gebhart/patrepeval huggingface dataset:
Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts. (2018)

335 Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.
Effect of loss on multiplexed single-photon sources (2015)

An on-demand single-photon source is a key requirement for scaling many optical quantum technologies. A promising approach to realize an on-demand single-photon source is to multiplex an array of heralded single-photon sources using an active optical switching network. However, the performance of multiplexed sources is degraded by photon loss in the optical components and the non-unit detection efficiency of the heralding detectors. We provide a theoretical description of a general multiplexed single-photon source with lossy components and derive expressions for the output probabilities of single-photon emission and multi-photon contamination. We apply these expressions to three specific multiplexing source architectures and consider their tradeoffs in design and performance. To assess the effect of lossy components on near- and long-term experimental goals, we simulate the multiplexed sources when used for many-photon state generation under various amounts of component loss. We find that with a multiplexed source composed of switches with ~0.2-0.4 dB loss and high efficiency number-resolving detectors, a single-photon source capable of efficiently producing 20-40 photon states with low multi-photon contamination is possible, offering the possibility of unlocking new classes of experiments and technologies.
The Digital Distributed System Security Architecture (1989)

The Digital Distributed System Security Architecture is a comprehensive specification for security in a distributed system that employs state-of-the-art concepts to address the needs of both commercial and government environments. The architecture covers user and system authentication, mandatory and discretionary security, secure initialization and loading, and delegation in a general-purpose computing environment of heterogeneous systems where there are no central authorities, no global trust, and no central controls. The architecture prescribes a framework for all applications and operating systems currently available or to be developed. Because the distributed system is an open OSI environment, where functional interoperability only requires compliance with selected protocols needed by a given application, the architecture must be designed to securely support systems that do not implement or use any of the security services, while providing extensive additional security capabilities...
Pigs Is Pigs (2000)

Since the first report of a cloned animal (Dolly the sheep) 3 years ago, cloning mammals has become something of a cottage industry. As Prather discusses in his Perspective, pigs can now be added to the august list of cloned animals, which includes cows, goats, and mice. This is a particularly spectacular achievement because pig cloning has turned out to be notoriously difficult. The pig is also a valuable domestic animal to have cloned because, being physiologically close to humans, its organs can be used in xenotransplantation.
High-level expression of secreted proteins from cells adapted to serum-free suspension culture. (1993)

We have developed a host cell/vector system based on the use of adenovirus-transformed cells and a promoter, designated GBMT, capable of being activated by the Ela tumor antigen produced in these cells. GBMT-based vectors were constructed with hygromycin phosphotransferase and murine dihydrofolate reductase as selective markers. We demonstrate their utility in two adenovirus-transformed cell lines, human kidney 293 and Syrian hamster AV12-664. Further, we describe methods and conditions for the direct adaptation of isolated recombinant clones to serum-free suspension growth conditions. For exemplary purposes, we describe the generation of stable recombinant 293 cell lines with single-copy integrated vectors secreting the highly complex clotting factor human protein C at levels as high as 20 mg/l in serum-free suspension culture. In addition, using the AV12-664 cell line with GBMT and direct dominant selection of the dhfr gene, we have isolated clones secreting a tissue plasminogen activator derivative at levels of about 40 mg/l under serum-free suspension conditions. The distinct advantages of this vector/host cell system are 1) the direct selection of stable clones expressing relatively high levels of recombinant protein, eliminating the need for the tedious stepwise gene amplification process and 2) the direct adaptation to serum-free suspension culture.
A multimodal platform for nonlinear optical microscopy and microspectroscopy (2009)

Multimodal nonlinear optical microscopy is a valuable tool to study complex biological samples. We present an easy-to-operate approach to perform coherent anti-Stokes Raman scattering (CARS), two-photon fluorescence (TPF), second harmonic generation (SHG), and third-harmonic generation (THG) imaging using a single laser source composed of an 80 MHz femtosecond (fs) laser, an optical parametric oscillator (OPO), and a PPLN crystal for frequency doubling. The platform allows vibrationally resonant CARS imaging of CH-rich myelin sheath in fresh spinal tissues and lipid bodies in live cells. Multimodal nonlinear optical imaging and microspectroscopy analysis of fresh liver tissues are demonstrated.
RELAXIN STIMULATES THE SYNTHESIS AND RELEASE OF PRORENIN FROM HUMAN DECIDUAL CELLS: EVIDENCE FOR AUTOCRINE/PARACRINE REGULATION (1990)

Porcine relaxin caused a time- and concentration-dependent increase in the release of renin from decidual cells cultured over a 96 h period. The increase in renin release occurred 24-48 h after exposure and was maximal at 48-72 h. Half-maximal stimulation occurred at a relaxin concentration of 5 ng/ml, and maximal stimulation (250-270%) occurred at concentrations greater than or equal to 10 ng/ml. At each time, greater than 95% of the renin released into the medium was in the form of prorenin. The stimulation of renin release was paralleled by a stimulation of cellular renin content and was completely inhibited by cycloheximide, indicating that relaxin also stimulated renin synthesis. Since renin is present in both cytotrophoblast and decidual cells, these results suggest a paracrine and/or autocrine relationship between relaxin- and prorenin-secreting cells.
Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. (1987)

We present evidence that human peripheral blood lymphocytes, free of contaminating monocytes, rapidly produce high levels of tumor necrosis factor (TNF) when stimulated with phorbol diester and calcium ionophore, and lower but significant levels of TNF when stimulated with mitogens. These two types of inducers act preferentially on T cells, both CD4+ and CD8+. NK cells produce TNF only when stimulated with phorbol diester and calcium ionophore, and they do so at a much lower level than T cells. The procedures used in the purification of lymphocytes and the differential ability to respond to various inducers allow us to exclude that monocytes or basophils contaminating the lymphocyte preparation participate in the production of TNF. In particular, LPS, a potent inducer of TNF production from monocytes, is unable to induce significant levels of TNF in the lymphocyte preparations. The TNF produced by lymphocytes has antigenic, physicochemical, and biochemical characteristics identical to those of the TNF produced by myeloid cell lines or monocytes upon stimulation with LPS. LT is also produced by lymphocyte preparations. Production of TNF and LT proteins in response to the different inducers is paralleled by accumulation of cytoplasmic TNF and LT mRNA. Both at mRNA and at protein levels, stimulation of T lymphocytes with phorbol diester and calcium ionophore preferentially induces TNF, whereas mitogen stimulation preferentially induces LT. Our data suggest that the TNF and LT genes, two closely linked genes encoding two partially homologous proteins with almost identical biological functions, are independently regulated in lymphocytes.
Long-Term Prediction of Prostate Cancer Up to 25 Years Before Diagnosis of Prostate Cancer Using Prostate Kallikreins Measured at Age 44 to 50 Years (2007)

A single PSA test at age 44 to 50 years predicts subsequent clinically diagnosed prostate cancer. This raises the possibility of risk stratification for prostate cancer screening programs.
Sensitive Windows of Human Reproduction and Development (2011)

Successful human reproduction and development is dependent upon men and women undergoing a series of highly interrelated and conditional biologic processes, many of which delineate critical or sensitive windows of human development. This chapter provides an overview of six sensitive windows including folliculogenesis, spermatogenesis and steriodogenesis, menstruation, ovulation and the fertile window, implantation window, and the intrauterine environment. Understanding the biology of these sensitive windows has methodologic implications for study design and the timing of data and biospecimens collection, particularly when attempting to identify fecundity determinants or reproductive and/or developmental toxicants. Sensitive windows are highly relevant for assessing the early origins of health and disease including the elucidation of epigenetic mechanisms that impact human reproduction and development across the lifespan and, possibly, across generations.
Current Concepts of Fat Graft Survival: Histology of Aspirated Adipose Tissue and Review of the Literature (2000)

Clinical longevity of correction after autologous fat transfer is determined by the degree of augmentation resulting from the amount of fibrosis induced and the number of viable fat cells. Survival of aspirated fat cell grafts depends mainly on the anatomic site, the mobility and vascularity of the recipient tissue, or underlying causes and diseases, and less on harvesting and reinjection methods.
Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma (2006)

Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.
Targeting of Chrolamphenicol Acetyltransferase to Human Immunodeficiency Virus Particles via Vpr and Vpx (1995)

Vpr and Vpx are the auxiliary proteins of human immunodeficiency viruses (HIVs) selectively incorporated into mature viral particles. We showed that the bacterial chloramphenicol acetyltransferase (CAT) fused to the N-terminus of HIV-1 Vpr, HIV-2 Vpr, or HIV-2 Vpx was incorporated into mature virions in a type-selective manner. By using chimeric proteins between HIV-1 Vpr and HIV-2 Vpx, we found that the N-terminal side of these proteins was mainly important for type-selective virion incorporation. The C-terminal arginine-rich region of HIV-1 Vpr was also found to transport CAT fusion proteins into virions but without any type selectivity. Furthermore, the corresponding regions of HIV-2 Vpr and HIV-2 Vpx had no such activity. This region of HIV-1 Vpr may interact nonspecifically with viral genomic RNA. Collectively, Vpr and Vpx may provide a means to introduce foreign proteins and other molecules into HIV virions for therapeutic purposes.
Engineering in a PTM: PEGylation (2009)

This chapter contains sections titled: Protein PEGylation General Properties of PEG Chemically Activated PEGs and the Process of PEGylation Potential Effects of PEGylation that are of Therapeutic Relevance Some Specific PEGylated Biopharmaceuticals Conclusions References
Mitochondrial trans-2-Enoyl-CoA Reductase of Wax Ester Fermentation from Euglena gracilis Defines a New Family of Enzymes Involved in Lipid Synthesis (2004)

Under anaerobiosis, Euglena gracilis mitochondria perform a malonyl-CoA independent synthesis of fatty acids leading to accumulation of wax esters, which serve as the sink for electrons stemming from glycolytic ATP synthesis and pyruvate oxidation. An important enzyme of this unusual pathway is trans-2-enoyl-CoA reductase (EC 1.3.1.44), which catalyzes reduction of enoyl-CoA to acyl-CoA. Trans-2-enoyl-CoA reductase from Euglena was purified 1700-fold to electrophoretic homogeneity and was active with NADH and NADPH as the electron donor. The active enzyme is a monomer with molecular mass of 44 kDa. The amino acid sequence of tryptic peptides determined by electrospray ionization mass spectrometry were used to clone the corresponding cDNA, which encoded a polypeptide that, when expressed in Escherichia coli and purified by affinity chromatography, possessed trans-2-enoyl-CoA reductase activity close to that of the enzyme purified from Euglena. Trans-2-enoyl-CoA reductase activity is present in mitochondria and the mRNA is expressed under aerobic and anaerobic conditions. Using NADH, the recombinant enzyme accepted crotonyl-CoA (km=68 microm) and trans-2-hexenoyl-CoA (km=91 microm). In the crotonyl-CoA-dependent reaction, both NADH (km=109 microm) or NADPH (km=119 microm) were accepted, with 2-3-fold higher specific activities for NADH relative to NADPH. Trans-2-enoyl-CoA reductase homologues were not found among other eukaryotes, but are present as hypothetical reading frames of unknown function in sequenced genomes of many proteobacteria and a few Gram-positive eubacteria, where they occasionally occur next to genes involved in fatty acid and polyketide biosynthesis. Trans-2-enoyl-CoA reductase assigns a biochemical activity, NAD(P)H-dependent acyl-CoA synthesis from enoyl-CoA, to one member of this gene family of previously unknown function.
Characterization and cDNA cloning of phospholipase C-gamma, a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. (1990)

Heparin-binding growth factors (HBGFs) bind to high-affinity cell surface receptors which possess intrinsic tyrosine kinase activity. A Mr 150,000 protein phosphorylated on tyrosine in response to class 1 HBGF (HBGF-1) was purified and partially sequenced. On the basis of this sequence, cDNA clones were isolated from a human endothelial cell library and identified as encoding phospholipase C-gamma. Phosphorylation of phospholipase C-gamma in intact cells treated with HBGF-1 was directly demonstrated by using antiphospholipase C-gamma antibodies. Thus, HBGF-1 joins epidermal growth factor and platelet-derived growth factor, whose receptor activation leads to tyrosine phosphorylation and probable activation of phospholipase C-gamma.
Submicrometer axial resolution optical coherence tomography (2002)

Optical coherence tomography (OCT) with unprecedented submicrometer axial resolution achieved by use of a photonic crystal fiber in combination with a compact sub-10-fs Ti:sapphire laser (Femtolasers Produktions) is demonstrated for what the authors believe is the first time. The emission spectrum ranges from 550 to 950 nm (lambda(c)=725 nm , P(out)=27 mW) , resulting in a free-space axial OCT resolution of ~0.75 mum , corresponding to ~0.5 mum in biological tissue. Submicrometer-resolution OCT is demonstrated in vitro on human colorectal adenocarcinoma cells HT-29. This novel light source has great potential for development of spectroscopic OCT because its spectrum covers the absorption bands of several biological chromophores.
Effect of insemination regimen on embryo production in superovulated cows (1985)

Three experiments tested the effects of six insemination regimens on embryo production in superovulated cows. One, two or three inseminations with one unit of semen at each time produced the same percentage fertilised (74, 68 and 74 per cent, P = 0.673) and the same number of fertilised embryos (8.2, 6.3 and 9.1, P = 0.136). However, the one and two inseminations group had less transferable (P = 0.008) and total (P = 0.051) embryos (3.9/9.6 and 3.9/8.9) than the three inseminations group (6.8/13.2). The percentage transferable remained the same (42, 45 and 58 per cent, P = 0.161). When two units of semen were used at the first or middle insemination and one, two and three inseminations were compared, the percentage fertilised (65, 77 and 77 per cent, P = 0.082) and the number fertilised (7.0, 7.4 and 8.6, P = 0.565) were again the same but the number (P = 0.047) and percentage transferable (P = 0.000) increased between the one and two inseminations (3.8 vs 5.7 and 30 per cent vs 54 per cent). The increase in transferable embryos with multiple inseminations could not be explained physiologically, but is of concern since transferable embryos are the "sales product' of superovulation. Two inseminations with one unit of semen was as effective as two inseminations with three units of semen, in terms of percentage fertilised (68 and 70 per cent, P = 0.762), number fertilised (10.3 and 8.3, P = 0.582), transferable embryos (6.7 and 5.7 P = 0.532), percentage transferable (44 and 46 per cent, P = 0.737) and total embryos recovered (14.8 and 12.7, P = 0.54).(ABSTRACT TRUNCATED AT 250 WORDS)
The entry of entry inhibitors: A fusion of science and medicine (2003)

For HIV-1 to enter a cell, its envelope protein (Env) must sequentially engage CD4 and a chemokine coreceptor, triggering conformational changes in Env that ultimately lead to fusion between the viral and host cell membranes. Each step of the virus entry pathway is a potential target for novel antiviral agents termed entry inhibitors. A growing number of entry inhibitors are under clinical development, with one having already been licensed by the Food and Drug Administration. With the emergence of virus strains that are largely resistant to existing reverse transcriptase and protease inhibitors, the development of entry inhibitors comes at an opportune time. Nonetheless, because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs. Env density, receptor expression levels, and differences in affinity and receptor presentation are all factors that could influence the clinical response to this promising class of new antiviral agents.
Potential Therapeutic Role of Histatin Derivative P‐113din Experimental Rat Models ofPseudomonas aeruginosaSepsis (2004)

These results provide evidence for double antiendotoxin and antimicrobial activity for P-113d and point to its potential use for the treatment of severe infections.
Targeting JNK for therapeutic depletion of stem-like glioblastoma cells (2012)

Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.
Laminins and other strange proteins (1992)

Laminins are large multidomain proteins of the extracellular matrix (ECM) with important functions in the development and maintenance of cellular organization and supramolecular structure, in particular in basement membranes. Each molecule is composed of three polypeptide chains, A (300-400 kDa) and B1 and B2 (180-200 kDa), which together form the characteristic cross-shaped laminin structure with three short arms and one long arm. Many different domains have been identified in laminin by sequence analysis, structural investigations, and functional studies. Each short arm is formed by homologous N-terminal portions of one of the three chains. Structurally, each short arm contains two or three globular domains which are connected by rows of manyfold-repeated Cys-rich "EGF-like" domains. In all three chains this region is followed by a long heptad repeat region similar to those found in many alpha-helical coiled-coil proteins. These parts of the three laminin chains constitute a triple-stranded coiled-coil domain, which forms the extended rodlike structure of the long arm. This is the only domain in the protein which is made up of more than one chain and consequently serves the function of chain assembly. The two B chains are terminated by the coiled-coil domain, but the A chain contains an additional C-terminal segment which accounts for five globular domains located at the tip of the long arm. Several important functions of laminin have been assigned to individual domains in either the short arms or terminal regions of the long arm.(ABSTRACT TRUNCATED AT 250 WORDS)