gebhart/patrepeval huggingface dataset:
Methylation of chloroplast DNA does not affect viability and maternal inheritance in tobacco and may provide a strategy towards transgene containment (2008)

We report the integration of a type II restriction-methylase, mFokI, into the tobacco chloroplast genome and we demonstrate that the introduced enzyme effectively directs the methylation of its target sequence in vivo and does not affect maternal inheritance. We further report the transformation of tobacco with an E. coli dcm methylase targeted to plastids and we demonstrate efficient cytosine methylation of the plastid genome. Both adenosine methylation of FokI sites and cytosine methylation of dcm sites appeared phenotypically neutral. The ability to tolerate such plastid genome methylation is a pre-requisite for a proposed plant transgene containment system. In such a system, a chloroplast located, maternally inherited restriction methylase would provide protection from a nuclear-encoded, plastid targeted restriction endonuclease. As plastids are not paternally inherited in most crop species, pollen from such plants would carry the endonuclease transgene but not the corresponding methylase; the consequence of this should be containment of all nuclear transgenes, as pollination will only be viable in crosses to the appropriate transplastomic maternal background.
Neuregulin Autocrine Signaling Promotes Self-Renewal of Breast Tumor-Initiating Cells by Triggering HER2/HER3 Activation (2013)

Currently, only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TIC) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2, or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2-targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of patients with breast cancer than they currently reach.
Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity (2009)

The phenomenon of concomitant tumor immunity involves a tumor-bearing host rejecting another similar tumor at a distant site and suggests the existence of tumor-specific immunity. Loss of this immunity may contribute to tumor metastasis. However, mechanisms underlying the loss of concomitant immunity are largely unknown. We set up a concomitant tumor immunity model in which this immunity is gradually lost as the primary tumor progresses. We found that CD8(+) T cells, especially tumor-infiltrating CD8(+) T cells, from mice that lost concomitant tumor immunity, possessed potent antitumor properties and strongly expressed effector molecules. Furthermore, effector/memory regulatory T cells (Treg cells, CD103(+)CD4(+)Foxp3(+) T cells) increased as the primary tumor progressed. They initially accumulated around the tumor and in the spleen at later points. Not only did these cells more greatly express killing molecules, they also suppressed the functions of tumor-bearing CD8(+) T cells in vitro and in vivo. Finally, we show that these effector/memory Treg cells inhibit concomitant tumor immunity in vivo. Taken together, data suggest that effector/memory Treg cells are responsible for the loss of concomitant tumor immunity associated with tumor progression.
The orexin system regulates alcohol‐seeking in rats (2006)

1. Orexin-containing neurons have been implicated in feeding, sleep-wake cycles and more recently in drug-seeking behaviour. 2. Pretreatment of alcohol-preferring (iP) rats with an orexin1 receptor antagonist (SB-334867, 20 mg kg(-1), intraperitoneally) completely abolished an olfactory cue-induced reinstatement of alcohol-seeking behaviour, and also attenuated alcohol responding under an operant fixed ratio regimen without affecting water responding. 3. The mRNA encoding orexin within the hypothalamus was expressed at a similar density in iP and non-preferring (NP) rats; chronic consumption of ethanol in iP rats did not significantly regulate the density of this expression, but did increase the area of expression within the lateral, but not medial, hypothalamus. 4. These data indicate that while orexin may not be implicated in the development of an alcohol preference, re-exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin-containing neurons and drive reinstatement of alcohol-seeking.
Osteopetrosis (1993)

Osteopetrosis is an inherited skeletal condition characterized by increased bone radiodensity. There are three clinical groups: infantile-malignant autosomal recessive, fatal within the first few years of life (in the absence of effective therapy); intermediate autosomal recessive, appears during the first decade of life but does not follow a malignant course; and autosomal dominant, with full-life expectancy but many orthopaedic problems. The infantile variant shows a myelophthisic anemia, granulocytopenia, and thrombocytopenia, and patients eventually die from infection or bleeding or both. Neurologic sequelae include cranial nerve compression (optic nerve, blindness; auditory nerve, deafness; facial nerve, paresis), hydrocephalus, convulsions, and mental retardation. Radiographs show uniform bone density without corticomedullary demarcation, broadened metaphyses, “bone within a bone” or endobone phenomena (tarsals, carpals, phalanges, vertebrae, ilium), and thickened growth plates if there is superimposed rickets. Transverse pathologic fractures occur, often followed by massive periosteal bone formation. Computed tomographic scans, magnetic resonance imaging, and bone scans provide specific information. Iliac crest bone biopsy is valuable to quantitate osteoclast and marrow changes by light and electron microscopy. Medical treatments involve high-dose calcitriol to stimulate osteoclast differentiation and bone marrow transplantation to provide monocytic osteoclast precursors. Orthopaedic problems in the intermediate and autosomal dominant forms include increased fractures, coxa vara, long-bone bowing, hip and knee degenerative arthritis, and mandibular and long-bone osteomyelitis. Cranial nerve compression also occurs. Osteotomy, plating, intramedullary rodding, and joint arthroplasty can be done, but are difficult because of bone hardness.
Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs (2012)

About the Editors xv Acknowledgments xvii Contributors xix Introduction 1 Michael J. Barratt and Donald E. Frail References 5 Part I. Drug Repositioning: Business Case, Strategies, and Operational Consideration 7 1. Drug Repositioning: The Business Case and Current Strategies to Repurpose Shelved Candidates and Marketed Drugs 9 John Arrowsmith and Richard Harrison 2. Opportunities and Challenges Associated with Developing Additional Indication for Clinical Development Candidates and Marketed Drugs 33 Donald E. Frail and Michael J. Barratt 3. Clinical and Operational Considerations in Repositioning Marketed Drugs and Drug Candidates 53 Damian O Connell, David J. Sequeira, and Maria L. Miller 4. Regulatory Considerations and Strategies for Drug Repositioning 65 Ken Phelps Part II. Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs 89 5. Computational and Bioinformatic Strategies for Drug Repositioning Drugs 91 Richard Mazzarella and Craig Webb 6. Mining Scientific and Clinical Databases to Identify Novel Uses for Existing Drugs 137 Christos Andronis, Anuj Sharma, Spyros Deftereos, Vassilis Virvilis, Ourania Konstanti, Andreas Persidis, and Aris Persidis 7. Predicting the Polypharmacology of Drugs: Identifying New Uses through Chemoinformatics, Structural Informatics, and Molecular Modeling-Based Approaches 163 Li Xie, Sarah L. Kinnings, Lei Xie, and Philip E. Bourne 8. Systematic Phenotypic Screening for Novel Synergistic Combinations: A New Paradigm for Repositioning Existing Drugs 207 Margaret S. Lee 9. Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates 253 Michael S. Saporito, Christopher A. Lipinski, and Andrew G. Reaume 10. Old Drugs Yield New Discoveries: Examples from the Prodrug , Chiral Switch, and Site-Selective Deuteration Strategies 291 Adam J. Morgan, Bhaumik A. Pandya, Craig E. Masse, and Scott L. Harbeson Part III. Academic and Nonprofit Initiatives and the Role of Alliances in the Drug Repostioning Industry 345 11. Repurposing Drugs for Tropical Disease: Case Studies and Open-Source Screening Initiatives 347 Curtis R. Chong 12. Drug Repositioning Efforts by Nonprofit Foundations 389 13. Business Development Strategies in the Repositioning Industry 433 Aris Persidis and Elizabeth T. Stark 14. A Case Study in Drug Repositioning: Sosei 445 Akinori Mochizuki and Makiko Aoyama Appendix Additional Drug Repositioning Resources and Links 457 Mark A. Mitchell and Michael J. Barratt Index 469
Overexpression of humanmutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer (1996)

Data regarding oxidatively modified DNA bases suggest that cancer cells are more exposed to oxidative stress than adjacent non-tumorous tissue. This novel concept may contribute to the understanding of certain aspects of tumor biology such as activated transcription factors, genetic instability, chemotherapy-resistance and metastasis. We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTH1, an enzyme preventing the misincorporation into DNA of 8-oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool. The expression of hMTH1 messenger RNA (mRNA) in RCC was significantly higher than that in adjacent non-tumorous kidney. Moreover, advanced-stage tumors showed significantly higher hMTH1 mRNA expression than early-stage tumors, and there was a modest linear correlation between hMTH1 expression and c-myc expression. The results provide logical support for the concept of "persistent oxidative stress in cancer" and suggest a role of hMTH1 mRNA level as a prognostic marker.
Homo- and heteropolynuclear Ni2+ and Cu2+ complexes of polytopic ligands, consisting of a tren unit substituted with three 12-membered tetraazamacrocycles (2007)

Two new polytopic ligands L1 and L2 have been synthesized. They consist of a central tren unit to which three 1,4,7,10-tetraazacyclododecane rings are attached via an ethylene and a trimethylene bridge, respectively. The complexation properties of L1 and L2 towards Cu2+ and Ni2+ were studied by potentiometric pH titration, UV-Vis, EPR spectroscopy and kinetic techniques. As a comparison, the Cu2+ and Ni2+ complexes with L3 (1-(N-methyl-2-aminoethyl-1,4,7,10-tetraazacyclododecane)) were also investigated. The crystal structures of [CuL3H(H2O)](ClO4)3 and [NiL3Cl](ClO4) were solved and show that the side chain in its protonated form is not involved in coordination, whereas deprotonated it binds to the metal ion. The thermodynamically stable 3 : 1 complexes of L1 or L2 have a metal ion in the three macrocyclic units. However, when three equivalents of Cu2+ are added to L1 or L2 the metal ion first binds to the tren unit and only then to the macrocycles. The kinetics of the different steps of complexation have been studied and a mechanism is proposed.
Biological purging of breast cancer cells using an attenuated replication-competent herpes simplex virus in human hematopoietic stem cell transplantation. (2001)

Autologous hematopoietic stem cell transplantation after myelosuppressive chemotherapy is used for the treatment of high-risk breast cancer and other solid tumors. However, contamination of the autologous graft with tumor cells may adversely affect outcomes. Human hematopoietic bone marrow cells are resistant to herpes simplex virus type 1 (HSV-1) replication, whereas human breast cancer cells are sensitive to HSV-1 cytotoxicity. Therefore, we examined the utility of G207, a safe replication-competent multimutated HSV-1 vector, as a biological purging agent for breast cancer in the setting of stem cell transplantation. G207 infection of human bone marrow cells had no effect on the proportion or clonogenic capacity of CD34+ cells but did enhance the proliferation of bone marrow cells in culture and the proportion of CD14+ and CD38+ cells. On the other hand, G207 at a multiplicity of infection of 0.1 was able to purge bone marrow of contaminating human breast cancer cells. Because G207 also stimulates the proliferation of human hematopoietic cells, it overcomes a limitation of other purging methods that result in delayed reconstitution of hematopoiesis. The efficient infection of human bone marrow cells in the absence of detected toxicity suggests that HSV vectors may also prove useful for gene therapy to hematopoietic progenitor cells.
Magnetic properties and microstructure of gas atomized MRE2(Fe,Co)14B powder with ZrC addition (MRE=Nd+Y+Dy) (2009)

Gas atomization powder with Zr substitutions for the MRE and ZrC additions were systematically studied. The results show that the partial substitutions of Zr and the ZrC additions effectively improved glass formability in the alloys. Scanning electron microscopy (SEM) revealed that the as-atomized powder with a particle size of less than 32 μm is predominately uniform equiaxed grains with an average grain size of 1.5 μm. X-ray diffraction and differential thermal analysis measurements detected very tiny amounts of amorphous phase. After annealing at 700 °C for 15 min, the SEM grain microstructure exhibits a minor change, but magnetic properties are substantially improved. M versus T measurements reveal that the phase composition evolved from 2:14:1 plus a small amount of 2:17 phases to a single 2:14:1 phase during the annealing process. The sieve analysis of the powders showed a particle size distribution with 90 wt % of the powder less than 45 μm. The magnetic properties of the annealed powder varied with particle size. (BH)max first increases with increasing particle size from 5 μm, reaches the peak value in the size range of 20–25 μm, and then decreases with increasing particle size. For the 20–25 μm powder sample annealed at 700 °C for 15 min, the (BH)max of 9.6 MG Oe at room temperature and 5.6 MG Oe at 200 °C were obtained, respectively.
Using secure coprocessors for privacy preserving collaborative data mining and analysis (2006)

Secure coprocessors have traditionally been used as a keystone of a security subsystem, eliminating the need to protect the rest of the subsystem with physical security measures. With technological advances and hardware miniaturization they have become increasingly powerful. This opens up the possibility of using them for non traditional use. This paper describes a solution for privacy preserving data sharing and mining using cryptographically secure but resource limited coprocessors. It uses memory light data mining methodologies along with a light weight database engine with federation capability, running on a coprocessor. The data to be shared resides with the enterprises that want to collaborate. This system will allow multiple enterprises, which are generally not allowed to share data, to do so solely for the purpose of detecting particular types of anomalies and for generating alerts. We also present results from experiments which demonstrate the value of such collaborations.
Suppression of Smooth Muscle Cell Proliferation by a c-myc RNA-cleaving Deoxyribozyme (1999)

A small catalytic DNA molecule targeting c-myc RNA was found to be a potent inhibitor of smooth muscle cell (SMC) proliferation. The catalytic domain of this molecule was based on that previously derived by in vitro selection (Santoro, S. W., and Joyce, G. F. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4262-4266) and is known as the "10-23" general purpose RNA-cleaving deoxyribozyme. In addition to inhibiting SMC proliferation at low concentration, this molecule (targeting the translation initiation region of c-myc RNA) was found to efficiently cleave its full-length substrate in vitro and down-regulate c-myc gene expression in smooth muscle cells. The serum nuclease stability of this molecule was enhanced without substantial loss of kinetic efficiency by inclusion of a 3'-3'-internucleotide inversion at the 3'-terminal. The extent of SMC suppression was found to be influenced by the length of the substrate binding arms. This correlated to some extent with catalytic activity in both the short substrate under multiple turnover conditions and the full-length substrate under single turnover conditions, with the 9 + 9 base arm molecule producing the greatest activity.
Vibrio vulnificus RTX toxin kills host cells only after contact of the bacteria with host cells (2008)

Vibrio vulnificus causes acute cell death and a fatal septicaemia. In this study, we show that contact with host cells is a prerequisite to the acute cytotoxicity. We screened transposon mutants defective in the contact-dependent cytotoxicity. Two mutants had insertions within two open reading frames in a putative RTX toxin operon, the rtxA1 or rtxD encoding an RTX toxin (4701 amino acids) or an ABC type transporter (467 amino acids). An rtxA1 mutation resulted in a cytotoxicity defect, which was fully restored by in trans complementation. The expression of RtxA1 toxin increased after host cell contact in a time-dependent manner. The RtxA1 toxin induced cytoskeletal rearrangements and plasma membrane blebs, which culminated in a necrotic cell death. RtxA1 colocalized with actin and caused actin aggregation coinciding with a significant decrease in the F/G actin ratio. The RtxA1 toxin caused haemolysis through pore formation (radius 1.63 nm). The rtxA1 deletion mutant was defective in invading the blood stream from ligated ileal loops of CD1 mice. The rtxA1 null mutation resulted in over 100-fold increase in both intragastric and intraperitoneal LD(50)s against mice. Overall, these results show that the RtxA1 toxin is a multifunctional cytotoxin and plays an essential role in the pathogenesis of V. vulnificus infections.
Combining cluster sampling with single pass methods for efficient sampling regimen design (2007)

Microarchitectural simulation is orders of magnitude slower than native execution. As more elements are accurately modeled, problems associated with slow simulation are further exacerbated. Given these issues, many researchers have devised sampling techniques to reduce simulation time. When cluster sampling techniques are used, care must be taken to remove sampling and non-sampling biases. Researchers have devised clever methods for effectively reducing non-sampling bias, but little work has been proposed for efficient reduction of sampling bias (sampling regimen design). Traditionally, sampling regimen design has been an iterative process that required a full workload simulation for error comparison. In this study, a single-pass simulation technique for sampling regimen design is proposed. Using this method, thousands of sampling regimen candidates can be simultaneously evaluated. With this technique, simulation speed was increased by an average factor of 17 with a maximum increase of 73 times relative to the total workload simulation. Additionally, this technique allows the user to effectively estimate the sample error without running the entire workload.
Productive human immunodeficiency virus-1 infection of megakaryocytic cells is enhanced by tumor necrosis factor-alpha (1992)

Abstract Recent findings have indicated that megakaryocytes may be susceptible to human immunodeficiency virus (HIV) infection, suggesting a potential role for megakaryocytes as viral reservoirs in HIV-infected patients. We report that the megakaryocytic cell line Dami could be productively infected with the HTLV III-B strain of HIV-1, in 26 different experiments (results of 16 experiments are reported); productive infection lasted up to 30 weeks. Despite a lack of detectable surface expression of the CD4 molecule and very low levels of CD4 mRNA, between 40% and 60% of megakaryocytic cells produced viral proteins after contact with HIV-1. Neither cytopathogenic effects nor syncytial formation was observed. Production of high levels of functional viral particles was indicated by analysis of p24 protein levels, reverse transcriptase activity, ultrastructural studies, and the capacity of supernatants from infected Dami cells to infect the Molt-4 T- lymphocytic cell line. HIV-1 RNA and protein levels in infected Dami cells were enhanced by treatment with tumor necrosis factor-alpha (TNF- alpha), and decreased by treatment with interferon-alpha (IFN-alpha) and IFN-gamma. Transient transfection of the megakaryocytic cells with various constructs of the HIV-1 promoter (LTR) linked to the luciferase reporter gene suggested that the effect of TNF-alpha was related, as in monocytic and T-cell lines, to transactivation of the enhancer region of the HIV-1 LTR. These findings indicate that signals provided by the immune system may modulate HIV-1 expression in cells of the megakaryocytic lineage.
Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma (2014)

GPC3-targeted CAR T cells could potently eliminate GPC3-positive HCC cells, thereby providing a promising therapeutic intervention for GPC3-positive HCC.
Sequencing and identification of a cDNA done for tomato polygalacturonase (1986)

The 2a isoenzyme of tomato polygalacturonase was purified from ripe fruit and characterised. The N-terminal amino acid sequence of the protein was determined in order to identify polygalacturonase cDNA clones. The nucleotide sequence of a ripening-related cDNA (pTOM 6) was determined and found to encode the N-terminal sequence of mature polygalacturonase 2a. The complete open reading frame encodes a polypeptide of molecular weight 50,051, including a putative pre-sequence of 71 amino acids.