gebhart/patrepeval huggingface dataset:
Assessment of Receptor Internalization and Recycling (2004)

Internalization of G-protein-coupled receptors (GPCRs) occurs in response to agonist activation of the receptors and causes a redistribution of receptors away from the plasma membrane toward endosomes. Internalization of lower-affinity small molecule GPCRs such as muscarinic acetylcholine and adrenergic receptors has been measured using hydrophilic antagonist radioligands that are membrane impermeant. In contrast, internalization of peptide hormone receptors is assessed by measuring the internalization of a radiolabeled- or fluorescently labeled peptide hormone. More recently, the use of epitope-tagged receptors has allowed the measurement of changes in receptor subcellular distribution by the use of immunoassay and immunofluorescence confocal microscopy. This chapter describes each of these approaches to the measurement of receptor internalization and describes the advantages and disadvantages of each method.
An Efficient Synthesis of Internal Guanidines (1995)

An efficient synthetic method for internal guanidines has been developed, employing as the key step, a nucleophilic substitution of bis-BOC-protected terminal guanidines.
Multiple Antiviral Activities of Cyanovirin-N: Blocking of Human Immunodeficiency Virus Type 1 gp120 Interaction with CD4 and Coreceptor and Inhibition of Diverse Enveloped Viruses (2000)

Cyanovirin-N (CV-N) is a cyanobacterial protein with potent neutralizing activity against human immunodeficiency virus (HIV). CV-N has been shown to bind HIV type 1 (HIV-1) gp120 with high affinity; moreover, it blocks the envelope glycoprotein-mediated membrane fusion reaction associated with HIV-1 entry. However, the inhibitory mechanism(s) remains unclear. In this study, we show that CV-N blocked binding of gp120 to cell-associated CD4. Consistent with this, pretreatment of gp120 with CV-N inhibited soluble CD4 (sCD4)-dependent binding of gp120 to cell-associated CCR5. To investigate possible effects of CV-N at post-CD4 binding steps, we used an assay that measures sCD4 activation of the HIV-1 envelope glycoprotein for fusion with CCR5-expressing cells. CV-N displayed equivalently potent inhibitory effects when added before or after sCD4 activation, suggesting that CV-N also has blocking action at the level of gp120 interaction with coreceptor. This effect was shown not to be due to CV-N-induced coreceptor down-modulation after the CD4 binding step. The multiple activities against the HIV-1 envelope glycoprotein prompted us to examine other enveloped viruses. CV-N potently blocked infection by feline immunodeficiency virus, which utilizes the chemokine receptor CXCR4 as an entry receptor but is CD4 independent. CV-N also inhibited fusion and/or infection by human herpesvirus 6 and measles virus but not by vaccinia virus. Thus, CV-N has broad-spectrum antiviral activity, both for multiple steps in the HIV entry mechanism and for diverse enveloped viruses. This broad specificity has implications for potential clinical utility of CV-N.
Photochemical microetching of GaAs (1983)

Controlled etching of III-V compound semiconductors is an important step in the fabrication of discrete and integrated components. We have developed a system which allows a 1.3 μm diameter light spot to be obtained. Displacement of the spot on the sample and speed are controlled by a computer for any desired figure. The light spot is used to photochemically etch GaAs immersed in aqueous solutions.
Regional Differences in Capillary Density of the Normal Human Dermis (1989)

Quantitative study of the capillary density of normal dermis of 113 biopsy specimens taken from 20 body sites from 6 cadavers was carried out. Histologic quantification of dermal capillaries using the alkaline phosphatase method to delineate vascular endothelium and automated image analysis demonstrates statistically significantly greater capillary density in the head-face/neck region both in the papillary and reticular dermis than in the lower parts of the body. The smallest numbers of the dermal capillary density were noted in the calf and shin areas. These data support the hypothesis that random-pattern skin flaps can be safely raised longer in the face and neck than in other parts of the body.
Development and first in human evaluation of PSMA I&T - A ligand for diagnostic imaging and endoradiotherapy of prostate cancer (2014)

1083 Objectives Based on its consistently high expression in prostate cancer, PSMA (Prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. A variety of Glu-urea-Lys (EuK)-based PSMA inhibitors have been evaluated preclinically, and EuK-Ahx-[68Ga]HBED-CC has already shown excellent clinical results. However, the HBED chelator is not suitable for radiolabeling with therapeutic nuclides. This prompted us to develop DOTAGA-coupled ligands, which may be radiolabeled with a variety of diagnostic and therapeutic radiometals. Methods The PSMA-affinity (IC50) and internalization kinetics were investigated on LNCaP cells. Biodistribution and PET imaging studies were performed in LNCaP-tumor bearing CD-1 nu/nu mice. Based on first human PET studies, SUVmean/max values (1 h p.i.) were calculated from VOIs at a 70% isocontour and normalized to gluteal musculature. Results Our ligand EuK-Sub-kff-DOTAGA showed PSMA-affinities of 13.1±2.2 and 15.9±0.5 nM for the natLu and natGa complex, respectively. For natLu- and natGa-PSMA I&T (EuK-Sub-kf-iodo-y-DOTAGA), IC50 values of 7.9±2.4 and 9.3±3.3 nM were obtained. Internalization kinetics were fast for all ligands, with an 50% increase in internalization efficiency for [68Ga/177Lu] PSMA I&T compared to EuK-Sub-kff-[68Ga/177Lu]DOTAGA. In mice, EuK-Sub-kff-[68Ga]DOTAGA showed lower non-specific tracer accumulation in lungs, liver, spleen and intestine than EuK-Ahx-[68Ga]HBED-CC and comparable PSMA-specific accumulation in tumor and kidney. Initial patient studies with [68Ga]PSMA I&T revealed high uptake in tumor lesions with tumor/background ratios of 29.6±13.5 (SUVmean ratio) and 33.5±9.7 (SUVmax ratio). Conclusions PSMA I&T shows high PSMA-affinity and efficient internalization into PSMA-expressing cells. The accumulation of [68Ga]PSMA I&T in tumor lesions is equal to that of EuK-Ahx-[68Ga]HBED-CC. With the possibility of 177Lu-based therapy, PSMA I&T opens new perspectives for theranostic probes in the management of prostate cancer.
Abstract 4831: Breast cancer cells metastasize to bone through E-selectin+ vascular gateways (2014)

Abstract The bone marrow (BM) has been suggested to serve as a protective environment for disseminated breast cancer cells (BCCs). The precise molecular signals that circulating BCCs use to identify and adhere to BM vasculature are unknown, yet these interactions are essential for the development of bone metastases. To address this question, we used in vivo fluorescence microscopy to track the interactions of estrogen receptor (ER)+ and ER- BCC lines with bone in real time in an intracardiac injection xenograft mouse model. Our data show that circulating tumor cells enter the bone through unique vascular niches where endothelial cell expression of the adhesive molecule E-selectin and of the chemokine SDF-1 are both upregulated. These vascular niches are the same sinusoidal capillary beds that serve as the site of entry for peripherally circulating hematopoietic stem and progenitor cells (HSPCs) returning to the BM. Similar to HSPCs, BCCs aberrantly express the major cell surface molecules known to regulate hematopoietic cell entry and exit through the BM, including CXCR4 (SDF-1 receptor) and multiple E-selectin ligands. While neither CXCR4 blockade nor general chemokine signaling inhibition in BCCs prevented BM dissemination, E-selectin blockade by the specific glycomimetic antagonist GMI-1271 decreased BCC entry in the BM by approximately three fold at 2 and 24 hours after treatment. Moreover, in studies comparing FACS isolated stem and non-stem MCF-7 BCCs, GMI-1271 inhibition of E-selectin specifically targeted CD44+CD24- breast cancer stem cell homing. Non-stem CD44+CD24+ BCCs demonstrated significantly less BM homing compared to stem BCCs, and their BM trafficking was less E-selectin dependent. These data reveal for the first time a molecular mediator of bone metastases at the point-of-entry for BCCs in the BM. In addition, the ability of BCCs to hijack HSPC trafficking pathways to metastasize to bone correlates with E-selectin ligand expression and may be a specific characteristic of the BCC stem cell subpopulation. Citation Format: Trevor Price, Monika Burness, Ayelet Sivan, Renee Cheng, John L. Magnani, Dorothy A. Sipkins. Breast cancer cells metastasize to bone through E-selectin+ vascular gateways. [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 4831. doi:10.1158/1538-7445.AM2014-4831
Optical coherence tomography allows for the reliable identification of laryngeal epithelial dysplasia and for precise biopsy: A clinicopathological study of 61 patients undergoing microlaryngoscopy (2010)

OCT allows for a fairly accurate assessment of benign and dysplastic laryngeal epithelial lesion and greatly facilitates the taking of precise biopsies. Laryngoscope, 2010.
A Novel α-Conotoxin Identified by Gene Sequencing Is Active in Suppressing the Vascular Response to Selective Stimulation of Sensory Nerves in Vivo (2003)

We describe the identification of a conopeptide sequence in venom duct mRNA from Conus victoriae that suppresses a vascular response to pain in the rat. PCR-RACE was used to screen venom duct cDNAs for those transcripts that encode specific antagonists of vertebrate neuronal nicotinic acetylcholine receptors (nAChRs). One of these peptides, Vc1.1, was active as an antagonist of neuronal nAChRs in receptor binding and functional studies in bovine chromaffin cells. It also suppressed the vascular responses to unmyelinated sensory nerve C-fiber activation in rats. Such vascular responses are involved in pain transmission. Furthermore, its ability to suppress C-fiber function was greater than that of MVIIA, an omega-conotoxin with known analgesic activity in rats and humans. Vc1.1 has a high degree of sequence similarity to the alpha-conotoxin family of peptides and has the 4,7 loop structure characteristic of the subfamily of peptides that act on neuronal-type nAChRs. The results suggest that neuronal alpha-conotoxins should be further investigated with respect to their potential to suppress pain.
Ras Activation in Jurkat T cells following Low-Grade Stimulation of the T-Cell Receptor Is Specific to N-Ras and Occurs Only on the Golgi Apparatus (2004)

Ras activation is critical for T-cell development and function, but the specific roles of the different Ras isoforms in T-lymphocyte function are poorly understood. We recently reported T-cell receptor (TCR) activation of ectopically expressed H-Ras on the the Golgi apparatus of T cells. Here we studied the isoform and subcellular compartment specificity of Ras signaling in Jurkat T cells. H-Ras was expressed at much lower levels than the other Ras isoforms in Jurkat and several other T-cell lines. Glutathione S-transferase-Ras-binding domain (RBD) pulldown assays revealed that, although high-grade TCR stimulation and phorbol ester activated both N-Ras and K-Ras, low-grade stimulation of the TCR resulted in specific activation of N-Ras. Surprisingly, whereas ectopically expressed H-Ras cocapped with the TCRs in lipid microdomains of the Jurkat plasma membrane, N-Ras did not. Live-cell imaging of Jurkat cells expressing green fluorescent protein-RBD, a fluorescent reporter of GTP-bound Ras, revealed that N-Ras activation occurs exclusively on the Golgi apparatus in a phospholipase Cgamma- and RasGRP1-dependent fashion. The specificity of N-Ras signaling downstream of low-grade TCR stimulation was dependent on the monoacylation of the hypervariable membrane targeting sequence. Our data show that, in contrast to fibroblasts stimulated with growth factors in which all three Ras isoforms become activated and signaling occurs at both the plasma membrane and Golgi apparatus, Golgi-associated N-Ras is the critical Ras isoform and intracellular pool for low-grade TCR signaling in Jurkat T cells.
Random mutagenesis of BoNT/E Hc nanobody to construct a secondary phage-display library (2014)

To construct secondary mutant phage-display library of recombinant single variable domain (VHH) against botulinum neurotoxin E by error-prone PCR.The gene coding for specific VHH derived from the camel immunized with binding domain of botulinum neurotoxin E (BoNT/E) was amplified by error-prone PCR. Several biopanning rounds were used to screen the phage-displaying BoNT/E Hc nanobodies. The final nanobody, SHMR4, with increased affinity recognized BoNT/E toxin with no cross-reactivity with other antigens especially with related BoNT toxins.The constructed nanobody could be a suitable candidate for VHH-based biosensor production to detect the Clostridium botulinum type E.Diagnosis and treatment of botulinum neurotoxins are important. Generation of high-affinity antibodies based on the construction of secondary libraries using affinity maturation step leads to the development of reagents for precise diagnosis and therapy.
Woulda, Coulda, Shoulda: Counterfactually-Guided Policy Search (2018)

Learning policies on data synthesized by models can in principle quench the thirst of reinforcement learning algorithms for large amounts of real experience, which is often costly to acquire. However, simulating plausible experience de novo is a hard problem for many complex environments, often resulting in biases for model-based policy evaluation and search. Instead of de novo synthesis of data, here we assume logged, real experience and model alternative outcomes of this experience under counterfactual actions, actions that were not actually taken. Based on this, we propose the Counterfactually-Guided Policy Search (CF-GPS) algorithm for learning policies in POMDPs from off-policy experience. It leverages structural causal models for counterfactual evaluation of arbitrary policies on individual off-policy episodes. CF-GPS can improve on vanilla model-based RL algorithms by making use of available logged data to de-bias model predictions. In contrast to off-policy algorithms based on Importance Sampling which re-weight data, CF-GPS leverages a model to explicitly consider alternative outcomes, allowing the algorithm to make better use of experience data. We find empirically that these advantages translate into improved policy evaluation and search results on a non-trivial grid-world task. Finally, we show that CF-GPS generalizes the previously proposed Guided Policy Search and that reparameterization-based algorithms such Stochastic Value Gradient can be interpreted as counterfactual methods.
Aggressive Variants of Castration-Resistant Prostate Cancer (2014)

A subset of patients with advanced castration-resistant prostate cancer may eventually evolve into an androgen receptor (AR)-independent phenotype, with a clinical picture associated with the development of rapidly progressive disease involving visceral sites and hormone refractoriness, often in the setting of a low or modestly rising serum prostate-specific antigen level. Biopsies performed in such patients may vary, ranging from poorly differentiated carcinomas to mixed adenocarcinoma-small cell carcinomas to pure small cell carcinomas. These aggressive tumors often demonstrate low or absent AR protein expression and, in some cases, express markers of neuroendocrine differentiation. Because tumor morphology is not always predicted by clinical behavior, the terms "anaplastic prostate cancer" or "neuroendocrine prostate cancer" have been used descriptively to describe these rapidly growing clinical features. Patients meeting clinical criteria of anaplastic prostate cancer have been shown to predict for poor prognosis, and these patients may be considered for platinum-based chemotherapy treatment regimens. Therefore, understanding variants within the spectrum of advanced prostate cancer has important diagnostic and treatment implications.
Efficient frequency domain video scrambling for content access control (1999)

Multimedia data security is very important for multimedia commerce on the Internet such as video-on-demand and real-time video multicast. Traditional cryptographic algorithms for data security are often not fast enough to process the vast amount of data generated by the multimedia applications to meet the real-time constraints. This paper presents a joint encryption and compression framework in which video data are scrambled efficiently in the frequency domain by employing selective bit scrambling, block shuffling and block rotation of the transform coefficients and motion vectors. The new approach is very simple to implement, yet provides considerable level of security, has minimum adverse impact on the compression efficiency, and allows transparency, transcodability, and other content processing functionalities without accessing the cryptographic key.
William Pember Reeves: Writing the Fortunate Isles (2013)

William Pember Reeves seldom appears in studies of Australians in London, for the simple reason that he was from New Zealand. Nonetheless, he was one of the leading ‘Anglo-Colonials’ in London in the late 1890s (Sinclair, WPR 247), and appears often in the pages of the British-Australasian and other journals interested in colonial life and topics. A journalist, politician, socialist, legislator, economist, diplomat, historian, and poet, he produced a good deal of writing in many genres. Most of his work was concerned with ‘writing New Zealand,’ or, in one of his favourite classical allusions, ‘the fortunate isles.’ This paper traces his political and literary career, arguing that his move from New Zealand to London allowed him not only to write with the clarity of distance and the authority of being published in the cultural metropolis, but to liaise or mediate between the cultural positions of the colonial and the metropolitan. Not simply colonial, English, or even cosmopolitan, his writerly personae remained firmly based in both New Zealand and London, making him a transnational colonial Briton, writing differences as well as writing across them.
Basic Principles and Clinical Advancements of Muscle Electrotransfer (2010)

Muscle electrotransfer covers the delivery of molecules to muscle tissue by means of electric pulses. This method has proven highly efficient in transferring, in particular, plasmid DNA to muscles, resulting in long-term expression of the transferred genes. DNA electrotransfer to muscle tissue has clinical potential within DNA vaccination, systemic delivery of therapeutic proteins and correction of gene defects in muscles. In the recent years, DNA electrotransfer to muscle tissue has reached clinical advancement with 8 on-going clinical trials. In the present review, I will draw on the experiences obtained from the clinical studies, in understanding the mechanistic and practical advantages and limits of muscle electrotransfer. The effect of applying electric pulses to muscle tissue will be described in details, while present and future clinical applications are reviewed.
Abstract 3589: Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy (2018)

Abstract Despite success in treating hematological malignancies, T cells expressing chimeric antigen receptors (CARs) have shown poor efficacy in solid tumor indications. The poor utility of CARs is thought to be due to a number of factors including T cell exhaustion and a lack of persistence. Utilizing only the CD3ζ chain of six distinct T cell receptor subunits in combination with a costimulatory domain, the CARs bypass the natural TCR signaling complex. The failure to initiate and harness a complete TCR response is arguably a primary underlying factor preventing CAR-T cell success in solid tumor indications. Here, we present a novel T cell engineering platform: T Cell Receptor Fusion Constructs (TRuC™s), which target tumors in a MHC non-restricted fashion. Unlike CARs, the constructs integrate into the TCR complex, harnessing the full potential of natural T cell activation, effector function and regulation. Here we demonstrate preclinical evidence underscoring the efficacy of TRuC™-T cells re-programmed to target the solid tumor antigen mesothelin (TC-210). TC-210 showed robust anti-tumor activity in vitro and in vivo in mesothelioma, lung and ovarian tumor models. Surprisingly, this activity was associated with less proinflammatory cytokine production compared to CAR-T cells with the same binder and was supported by strong TRuC™-T cell persistence. Taken together, mesothelin targeting TRuC™-T cells have potent anti-tumor activity and present a promising approach for treating mesothelin-expressing solid tumors. Citation Format: Jian Ding, Ekta Patel, Patrick Tavares, Justin Quinn, Rashmi Choudhary, Bonnie Le, Olga Kiner, Solly Weiler, Daniel R. Getts, Patrick Baeuerle, Robert Hofmeister. Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3589.
Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. (1995)

Adhesion molecules that tether circulating leukocytes to endothelial cells may also transduce or modulate outside-in signals for cellular activation, providing an initial regulatory point in the inflammatory response. Adhesion of human monocytes to P-selectin, the most rapidly expressed endothelial tethering factor, increased the secretion of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) by the leukocytes when they were stimulated with platelet-activating factor. Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding to its ligand (P-selectin glycoprotein ligand-1) on myeloid cells. Moreover, tethering by P-selectin specifically enhanced nuclear translocation of nuclear factor-kappa B (NF-kappa B), a transcription factor required for expression of MCP-1, TNF-alpha, and other immediate-early genes. These results demonstrate that P-selectin, through its ligands on monocytes, may locally regulate cytokine secretion in inflamed tissues.
Electrochemical assay system with single-use electrode strip for measuring lactate in whole blood (1993)

We have developed an assay system for measuring lactate in whole blood, consisting of a single-use strip of an enzyme-coated electrode and a small meter. The electrode strip is made of three plastic films: a cover sheet, a spacer, and an insulation layer printed with electrodes that are coated with lactate oxidase (EC 1.1.3.x) and ferricyanide as an electron mediator. The meter measures the magnitude of the anodic current of the reduced mediator by the enzymatic reaction and displays the lactate concentration 60 s after a blood sample (5 microL) is applied. The calibration curve was linear up to 20 mmol/L, and the between-run CVs at three concentrations were 1.7-8.4%. Lactate concentrations determined by this method (y) in blood samples from healthy individuals before and after exercise agreed with the results obtained by the conventional enzymatic method (x): y = 0.97x - 0.3, Sy/x = 0.7. This assay provides a rapid and convenient test for measuring blood lactate concentrations.