gebhart/patrepeval huggingface dataset:
Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid (2004)

Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. We treated 18 patients with myelodysplastic syndromes (MDS) and AML secondary to MDS (sAML/MDS) with VPA monotherapy (serum concentrations 346-693 microM [50-100 microg/mL]). Five patients received VPA and ATRA (80 mg/m(2)/d, days 1-7, every other week). Response according to international working group (IWG) criteria was observed in 8 patients (44%) on VPA monotherapy, including 1 partial remission. Median response duration was 4 months (range, 3-9 months). Four of 5 patients relapsing were treated with VPA + ATRA, 2 of them responding again. Among 5 patients receiving VPA + ATRA from the start, none responded according to IWG criteria, but 1 patient with sAML/MDS achieved a marked reduction in peripheral and marrow blasts. Thus, VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.
Influenza A virus nucleoprotein is a major target antigen for cross-reactive anti-influenza A virus cytotoxic T lymphocytes. (1985)

Influenza A virus-specific cytotoxic T lymphocytes (CTL) capable of lysing cells infected with any influenza A virus ("cross-reactive CTL") constitute a major portion of the host CTL response to influenza. The viral nucleoprotein (NP), a major internal virion structural protein, has been implicated as a possible target antigen for cross-reactive CTL. To directly examine CTL recognition of NP, a vaccinia virus recombinant containing a DNA copy of an influenza A virus NP gene was constructed. We found that murine cells infected with this virus were efficiently lysed in a major histocompatibility complex-restricted manner by cross-reactive CTL populations obtained by immunization with a variety of influenza A virus subtypes. In addition, the recombinant vaccinia virus containing the PR8 NP gene was able to both stimulate and prime for a vigorous secondary cross-reactive CTL response. Significantly, splenocytes from mice primed by inoculation with the recombinant vaccinia virus containing the PR8 NP gene could be stimulated by influenza A viruses of all three major human subtypes. Finally, unlabeled target competition experiments suggest that NP is a major, but not the sole, viral target antigen recognized by cross-reactive CTL.
New therapeutic opportunities for Hepatitis C based on small RNA (2007)

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.
Microinjection of gelsolin into living cells. (1987)

Gelsolins are actin-binding proteins that cap, nucleate, and sever actin filaments. Microinjection of cytoplasmic or plasma gelsolin into living fibroblasts and macrophages did not affect the shape, actin distribution, deformability, or ruffling activity of the cells. Gelsolin requires calcium for activity, but the NH2-terminal half is active without calcium. Microinjection of this proteolytic fragment had marked effects: the cells rounded up, stopped ruffling, became soft, and stress fibers disappeared. These changes are similar to those seen with cytochalasin, which also caps barbed ends of actin filaments. Attempts to raise the cytoplasmic calcium concentration and thereby activate the injected gelsolin were unsuccessful, but the increases in calcium concentration were minimal or transient and may not have been sufficient. Our interpretation of these results is that at the low calcium concentrations normally found in cells, gelsolin does not express the activities observed in vitro at higher calcium concentrations. We presume that gelsolin may be active at certain times or places if the calcium concentration is elevated to a sufficient level, but we cannot exclude the existence of another molecule that inhibits gelsolin. Microinjection of a 1:1 gelsolin/actin complex had no effect on the cells. This complex is stable in the absence of calcium and has capping activity but no severing and less nucleation activity as compared with either gelsolin in calcium or the NH2-terminal fragment. The NH2-terminal fragment-actin complex also has capping and nucleating activity but no severing activity. On microinjection it had the same effects as the fragment alone. The basis for the difference between the two complexes is unknown. The native molecular weight of rabbit plasma gelsolin is 82,500, and the extinction coefficient at 280 nm is 1.68 cm2/mg. A new simple procedure for purification of plasma gelsolin is described.
Predominant T cell receptor gene elements in TNP-specific cytotoxic T cells (1991)

H-2b class I-restricted, TNP-specific CTL clones were obtained by limiting dilution cloning of either short term polyclonal CTL lines or spleen cells of TNP-immunized mice directly ex vivo. Sequence analyses of mRNA coding for TCR alpha- and beta-chains of 11 clones derived from CTL lines from individual C57BL/6 mice revealed that all of them expressed unique but clearly nonrandom receptor structures. Five alpha-chains (45%) employed V alpha 10 gene elements, and four of those (36%) were associated with J beta 2.6-expressing beta-chains. The alpha-chains from these four TCR, moreover, contained an acidic amino acid in position 93 of their N or J region-determined sequences. Clones isolated directly from spleen cells carried these types of receptors at lower frequency, 27% V alpha 10 and 19% J beta 2.6, indicating that bulk in vitro cultivation on Ag leads to selection for these particular receptors. However, even in TNP-specific CTL cloned directly ex vivo, V alpha 10 usage was increased about fivefold over that in Ag-independently activated T cells in H-2b mice (4 to 5%). The selection for V alpha 10/J beta 2.6-expressing cells was obtained repeatedly in other TNP-specific CTL lines from C57BL/6 mice but not in FITC-specific CTL from the same strain or in TNP-specific CTL lines from B10.BR (H-2k) or B10.D2 (H-2d) mice. We conclude from this (a) that the selection for V alpha 10/J beta 2.6+ T cells is driven by the complementarity of these receptors to a combination of TNP and MHC epitopes and (b) that predominant receptor structures reflect the existence of a surprisingly limited number of "T cell-relevant" hapten determinants on the surface of covalently TNP-modified cells.
Insect Toxins from an Endophytic Fungus from Wintergreen (1997)

Two new compounds, 5-hydroxy-2- (1‘-oxo-5‘-methyl-4‘-hexenyl)benzofuran (1) and 5-hydroxy-2-(1‘-hydroxy-5‘-methyl-4‘-hexenyl)benzofuran (2), have been isolated via bioassay-directed fractionation of culture extracts of an unidentified endophytic fungus obtained from wintergreen, Gaultheria procumbens L. Their structures have been deduced from spectral data and confirmed by synthesis. Both 1 and 2 show toxicity to spruce budworm (Christoneura fumiferana Clem.) cells, and 1 is also toxic to the larvae.
Angled multimode interferometer for bidirectional wavelength division (de)multiplexing (2015)

We have demonstrated a bidirectional wavelength division (de)multiplexer (WDM) on the silicon-on-insulator platform using two 4-channel angled multimode interferometers (AMMIs) sharing the same multimode interference waveguide. An excellent match of the peak transmission wavelength of each channel between the two AMMIs was achieved. The input and output access waveguides were arranged in a configuration such that the propagation of light of one AMMI in the multimode interference waveguide suffered minimal perturbation by the input and output waveguides of the other AMMI. This type of device is ideal for the WDM system for datacom or telecom applications, e.g. an integrated optical transceiver, where the transmission wavelengths are required to match with the receiving wavelengths. The device also benefits from simple fabrication (as only a single lithography and etching step is required), improved convenience for the transceiver layout design, a reduction in tuning power and circuitry and efficient use of layout space. A low insertion loss of 3-4 dB, and low crosstalk of -15 to -20 dB, was achieved.
Interactive network planning and analysis on a personal computer (1990)

Features of POSCODAM, a power system planning and analysis software package, are described. POSCODAM (power system computation and data management) is an integrated package of three program systems, namely, POSDAM (power system data management), POSCO (power system computation), which consists of load-flow and short-circuit analysis modules, and POSGRAPH (power system graph), for graphical input and output of network topologies and computed results. During the past six years, this package has been used for applications such as optimization of energy transmission in regional electric networks, determination of reactive power compensation, investigation of system and equipment overloads, determination of system short-circuit power levels, dimensioning of switchgear and protection coordination, and grounding of power system neutrals.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Reciprocal Antagonism Coordinates C-type Natriuretic Peptide and Mitogen-signaling Pathways in Fibroblasts (1999)

The fibroblast, a cell central to effective wound remodeling, not only contains various growth factor receptors but also high activities of a guanylyl cyclase receptor (GC-B). Here we demonstrate that marked elevations of cyclic GMP induced by C-type natriuretic peptide (CNP), the ligand of GC-B, blocks activation of the mitogen-activated protein kinase cascade in fibroblasts. We also show that platelet-derived growth factor, fibroblast growth factor, serum, or Na3VO4 rapidly (within 5 min) and extensively (up to 85% inhibition) disrupt CNP-dependent elevations of cyclic GMP. In addition, the mitogens also lower cyclic GMP concentrations (50% decrease) in cells not treated with CNP. Cytoplasmic forms of guanylyl cyclase, in contrast to the CNP-stimulated pathway, are not antagonized by the various mitogens. The effects of the mitogens on cellular cyclic GMP are fully explained by a direct and stable inactivation of GC-B. Homogenates obtained from fibroblasts treated with or without the various mitogens contain equivalent amounts of GC-B protein, but both ligand-dependent and ligand-independent activity are markedly (up to 90% inhibition of CNP-dependent activity) decreased after mitogen addition. The stable inactivation is correlated with the dephosphorylation of phosphoserine and phosphothreonine residues of the cyclase receptor. These results not only establish a specific and reciprocal antagonistic relationship between mitogen-activated and GC-B-regulated signaling pathways in the fibroblast but also suggest that one of the earliest events following mitogen activation of a fibroblast is an interruption of cyclic GMP production from this receptor.
The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin (2008)

A number of large noncoding RNAs (ncRNAs) epigenetically silence genes through unknown mechanisms. The Air ncRNA is imprinted--monoallelically expressed from the paternal allele. Air is required for allele-specific silencing of the cis-linked Slc22a3, Slc22a2, and Igf2r genes in mouse placenta. We show that Air interacts with the Slc22a3 promoter chromatin and the H3K9 histone methyltransferase G9a in placenta. Air accumulates at the Slc22a3 promoter in correlation with localized H3K9 methylation and transcriptional repression. Genetic ablation of G9a results in nonimprinted, biallelic transcription of Slc22a3. Truncated Air fails to accumulate at the Slc22a3 promoter, which results in reduced G9a recruitment and biallelic transcription. Our results suggest that Air, and potentially other large ncRNAs, target repressive histone-modifying activities through molecular interaction with specific chromatin domains to epigenetically silence transcription.
Dynamic interactions within sub-complexes of the H/ACA pseudouridylation guide RNP (2007)

H/ACA RNP complexes change uridines to pseudouridines in target non-coding RNAs in eukaryotes and archaea. H/ACA RNPs are comprised of a guide RNA and four essential proteins: Cbf5 (pseudouridine synthase), L7Ae, Gar1 and Nop10 in archaea. The guide RNA captures the target RNA via two antisense elements brought together to form a contiguous binding site within the pseudouridylation pocket (internal loop) of the guide RNA. Cbf5 and L7Ae interact independently with the guide RNA, and here we have examined the impacts of these proteins on the RNA in nucleotide protection assays. The results indicate that the interactions observed in a fully assembled H/ACA RNP are established in the sub-complexes, but also reveal a unique Cbf5-guide RNA interaction that is displaced by L7Ae. In addition, the results indicate that L7Ae binding at the kink (k)-turn of the guide RNA induces the formation of the upper stem, and thus also the pseudouridylation pocket. Our findings indicate that L7Ae is essential for formation of the substrate RNA binding site in the archaeal H/ACA RNP, and suggest that k-turn-binding proteins may remodel partner RNAs with important effects distant from the protein-binding site.
Analysis of Fractalkine Receptor CX3CR1 Function by Targeted Deletion and Green Fluorescent Protein Reporter Gene Insertion (2000)

The seven-transmembrane receptor CX3CR1 is a specific receptor for the novel CX3C chemokine fractalkine (FKN) (neurotactin). In vitro data suggest that membrane anchoring of FKN, and the existence of a shed, soluble FKN isoform allow for both adhesive and chemoattractive properties. Expression on activated endothelium and neurons defines FKN as a potential target for therapeutic intervention in inflammatory conditions, particularly central nervous system diseases. To investigate the physiological function of CX3CR1-FKN interactions, we generated a mouse strain in which the CX3CR1 gene was replaced by a green fluorescent protein (GFP) reporter gene. In addition to the creation of a mutant CX3CR1 locus, this approach enabled us to assign murine CX3CR1 expression to monocytes, subsets of NK and dendritic cells, and the brain microglia. Analysis of CX3CR1-deficient mice indicates that CX3CR1 is the only murine FKN receptor. Yet, defying anticipated FKN functions, absence of CX3CR1 interferes neither with monocyte extravasation in a peritonitis model nor with DC migration and differentiation in response to microbial antigens or contact sensitizers. Furthermore, a prominent response of CX3CR1-deficient microglia to peripheral nerve injury indicates unimpaired neuronal-glial cross talk in the absence of CX3CR1.
The use of the oxygen electrode and fluorescence probes in simple measurements of photosynthesis (1987)

This PDF version was transcribed from the original text on paper by Hansatech Instruments. It is brought to you now by courtesy of its author, it’s illustrator and Oxygraphics. Appropriate acknowledgement of source, by you, in any future publication would be most welcome.
Identification of a Tumor-Associated Antigen in Cervical Carcinoma by Two-Dimensional (Crossed) Immunoelectrophoresis2 (1977)

Two-dimensional immunoelectrophoresis was used to evaluate 8 cervical cancer speciments, 11 other gynecologic tumors, and 5 specimens of normal cervix. Antigens were water-soluble tissue extracts and antisera prepared in rabbits. When tested against antisera to cervical cancer, cancer antigens showed 14-17 precipitin lines whereas normal cervix showed 10-16. A single heavy heterogeneous precipitin line with an electrophoretic mobility of 0.58 relative to bovine albumin was observed in all cervical cancer specimens but not in normal cervical or other tumor specimens. Further evidence for the uniqueness of this antigen was sought by enhancement (addition of another antigen to the first phase of electrophoresis which increased the size of common peaks) and suppression (addition of another antiserum to the second phase, whereby the peak size of components to which both sera have antibody was decreased). The specific precipitin line was neither suppressed by the addition of antisera to normal tissue nor enhanced when normal tissue antigen was added to the tumor antigen preparation. More conclusively, adsorption of the tumor antiserum with normal tissue had no effect on the unique tumor-associated precipitin line, whereas all other precipitin lines were removed. This antigen was common to other cervical tumors because enhancement was demonstrated with three other cervical tumor specimens. The identification of a distinct and separate antigen associated with cervical carcinoma will permit further characterization and possible development of immunodiagnostic methods.
Gain-of-function proteins for gene transfer in hemophilia (2005)

Comment on Schuettrumpf et al, page [2316][1]

Schuettrumpf and colleagues report in this issue of Blood an innovative mouse model of gene therapy for hemophilia B that could substantially improve the efficacy of gene transfer.

Hemophilia B, an X-linked bleeding disorder characterized by a
Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation (1991)

Murine Th1 clones that receive signals through their TCR in the absence of APC-derived co-stimulatory signals do not produce IL-2 and instead become anergic, i.e., they are subsequently unable to produce IL-2 in response to Ag and normal APC. The critical cellular event required to prevent the induction of this anergic state appears to be T cell proliferation. Anergy was induced when T cell clones were stimulated under conditions where both TCR occupancy and costimulatory signals were provided but where proliferation in response to the IL-2 produced was prevented. Once induced, anergy could be reversed if the T cells were allowed to undergo multiple rounds of cell division. These results show that anergy is induced as a consequence of TCR occupancy in the absence of cell division; this can be achieved either by limiting IL-2 production because of deficient provision of co-stimulatory signals or by preventing response to IL-2.
Abstract 2952: Image-guided miRNA therapy for metastatic breast cancer (2012)

Abstract Metastases, and not the primary tumor from which they originate, are the main reason for mortality from breast carcinoma. New therapeutic approaches for metastatic breast cancer are urgently needed. The specific involvement of miRNAs in the development of metastases has been recently described and identified microRNA-10b (miR-10b) in initiation of breast cancer invasion and metastasis (Ma et al, Nature, 2007). Here, we describe a nanodrug for image-guided therapy of lymph node metastatic breast cancer. It consists of RGD-targeted ultrasmall magnetic nanoparticles that mediate their therapeutic effect by delivering locked nucleic acid to knockdown microRNA-10b (MN-anti-miR10b). Nanodrug bearing scrambled locked nucleic acid (MN-scr-miR) was also synthesized. The size and composition of the nanoparticles promote their extended persistence in the circulation (blood half-life &amp;gt;12 hrs) and transcytosis into the tumoral and lymph node interstitium. The nanodrug is detectable by magnetic resonance and optical imaging and is designed so that it targets both primary tumor cells and lymph node metastases. We show that treatment of invasive human breast tumor cells in vitro expressing luciferase (MDA-MB-231-luc) with the nanodrug results in an 88% downregulation of miRNA-10b with the application of just 1.5 nmoles/ml of LNA and abolishes the invasion and migration of the tumor cells. In vivo, we showed that the nanodrug could be delivered to primary tumors as well as to lymph nodes and lymph node and lung metastasis. Therapeutic treatment of animal bearing orthotopic MDA-MB-231-luc tumors was performed with tail vein injections (10mg/kg of iron) delivered once a week for four weeks. Two therapeutic scenarios were used: 1) preventing tumor cell dissemination from the primary tumor beginning prior to the formation of detectable lymph node metastases and 2) beginning the treatment after the formation of lymph node metastasis but prior to metastasis to the lungs. In scenario (1) we observed that by the end of the treatment course, bioluminsecence signal from the tumors in the experimental animals treated with MN-anti-miR10b was at pre-metastatic levels, indicating a prevention of tumor cell metastasis from the primary tumor to lymph nodes. In contrast, there was visible dissemination of tumor cells to the lymph nodes of control animals treated with the MN-scr-miR. This therapeutic effect was highly reproducible. In scenario (2) there was a 20-fold increase in lymph node metastatic burden in controls treated with MN-scr-miR. By contrast, in the experimental animals treated with MN-anti-miR10b, there was a dramatic reduction of metastatic progression (p &amp;lt; 0.001, n = 6) and a prevention of tumor cell dissemination to the lungs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2952. doi:1538-7445.AM2012-2952
Correlation Between Semen Parameters and the Hamster Egg Penetration Test (HEPT) Among Fertile and Subfertile Men in Singapore (2006)

The objective of this retrospective study was to distinguish between fertile and subfertile men based on their semen parameters and hamster egg penetration test (HEPT) outcome. This study involved 110 subfertile men recruited from an infertility clinic and 48 fertile men attending an antenatal clinic in Singapore. The men were required to donate a semen specimen for semen analysis and HEPT assay. The results indicated that the subfertile group had significantly lower normal sperm morphology according to the Tygerberg strict criteria, and lower progressive motility (P < .05). Semen volume, density, HEPT decondensation rate, and sperm penetration index were not significantly different between the 2 groups. Receiver operating characteristic curve analysis indicated that sperm morphology had the highest predictive power of 65.7% with a threshold value of 7%, and progressive motility had a predictive power of 61.8% with a threshold value of 50%. Using the tenth percentile of the fertile population as the cutoff, lower adjusted thresholds of 3% for sperm morphology and 28% for progressive motility were obtained, giving higher positive predictive values of 81.8% and 84.4%, respectively. This study shows that these new cutoff values can be used to screen the general population to identify subfertile men. In contrast, the HEPT proved to be an insensitive and unreliable assay in identifying subfertile males. To our knowledge the comparison of HEPT and semen parameters between subfertile and fertile men has not been previously reported in an Asian population.