gebhart/patrepeval huggingface dataset:
Tissue distribution, metabolism, and excretion of the antibody-drug conjugate Herceptin-monomethyl auristatin E in rats (2005)

5063 Antibody-drug conjugates (ADC) are a relatively new and evolving approach to improve the potency and selectivity of anti-tumor agents. Key questions exist regarding the in vivo disposition of the drug conjugate (i.e. the cytotoxic moiety) as it relates to optimizing dosing and understanding safety. In this study, Herceptin, a humanized monoclonal antibody directed against the Her2 receptor, was conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) through a highly stable protease-cleavable dipeptide linker. The linker is selectively cleaved by lysosomal enzymes after internalization and free MMAE is capable of binding tubulin and blocking cell proliferation. Initial studies in mouse xenograft tumor models have demonstrated enhanced tumor-specific cell killing relative to unconjugated Herceptin. The objective of this study was to characterize the tissue distribution, metabolism and route of elimination of Herceptin-Val-Cit-[14C]MMAE following an IV bolus dose of (11 mg/kg, 100uCi/kg) of the radiolabeled ADC in Sprague-Dawley rats. Tissue distribution was assessed by quantitative whole body autoradiography (QWBA) 1, 4, 7, and 14 days following dosing. The results from QWBA indicated the presence of radioactivity in highly perfused organs (lungs>liver>heart>kidney) on day 1 post-dose, with evidence for hepatic elimination of the drug via the bile/gastro-intestinal tract (GI) on day 4. Radioactivity decreased in most organs with a similar pharmacokinetic profile as blood radioactivity. Persistence of radioactivity was observed in tissues with rapidly dividing cells such as the GI epithelia, bone marrow, spleen and thymus on days 4 and 7. These data are consistent with target organs of toxicity identified in previous toxicology studies. Excretion studies indicated that MMAE was primarily eliminated intact in feces (∼80%) and urine (∼ 6%) within 7 days following dosing. Characterization of radioactivity in rat plasma showed evidence for a time-dependent biotransformation of Herceptin-Val-Cit-[14C]MMAE including the liberation of low levels of free drug. In conclusion, Herceptin-Val-Cit-[14C]MMAE distributes to highly perfused organs. The majority of blood radioactivity represented radiolabeled ADC, however, low levels of free drug were detected. The cytotoxic moiety, MMAE, was primarily eliminated intact in the feces with greater than 86% of drug being excreted 7 days post dose.
Expression profiling of microRNAs by deep sequencing (2009)

MicroRNAs are short non-coding RNAs that regulate the stability and translation of mRNAs. Profiling experiments, using microarray or deep sequencing technology, have identified microRNAs that are preferentially expressed in certain tissues, specific stages of development, or disease states such as cancer. Deep sequencing utilizes massively parallel sequencing, generating millions of small RNA sequence reads from a given sample. Profiling of microRNAs by deep sequencing measures absolute abundance and allows for the discovery of novel microRNAs that have eluded previous cloning and standard sequencing efforts. Public databases provide in silico predictions of microRNA gene targets by various algorithms. To better determine which of these predictions represent true positives, microRNA expression data can be integrated with gene expression data to identify putative microRNA:mRNA functional pairs. Here we discuss tools and methodologies for the analysis of microRNA expression data from deep sequencing.
Complement C5b-9 Increases Plasminogen Binding and Activation on Human Endothelial Cells (1997)

Deposition of the terminal complement proteins (C5b-9) on human endothelial cells can result in cell lysis or nonlytic alterations of cell function including procoagulant responses. Because regulation of fibrinolysis is a central endothelial function and because C9 contains a carboxyl-terminal lysine similar to other proteins that bind and facilitate activation of plasminogen (PG), the effects of complement injury on PG binding and activation on these cells were investigated. Activation of complement through deposition of C5b67 complexes on endothelial cells resulted in a small increase (approximately 20%) in PG binding. Incorporation of C8 into C5b-8 resulted in no further increase in binding; however, specific 125I-PG binding was increased by approximately 100% after C5b-9 deposition. Moreover, PG was found to bind specifically to C7 and C9. The PG bound to endothelial cells after C5b-9 deposition was readily activated by tissue-type plasminogen activator (TPA). In a cell-free system, complement C9 and a synthetic peptide composed of the 20 carboxyl-terminal amino acids of C9 enhanced PG activation by TPA. Removal of the carboxyl-terminal lysine of C9 abolished the enhancement of PG activation without diminishing PG binding. We conclude that membrane C9 may comprise a binding site for PG and serve to enhance activation of this zymogen by TPA. These findings suggest that immune injury to the endothelium may enhance both the fibrin-generating and fibrinolytic capacity of the vessel wall.
Angiotensin-ll-lnduced Angiogenesis in Sponge Implants in Mice (1996)

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating would healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (AII) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with AII (1 microgram), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with AII (2 micrograms) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 +/- 15 vs. 424 +/- 27 mg), total protein (18 +/- 1 vs. 25 +/- 1 micrograms/ww) and GAG (98 +/- 10 vs. 160 +/- 13 ng/ww). The local blood flow has been determined by measuring the washout rate of 133Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.
Aproximación a la optimización del transporte de caña de azúcar desde el campo a un central azucarero en Cuba (2001)

En el presente trabajo se presenta una aproximacion al problema de la minimizacion del coste del transporte de la cana de azucar cosechada en diferentes campos productores y transportada hasta un central azucarero para su transformacion. La complejidad del problema viene determinada basicamente por el numero de variables y restricciones consideradas. Las restricciones hacen referencia a la necesidad de abastecimiento continuo del central, los medios utilizados en la cosecha, los distintos tipos de transporte y las rutas de aprovisionamiento caracterizadas por la existencia de centros de acopio de la cana para su posterior transporte al central por ferrocarril.
Abnormal skeletal patterning in embryos lacking a single Cbp allele: A partial similarity with Rubinstein–Taybi syndrome (1997)

CBP is a transcriptional coactivator required by many transcription factors for transactivation. Rubinstein-Taybi syndrome, which is an autosomal dominant syndrome characterized by abnormal pattern formation, has been shown to be associated with mutations in the Cbp gene. Furthermore, Drosophila CBP is required in hedgehog signaling for the expression of decapentapleigic, the Drosophila homologue of bone morphogenetic protein. However, no direct evidence exists to indicate that loss of one copy of the mammalian Cbp gene affects pattern formation. Here, we show that various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice resulting from a C57BL/6-CBA x BALB/c cross. In support of a conserved signaling pathway for pattern formation in insects and mammals, the expression of Bmp7 was found to be reduced in the heterozygous mutants. The frequency of the different abnormalities was significantly lower in a C57BL/6-CBA background, suggesting that the genetic background is an important determinant of the variability and severity of the anomalies seen in Rubinstein-Taybi syndrome patients.
Updated Functional Classification of β-Lactamases (2009)

Two classification schemes for beta-lactamases are currently in use. The molecular classification is based on the amino acid sequence and divides beta-lactamases into class A, C, and D enzymes which utilize serine for beta-lactam hydrolysis and class B metalloenzymes which require divalent zinc ions for substrate hydrolysis. The functional classification scheme updated herein is based on the 1995 proposal by Bush et al. (K. Bush, G. A. Jacoby, and A. A. Medeiros, Antimicrob. Agents Chemother. 39:1211-1233, 1995). It takes into account substrate and inhibitor profiles in an attempt to group the enzymes in ways that can be correlated with their phenotype in clinical isolates. Major groupings generally correlate with the more broadly based molecular classification. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrum beta-lactamases and serine carbapenemases; and group 3 metallo-beta-lactamases. Several new subgroups of each of the major groups are described, based on specific attributes of individual enzymes. A list of attributes is also suggested for the description of a new beta-lactamase, including the requisite microbiological properties, substrate and inhibitor profiles, and molecular sequence data that provide an adequate characterization for a new beta-lactam-hydrolyzing enzyme.
Analysis and use of the serum albumin binding domains of streptococcal protein G (1988)

Streptococcal protein G is an IgG-binding receptor with a molecular weight of 63 kDa as predicted from the sequence of the corresponding gene. Here we show that a truncated recombinant protein of 23 kDa still has IgG-binding capacity and also interacts specifically with human serum albumin (HSA). This demonstrates that protein G is a bifunctional receptor. To investigate the structures needed for IgG- and albumin-binding, different parts of the receptor molecule were produced in E. coli using a coupled expression/secretion system. Affinity chromatography, using IgG or HSA immobilized on Sepharose, showed that the two binding activities are structurally separated. From these experiments, it was concluded that a region of 64 amino acid residues is sufficient for albumin-binding. The structure of this part of the protein suggests either a divalent or a trivalent binding capacity. The specific interaction to albumin was used to purify a heterologous protein by affinity chromatography to yield a pure fusion protein in a one-step procedure. The implication of this novel affinity system as a tool to facilitate protein immobilization and purification is discussed.
Radiocarbon Anomalies from Old CO2 in the Soil and Canopy Air (2011)

The canopies of forests and cultivated fields can retard the ventilation of CO 2 respired from the soil. The plants in dense canopies can then acquire a small fraction of their carbon by recycling some of the respired CO 2 . Furthermore, some plants can assimilate a small fraction of their carbon by uptake of CO 2 in the soil via their roots. In tectonically active areas, the diffuse flux of CO 2 from geological sources may be comparable to that from normal soil respiration. In such areas, both the canopy and root uptake effects may allow plants to acquire a measurable fraction of their carbon from geological sources. Because this “old” carbon lacks radiocarbon, its assimilation would increase the apparent 14 C ages of the plants. These effects may account for some of the discrepancies between archaeological and 14 C dates.
Isolation of High‐Affinity Trypsin Inhibitors from a DNA‐Encoded Chemical Library (2007)

Maturing is easy to do: Annealing benzamidine–oligonucleotide conjugates with a library of DNA-encoded compounds allows the affinity capture of pharmacophores that are capable of binding to exosites adjacent to the primary substrate-binding pocket of the serine protease trypsin. Selected conjugates show an improvement in IC50 values of several orders of magnitude compared with the starting benzamidine.
Stereoselective synthesis of 1,6-dioxaspirolactones from spiro-cyclopropanecarboxylated sugars: total synthesis of dihydro-pyrenolide D (2014)

A one-pot protocol for the stereoselective construction of γ-spiroketal γ-lactone frameworks from sugar derived spiro-cyclopropanecarboxylic acids involving a ring enlargement and cyclization reaction is revealed.
Improvement of Lactose Digestion by Humans Following Ingestion of Unfermented Acidophilus Milk: Influence of Bile Sensitivity, Lactose Transport, and Acid Tolerance of Lactobacillus acidophilus (1997)

The influence of bile sensitivity, lactose transport, and acid tolerance of Lactobacillus acidophilus on in vivo digestion of lactose was investigated. Four strains of L. acidophilus exhibiting varied degrees of lactose transport, beta-galactosidase activity, and bile sensitivity were used to prepare unfermented acidophilus milks. Lactose malabsorption was evaluated by measuring breath H2 excretion off 11 lactose maldigesting subjects following ingestion of four acidophilus test milks. Test meals were fed in a randomized double-blind protocol. Consumption of acidophilus milk (2% fat) containing strains B, N1, and E significantly reduced mean total H2 production compared with that of the control reduced-fat (2% fat) milk, but milk containing strain ATCC 4356 did not differ from the control. Acidophilus milk containing L. acidophilus N1 was the most effective of the four acidophilus milks in improving lactose digestion and tolerance. Strain N1 exhibited the lowest beta-galactosidase activity and lactose transport but the greatest bile and acid tolerance of the four strains. The results indicated that bile and acid tolerance may be important factors to consider when L. acidophilus strains are selected for improving lactose digestion and tolerance.
Stable growth transformation of human T lymphocytes by herpesvirus saimiri. (1992)

Herpesvirus saimiri induces T-cell lymphomas in various species of New World monkeys and in rabbits, and it is able to immortalize monkey T lymphocytes in vitro. Sequences responsible for these effects have been localized to a region of the genome that varies significantly among the virus subgroups A, B, and C. We now report that infection of human blood lymphocytes and thymocytes with strains of subgroup C, in contrast to viruses of the other subgroups, yields continuously proliferating T-cell lines with the phenotype of mature CD4- or CD8-positive cells. Infection with strains of Herpes-virus saimiri subgroup C can thus be used to generate human T-cell lines for a variety of immunological and developmental studies.
Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas (2019)

BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)
Ontology based personalized search (2003)

With the exponentially growing amount of information available on the Internet, the task of retrieving documents of interest has become increasingly difficult. Search engines usually return more than 1,500 results per query, yet out of the top twenty results, only one half turn out to be relevant to the user. One reason for this is that Web queries are in general very short and give an incomplete specification of individual users' information needs. This paper explores ways of incorporating users' interests into the search process to improve the results. The user profiles are structured as a concept hierarchy of 4,400 nodes. These are populated by 'watching over a user's shoulder' while he is surfing. No explicit feedback is necessary. The profiles are shown to converge and to reflect the actual interests quite well. One possible deployment of the profiles is investigated: re-ranking and filtering search results. Increases in performance are moderate but noticeable and show that fully automatic creation of large hierarchical user profiles is possible.
High resolution X‐ray crystallographic structure of bovine heart cytochrome c and its application to the design of an electron transfer biosensor (2007)

Cytochrome c is one of the most studied proteins probably due to its electron-transfer properties in aerobic and anaerobic respiration. Particularly, cytochrome c from bovine heart is a small protein, M(r) 12,230 Da, globular (hydrodynamic diameter of 3.4 nm), soluble in different buffer solutions, and commercially available. Despite being a quite well-studied protein and relatively easy to manipulate from the biochemical and electrochemical viewpoint, its 3D structure has never been published. In this work, the purification, crystallization and 3D structure of one of the cytochrome c isoforms is presented to 1.5 A resolution. It is also shown how the presence of isoforms made both the purification and crystallization steps difficult. Finally, a new approach for protein electrocrystallization and design of biosensors is presented.
Increased Incidence of CAD Gene Amplification in Tumorigenic Rat Lines as an Indicator of Genomic Instability of Neoplastic Cells (1989)

It has been hypothesized that genomic instability is an important component of tumorigenesis. In an attempt to establish this relationship, we determined the frequencies with which two nontumorigenic and four tumorigenic rat liver epithelial cell lines underwent a particular type of genetic instability, gene amplification. By exposing cells to N-(phosphonoacetyl)-L-aspartate (PALA), a drug which specifically inhibits the aspartate transcarbamylase activity of the multifunctional CAD enzyme and selects for amplification of the CAD gene, we observed a striking parallel between the ability of these cell lines to become resistant to this drug and the ability of these same cells to form tumors after injection into day-old syngeneic rats. Cells of one highly tumorigenic line became resistant to PALA greater than 70 times more often than those of a non-tumorigenic line. Molecular analyses of eight independent PALA-resistant subclones confirmed that, in each case, this resistance was due to amplification of the CAD gene. Thus, our results demonstrate the relationship between tumorigenicity and at least one measure of genomic instability, CAD gene amplification. The method developed in this study provides a quantitative, rapid indicator of tumorigenicity and should prove useful in trying to elucidate the underlying basis of genomic instability in neoplastic cells.
Bulk content delivery using co-operating end-nodes with upload/download limits (2013)

We study the problem of optimizing the cost of content delivery in a cooperative network of caches at end-nodes. The caches could be, for example, within the computers of users downloading videos from websites (such as Netflix, Blockbuster etc.), DVRs (such as TiVo, or cable boxes) used as part of video on demand services or public hot-spots (e.g. Wi-Fi access points with a cache) deployed over a city to serve content to mobile users. Each cache serves user requests locally over a medium that incurs no additional costs (i.e. WiFi, home LAN); if a request is not cached, it must be fetched from another cache or a central server. In our model, each cache has a tiered back-haul internet connection, with a usage cap (and fixed per-byte costs thereafter). Redirecting requests intended for the central server to other caches with unused back-haul capacity can bring down the network costs. Our goal is to develop a mechanism to optimally 1) place data into the caches and 2) route requests to caches to reduce the overall cost of content delivery. We develop a multi-criteria approximation based on a LP rounding procedure that with a small (constant factor) blow-up in storage and upload limits of each cache, gives a data placement that is within constant factor of the optimum. Further, to speed up the solution, we propose a technique to cluster caches into groups, solve the data placement problem within a group, and combine the results in the rounding phase to get the global solution. Based on extensive simulations, we show that our schemes perform very well in practice, giving costs within 5-15% to the optimal, and reducing the network load at a central server by as much as 55% with only a marginal blow up in the limits. Also we demonstrate that our approach out-performs a non-cooperative caching mechanism by about 20%.