either paclitaxel or nab-paclitaxel compared to the combination with carboplatin. A potential mechanism to account for these results involves on the observation that Wnt/beta-catenin signaling is under cell cycle control and peaks at the G2/M phase. Taxanes inhibit microtubule function and block the cell cycle at G2/M. In contrast, other chemotherapeutic agents, such as platinum compounds and nucleoside analogs, inhibit DNA synthesis and block cell proliferation at S phase. We hypothesize that combination of Wnt blockade with chemotherapeutic agents, such as taxanes, that induce G2/M arrest may result in optimal anti-tumor activity. Citation Format: Wan-Ching Yen, Marcus M. Fischer, John Lewicki, Austin Gurney, Timothy Hoey. Enhanced anti-tumor effect of WNT pathway antagonists in combination with taxanes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4547. doi:10.1158/1538-7445.AM2014-4547
Extended Storage of Platelets in an Artificial Medium with the Platelet Activation Inhibitors Prostaglandin E(1) and Theophylline (1991)

The addition of platelet activation inhibitors to the anticoagulant and the replacement of plasma with a fortified electrolyte medium have been shown separately in previous work to improve the storage of platelets during a 2-week period. In the present study, we have combined these strategies to investigate whether a synergistic improvement could be obtained. A total of 85 concentrates was studied with 300nM prostaglandin E(1) (PGE(1)) and 1.9mM theophylline added to the whole blood, platelet-rich plasma (PRP), and/or the storage medium during the preparation of platelet concentrates. In vitro markers of platelet aggregation, respiration, and cell integrity were measured over a 20-day storage period and evaluated in an analysis of variance. We found that a single-step addition of PGE(1) and theophylline to the PRP prior to centrifugation was not sufficient in terms of preventing a rapid fall in pH, rise in pO(2), fall in pCO(2), loss of hypotonic shock response, and loss of aggregation response, compared to the addition of the inhibitors to the storage medium used to resuspend the platelet pellet. Factorial analysis showed that a reduction in the surface-to-volume ratio of the storage container further improved the maintenance of platelet respiration and, for three in vitro markers (hypotonic shock response, released lactic dehydrogenase, and surface glycoprotein lb levels) displayed an interactive effect with the inhibitors. The addition of protease inhibitors to the formulation of PGE(1) and theophylline showed further improvement in several markers. These findings demonstrate the possibility of preserving platelets for 15-20 days with the synergistic effects of activation inhibitors and an electrolyte storage medium fortified with citrate, buffers, and dextrose. In addition, these data suggest that platelet agonists generated in plasma accelerate the in vitro aging process of stored platelets.
Expressed sequence tag analysis of human retina for the NEIBank Project: retbindin, an abundant, novel retinal cDNA and alternative splicing of other retina-preferred gene transcripts. (2002)

The new retina cDNA libraries compare favorably in quality with those already represented in public databases. They are rich in retina specific sequences and include abundant cDNAs for a novel protein, retbindin. The function of retbindin remains to be determined, but it is a candidate for flavinoid or carotenoid binding. Analysis of multiple clones for highly expressed retina genes reveals several alternative splice variants in both coding and noncoding sequences which may have functional significance. The validated set of retina cDNAs will contribute to a nonredundant set for microarray construction.
Effect of dietary supplementation of beta-carotene on human monocyte-macrophage-mediated oxidation of low density lipoprotein. (1996)

Oxidative modification of low density lipoprotein (LDL), a key step in early atherosclerosis, is protected by the lipoprotein-associated antioxidants. The present study analyzes the effect of beta-carotene in plasma, in LDL and in monocyte-macrophages, on macrophage-mediated oxidation of LDL. We investigated the effect of dietary supplementation of beta-carotene on plasma lipid peroxidation [induced by AAPH (2,2-Azobis-2-amidinopropane hydrochloride)] and on cell-free and cell-mediated oxidation of LDL by human monocyte-derived macrophages (HMDM) in the presence of CuSO4. Significant enrichment with beta-carotene was noted in plasma (twofold), in LDL (2.6-fold) and in HMDM (1.6-fold) 2 weeks after dietary supplementation with 180 mg/day of beta-carotene. Plasma lipid peroxidation analyzed by conjugated dienes generation decreased by 22% (P < 0.01) and LDL susceptibility to oxidation analyzed by malondialdehyde generation decreased by 40% (P < 0.01). After beta-carotene supplementation, beta-carotene-enrichment of HMDM capacity to oxidize native LDL, whereas beta-carotene enrichment of LDL significantly reduced LDL oxidation. In conclusion, then, our results suggest that beta-carotene content of LDL, but not that of the macrophages, is responsible for the inhibition of oxidation of LDL.
Nonstatistical binding of a protein to clustered carbohydrates (1999)

Carbohydrate-derivatized self-assembled monolayers (SAMs) are used as a model system to address issues involving cell-surface carbohydrate-protein interactions. Here we examine the influence of carbohydrate surface density on protein-binding avidity. We show that the binding selectivity of Bauhinia purpurea lectin switches from one carbohydrate ligand to another as the surface density of the carbohydrate ligands increases from values of chi(sugar) approximately 0.1-1.0. Polyvalent binding is possible at all surface densities investigated; hence, the switch in selectivity is not due simply to the achievement of a critical density that permits polyvalent contacts. Instead, secondary interactions at high surface densities promote a switch in carbohydrate-binding selectivity. These findings may have implications for how changes in the composition and the density of cell-surface carbohydrates influence biological recognition processes and regulatory pathways.
The Fidelity Index provides a systematic quantitation of star activity of DNA restriction endonucleases (2008)

Restriction endonucleases are the basic tools of molecular biology. Many restriction endonucleases show relaxed sequence recognition, called star activity, as an inherent property under various digestion conditions including the optimal ones. To quantify this property we propose the concept of the Fidelity Index (FI), which is defined as the ratio of the maximum enzyme amount showing no star activity to the minimum amount needed for complete digestion at the cognate recognition site for any particular restriction endonuclease. Fidelity indices for a large number of restriction endonucleases are reported here. The effects of reaction vessel, reaction volume, incubation mode, substrate differences, reaction time, reaction temperature and additional glycerol, DMSO, ethanol and Mn(2+) on the FI are also investigated. The FI provides a practical guideline for the use of restriction endonucleases and defines a fundamental property by which restriction endonucleases can be characterized.
Fast and Furious: Real Time End-to-End 3D Detection, Tracking and Motion Forecasting with a Single Convolutional Net (2020)

In this paper we propose a novel deep neural network that is able to jointly reason about 3D detection, tracking and motion forecasting given data captured by a 3D sensor. By jointly reasoning about these tasks, our holistic approach is more robust to occlusion as well as sparse data at range. Our approach performs 3D convolutions across space and time over a bird's eye view representation of the 3D world, which is very efficient in terms of both memory and computation. Our experiments on a new very large scale dataset captured in several north american cities, show that we can outperform the state-of-the-art by a large margin. Importantly, by sharing computation we can perform all tasks in as little as 30 ms.
Complete nucleotide sequence of the cosmid vector pWE15A (1992)

Journal Article Complete nucleotide sequence of the cosmid vector pWE15A Get access Donald Seto, Donald Seto Division of Biology (147–75), California Institute of TechnologyPasadena, CA 91125, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Ben F. Koop, Ben F. Koop Division of Biology (147–75), California Institute of TechnologyPasadena, CA 91125, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Jason Seto, Jason Seto Division of Biology (147–75), California Institute of TechnologyPasadena, CA 91125, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Leroy Hood Leroy Hood Division of Biology (147–75), California Institute of TechnologyPasadena, CA 91125, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 20, Issue 14, 25 July 1992, Page 3786, https://doi.org/10.1093/nar/20.14.3786 Published: 25 July 1992 Article history Received: 26 May 1992 Published: 25 July 1992
Expression of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer. (1995)

The proto-oncogene bcl-2 encodes a protein that inhibits apoptosis, a common mechanism of cell death caused by hormone and chemotherapy. We have analyzed bcl-2 protein expression by immuno-cytochemistry in primary node-positive breast cancers in two groups of patients (for a total of 180 cases). One group received adjuvant hormone therapy, the other chemotherapy (cyclophosphamide, methotrexate, and fluorouracil), and both groups were followed for a median time of 63 months. We compared our findings with conventional clinicopathological indicators [menopausal status, number of axillary nodes, histological grade, tumor size and type, estrogen receptor (ER), and progesterone receptor] and with p53 protein expression. bcl-2 protein was present in 65% of the carcinomas (117/180) and it was significantly associated with ER and progesterone receptor and inversely associated with p53 in both the groups of patients treated with adjuvant chemotherapy and tamoxifen. In patients treated either with adjuvant chemotherapy or tamoxifen, relapse-free survival at 5 years was significantly better among patients with bcl-2-positive tumors than in those with bcl-2 negative ones (P = 0.05 and 0.02, respectively). As far as overall survival is concerned, patients with bcl-2-positive tumors had a significantly better outcome in the group treated with adjuvant chemotherapy (P = 0.03). Multivariate analyses were performed for the two treatment groups. In the group treated with tamoxifen, lack of expression of ER and of bcl-2 was the only significant and independent predictor for poor relapse-free survival (P < 0.01). A number of nodes above 3 was the only significant and independent predictor for poor overall survival (P < 0.01). In the cyclophosphamide-methotrexate-fluorouracil-treated group, bcl-2 absence was significant for poor overall survival (P = 0.02) as well as a number of nodes above 3 (P = 0.04) and a tumor size above 2 cm (P = 0.05). For poor relapse-free survival only a number of nodes above 3 (P < 0.01) and progesterone negativity (P = 0.02) were significant and independent predictors of a higher probability of relapse. Thus, in contrast to in vitro data on drug resistance, bcl-2 expression was associated with better outcomes in patients treated with hormone and chemotherapy. Overall, these results suggest that expression of bcl-2 protein and the number of metastatic lymph nodes are independent features predictive of clinical outcome in patients with node-positive breast cancer, irrespective of the type of adjuvant treatment. The determination of bcl-2 protein may prove to be a useful tool to distinguish patients for whom conventional forms of adjuvant therapy are beneficial from those with bcl-2 negative and ER-negative tumors for whom novel therapeutic strategies are needed.
The NF- B Family of Transcription Factors and Its Regulation (2009)

Nuclear factor-kappaB (NF-kappaB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-kappaB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-kappaB proteins (IkappaBs), which retain inactive NF-kappaB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-kappaB activation converge on the IkappaB kinase (IKK) complex, which is responsible for IkappaB phosphorylation and is essential for signal transduction to NF-kappaB. Additional regulation of NF-kappaB activity is achieved through various post-translational modifications of the core components of the NF-kappaB signaling pathways. In addition to cytosolic modifications of IKK and IkappaB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-kappaB response. This has made the NF-kappaB pathway a paradigm for understanding general principles of signal transduction and gene regulation.
Toward Quantifying the Electrostatic Transduction Mechanism in Carbon Nanotube Molecular Sensors (2012)

Despite the great promise of carbon nanotube field-effect transistors (CNT FETs) for applications in chemical and biochemical detection, a quantitative understanding of sensor responses is lacking. To explore the role of electrostatics in sensor transduction, experiments were conducted with a set of highly similar compounds designed to adsorb onto the CNT FET via a pyrene linker group and take on a set of known charge states under ambient conditions. Acidic and basic species were observed to induce threshold voltage shifts of opposite sign, consistent with gating of the CNT FET by local charges due to protonation or deprotonation of the pyrene compounds by interfacial water. The magnitude of the gate voltage shift was controlled by the distance between the charged group and the CNT. Additionally, functionalization with an uncharged pyrene compound showed a threshold shift ascribed to its molecular dipole moment. This work illustrates a method for producing CNT FETs with controlled values of the turnoff gate voltage, and more generally, these results will inform the development of quantitative models for the response of CNT FET chemical and biochemical sensors.
Synthesis and Reactions of 3-C-Branched-Chain Analogues of 3,6-Anhydrodeoxynojirimycin (1997)

ABSTRACT The syntheses of 3,6-anhydro-1-deoxy-3-C-ethoxycarbonylmethyl- (4) and 3-C-(2-hydroxyethyl)nojirimycin (5) from 5-azido-6-O-tert-butyldiphenylsilyl-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (8) are described. The key intermediate is 5-azido-6-O-tert-butyldiphenylsilyl-3,5-dideoxy-3-C-ethoxycarbonylmethylene-1,2-O-isopropylidene-α-D-ribo-hex-3-enofuranose (11) which was obtained by condensation of 5-azido-6-O-tert-butyldiphenylsilyl-5-deoxy-1,2-O-isopropylidene-α-D-ribo-hexos-3-ulofuranose (10) with (ethoxycarbonylmethylene)triphenylphosphorane. Conventional benzoylation of 4 resulted in the formation of the lactones 13a and 13b. The 3-C-(2-hydroxyethyl) analogue (5) was synthesized by lithium aluminum hydride reduction of 3,6-anhydro-5-azido-5-deoxy-3-C-ethoxycarbonylmethyl-1,2-O-isopropylidene-α-D-glucofuranose (12), followed by deacetalation, and hydrogenation.