tbuckley/cabot-search huggingface dataset:
601. HIV-1 TAT Protein Transduction Domain-Mediated Enhancement of HSV-TK/Ganciclovir Suicide Gene Therapy
Authors: Outi Meriläinen, Tanja Hakkarainen, Tiina Pasanen, Riikka Pellinen, Jarmo Wahlfors
Journal: Molecular Therapy (2004)

Top of pageAbstract
INTRODUCTION

Suicide gene therapy using herpes simplex thymidine kinase gene combined to prodrug ganciclovir (GCV) is one of the most prominent approaches in cancer gene therapy. However, efficacy of the therapy is often insufficient due to the poor rate of gene transfer and due to the limited bystander effect. Recent studies have shown that a protein transduction domain from HIV-1 transactivator protein (TAT-PTD) can translocate through plasmamembrane and deliver proteins into cell. Aim of this study was to make intercellularly spreading HSV-TK protein with the aid of cell penetrating peptide TAT and thus enhance the cytotoxic effect of HSV-TK/GCV gene therapy.METHODS

We constructed a novel triple fusion protein containing TAT protein transduction domain (TAT-PTD), HSV-TK suicide gene and GFP marker gene (TAT-TK-GFP) to study effect of TAT-PTD on HSV-TK/GCV-suicide gene therapy. Sensitivity to ganciclovir was tested in different cell lines by comparing cells expressing TAT-TK-GFP to cells expressing TK-GFP. Biodistribution of TAT-TK-GFP from transfected cell to surrounding cells was analyzed by direct fluorescence microscopy or by immunofluorescence staining.RESULTS

We found that TAT-peptide enhances cytotoxic effect of HSV-TK/GCV-suicide gene therapy in rapidly dividing cells e.g. in BTC4 rat glioma cell line or in SKOV3.ip1 ovarian cancer cell line. However, enhancement was abolished after serum deprevation. Intercellular spreading of TAT-TK-GFP-protein was not visualized by direct fluorescence microscopy or immunofluorescence staining. Control fusion protein, VP22-GFP, contrast to TAT-fusion protein showed spreading from transfected cell to adjacent cells after methanol fixation.CONCLUSION

This study shows that the triple fusion gene TAT-TK-GFP is useful tool for investigating the utility of TAT fusion proteins in suicide gene therapy. Our data with TAT-TK-GFP demonstrate that HSV-TK/GCV cytotoxicity can be enhanced in rapidly growing cancer cells, despite the fact that intercellular spreading cannot be visualized.
Weaning from tracheotomy in long-term mechanically ventilated patients: feasibility of a decisional flowchart and clinical outcome
Authors: Piero Ceriana, Annalisa Carlucci, Paolo Navalesi, Ciro Rampulla, Monica Delmastro, GianCarlo Piaggi, Elisa De Mattia, Stefano Nava
Journal: Intensive Care Medicine (2003)
Isolation of cancer-specific CDKN2A breakpoint fusion sequences in the presence of contaminating normal DNA
Authors: Yu-Tsueng Liu, Dennis A. Carson
Journal: Clinical Cancer Research (2006)

A87   Currently, there are few practical molecular tools for the monitoring of patients with solid tumors. Deletions of the CDKN2A (INK4A/ARF) locus on chromosome 9p21 are the most common chromosomal anomalies in solid tumors, including cancers of the lung, esophagus, head and neck, pancreas, liver, bladder, and brain. Accordingly, there is a critical need for the development of technologies that can quickly identify signature deletion breakpoint sequences in the CDKN2A region, and that can generate personalized molecular probes for cancer monitoring in patients with solid tumors, similar to the case of BCR-ABL transcript monitoring in chronic myelogenous leukemia. However, most current breakpoint mapping techniques are imprecise, and/or require the laborious purification of tumor DNA from normal DNA. In order to use DNA from non-isolated primary tumors as templates, we have adapted a technique designated Primer Approximation Multiplex PCR (PAMP), which selectively enriches for, and amplifies, DNA segments with deletions. The method is based on the fact that the geometric amplification rate of the polymerase chain reaction (PCR) is inversely proportional to the distance between the 39- and 59-flanking primers. Accordingly, amplified PCR products are more efficiently generated when the PCR primers are close together, as occurs in a deletion or translocation. Multiplex PCR with appropriately spaced primers, followed by deletion scanning with genomic tiling arrays, allows for the precise identification of the breakpoints, to yield clone-specific, personalized PCR primers spanning the breakpoint regions. PAMP enables deletions to be mapped in the presence of 99.9% wild type DNA contamination.
Factors associated with emergence of pristinamycin-resistant <i>Staphylococcus aureus</i> in a dermatology department: a case-control study
Authors: L. Verneuil, C. Marchand, J.S. Vidal, R. Ze Bekolo, C. Daurel, G. Lebouvier, D. Leroy, R. Leclercq
Journal: British Journal of Dermatology (2010)

Journal Article Factors associated with emergence of pristinamycin‐resistant Staphylococcus aureus in a dermatology department: a case–control study Get access L. Verneuil, L. Verneuil Service de Dermatologie Laurence Verneuil. E‐mail: verneuil‐l@chu‐caen.fr Search for other works by this author on: Oxford Academic Google Scholar C. Marchand, C. Marchand Service de Maladies Infectieuses Search for other works by this author on: Oxford Academic Google Scholar J.S. Vidal, J.S. Vidal Institut National de la Santé et de la Recherche Médicale (INSERM‐U708), F‐75651 Paris, France Search for other works by this author on: Oxford Academic Google Scholar R. Ze Bekolo, R. Ze Bekolo Service de Maladies Infectieuses Search for other works by this author on: Oxford Academic Google Scholar C. Daurel, C. Daurel Service de Microbiologie, CHU Caen and EA2128, Université de Caen Basse‐Normandie, F‐14033 Caen, France Search for other works by this author on: Oxford Academic Google Scholar G. Lebouvier, G. Lebouvier Service de Pharmacie, CHU Caen, F‐14033 Caen, France Search for other works by this author on: Oxford Academic Google Scholar D. Leroy, D. Leroy Service de Dermatologie Search for other works by this author on: Oxford Academic Google Scholar R. Leclercq R. Leclercq Service de Microbiologie, CHU Caen and EA2128, Université de Caen Basse‐Normandie, F‐14033 Caen, France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 163, Issue 2, 1 August 2010, Pages 329–333, https://doi.org/10.1111/j.1365-2133.2010.09826.x Published: 01 August 2010
Discovery and Development of Small Molecule SHIP Phosphatase Modulators
Authors: Dennis R. Viernes, Lydia B. Choi, William G. Kerr, John D. Chisholm
Journal: Medicinal Research Reviews (2013)

Abstract Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) containing inositol 5‐phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein–protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity, and solubility properties of these compounds.
STUDIES ON THE MODE OF ACTION OF IRRADIATED ERGOSTEROL
Authors: Walter Bauer, Alexander Marble, Dorothy Claflin
Journal: Journal of Clinical Investigation (1932)

The hypothesis has been advanced that irradiated ergosterol acts only by stimulating the parathyroid glands (1-3).Yet various workers have reported beneficial results in the treatment of parathyroid deficiency with irradiated ergosterol (1), ( 3), (4-10).It is difficult to believe that if irradiated ergosterol acts by stimulating the parathyroid glands, its administration to completely parathyroidectomized animals should result in alleviation of the tetany and restoration of the serum calcium and phos- phorus to normal values.The lack of complete calcium and phosphorus metabolism data, failure to state the dietary intake, and variations in dosage as well as differences in potency of the irradiated ergosterol prepa- rations employed, make it difficult to draw any conclusions from the work reported in the literature as to the mode of action of irradiated ergosterol in parathyroid tetany.The results obtained in certain instances may very well have been due to overdosage of this potent vitamin D prepara- tion (8).In previous communications (11-13), data have been presented which were interpreted as signifying that irradiated ergosterol acted by increas- ing the absorption of calcium and phosphorus from the gastro-intestinal tract.If such an interpretation of the data is correct, then the beneficial results obtained in the treatment of parathyroid deficiency must bear a direct relation to the calcium intake.In an attempt to substantiate or disprove such a theory, calcium and phosphorus metabolism experiments were carried out on patients with parathyroid tetany, on varying calcium intakes, with and without irradiated ergosterol therapy.The phosphorus intake was kept constant throughout each experiment.Three cases of hypoparathyroidism, two with idiopathic and one with postoperative parathyroid tetany, were studied.They all showed the characteristic features of this disease syndrome, namely: the signs and 'This is publication No.
Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-α therapy or allogeneic bone marrow transplantation
Authors: Jean-Claude Chomel, Françoise Brizard, Anne Veinstein, Jérôme Rivet, Alain Sadoun, Alain Kitzis, François Guilhot, André Brizard
Journal: Blood (2000)
723. Sendai Virus Vectors without All of the Envelop-Related Genes: Successful Recovery and Characterization of the Three Genes (Matrix, Fusion and Hemagglutinin-Neuraminidase)-Deleted Vectors
Authors: Makoto Inoue, Mariko Yoshizaki, Yumiko Tokusumi, Takashi Hironaka, Hiroshi Ban, Yoshiyuki Nagai, Akihiro Iida, Mamoru Hasegawa
Journal: Molecular Therapy (2004)

Sendai virus (SeV) vector is a new class of vector bearing a new concept of “cytoplasmic RNA vector”. This vector based on SeV belonging to the genus Respirovirus of the family Paramyxoviridae, infects and replicates in most mammalian cells, and directs high-level transgene expression. Its replication is independent of nuclear functions and does not have a DNA phase during its life cycle so that the transformation of cells by integration of vector materials into the cellular genome is not a concern. These properties make SeV vectors very promising for application to gene therapy and vaccination via the expression of therapeutic genes and antigens. We have previously succeeded in the recovery of fusion (F) gene-deleted SeV vector (SeV/ΔF), matrix (M) gene-deleted SeV vector (SeV/ΔM), both M and F genes-deleted SeV vector (SeV/ΔMΔF) and other types of the vectors in high titers. F gene-deletion made SeV vector non-transmissible, and M gene-deletion worked well on the vector to become incapable of formation of the particles from infected cells. All of the above SeV vectors maintain efficient infectivity in vitro and in vivo as wild type SeV does. The hemagglutinin-neuraminidase (HN) protein, which mediates the attachment of SeV, is known to be one of the major targets for host immune responsive machineries on SeV infection such as natural killer cell (NK), cytotoxic T lymphocyte (CTL) and neutralizing antibodies. The HN gene-deletion from the genome would be one of the important ways to reduce the immune response against SeV vector. Therefore, the HN gene was further deleted from the genome of SeV/ΔMΔF, and thus SeV/ΔMΔFΔHN was generated. The SeV/ΔMΔFΔHN possesses only nucleoprotein (NP), phosphoprotein (P) and large protein (L)-genes on its genome. All of them are essential for efficient expression of SeV vector by consisting ribonucleoprotein (RNP) complex. The new vector was successfully recovered and propagated in a new packaging cell line expressing M, F and HN proteins by using a Cre/loxP inducible system. The titer of SeV/ΔMΔFΔHN carrying the enhanced green fluorescent protein (GFP) was and above 1×107 cell infectious units (CIU)/ml. This vector showed efficient infectivity and gene expression in various types of cell lines and primary cells in vitro. When this vector was administered into the auricle of the ear of mice (5×106 CIU), a visible transduction was confirmed as in the cases of wild type SeV vector in vivo. The important investigation for immune reaction of this vector is in progress. The SeV/ΔMΔFΔHN vector is the most advanced type of cytoplasmic RNA virus vector and the like Sendai virus vector.
Abstract 1686: Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines
Authors: Sonia Avila, Marta Martínez, Victoria Moneo, Juan F. Martínez-Leal, Carmen Cuevas, Luis F. Garcia-Fernández, Carlos M. Galamarini
Journal: Cancer Research (2014)

Abstract Trabectedin (Yondelis, ET-743) is a marine-derived antitumor agent that is currently used for the treatment of sarcoma and, in combination with pegylated-liposomal doxorubicin, of platinum-sensitive ovarian cancer patients. After binding to the DNA minor groove, trabectedin induces a potent transcription inhibition on tumor cells and tumor-associated macrophages. The resolution of functional DNA adducts generated by the drug is known to occur through the coordinated action of multiple DNA repair pathways, including homologous recombination (HR), a process that gives rise to double-strand breaks (DSBs). Trabectedin treatment at nanomolar concentrations does indeed produce a high proportion of DSB-positive tumor cells with abundant γ-H2AX foci and an S-phase delay/arrest by activation of the DNA replication checkpoints. We had previously shown the synergism (CI &amp;lt; 1) of the combination of Trabectedin with Olaparib (AZD-2281) in the breast cancer cell lines HCC-1937, MCF-7, MDA-MB-231 and MDA-MB-436. In this work we have investigated the mechanism of this synergistic effect at the molecular level. While the treatment with either compound alone (0.05 nM Trabectedin or 5 μM Olaparib for 72 hours) induced only a mild antiproliferative effect, the combination of both compounds at the mentioned concentrations induced strong apoptosis in all the breast cancer cell lines. Exposure to 0.5 and 2.5 nM Trabectedin for 72 hours induced a clear accumulation of γ-H2AX foci. Exposure to Olaparib alone induced only a mild DNA damage at 72 hours with all the concentrations tested. Olaparib induced a clear inhibition of PARylation at concentrations from 1-2.5 μM of the compound. The combination of both drugs, keeping Olaparib at 5 μM and varying the concentrations of Trabectedin from 0.05 to 2.5 nM, demonstrated a synergistic effect on the accumulation of histone H2AX phosphorylation, as analyzed both by western blotting and immunofluorescence microscopy. When comparing all these results, it was clearly seen that, although Trabectedin or Olaparib generated a considerable amount of DSBs, the combination of both drugs induced a higher proportion of DNA damage that remained at very high levels even after 72 hours of treatment. Thus, the observed synergistic effect seems to be the result of higher accumulation of DSBs after the administration of the combination of Trabectedin with Olaparib. Citation Format: Sonia Avila, Marta Martínez, Victoria Moneo, Juan F. Martínez-Leal, Carmen Cuevas, Luis F. Garcia-Fernández, Carlos M. Galamarini. Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1686. doi:10.1158/1538-7445.AM2014-1686
ROS generation and antioxidant enzyme expression in NNK-induced cancer cells with radioresistant phenotype
Authors: Yusuke Demizu, Ryohei Sasaki, Dunyaporn Trachootham, Peng Huang
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4416 

Reactive oxygen species (ROS) play an important role in the indirect action of ionizing radiation (IR) and mediate many of the biological effects induced by IR. ROS can be eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), and peroxiredoxin (PRX). Among these enzymes, manganese SOD (MnSOD) has been reported to be overexpressed in highly radioresistant glioma cells and protect against IR-induced cytotoxicity in cultured cells. However, the correlation between radioresistance and antioxidant enzymes is not fully understood. We established a cancer cell clone (BEAS/NNK) by exposing immortalized human bronchial epithelial cells (BEAS) to the tobacco carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Anchorage-independent assay showed that BEAS/NNK cells were able to formed colonies, whereas BEAS cells did not. Gap-filling assay demonstrated that BEAS/NNK cells were more migrative than BEAS cells. Colony formation assay revealed that BEAS/NNK cells were more resistant to IR than BEAS cells. Western blotting showed higher levels of MnSOD, copper-zinc SOD (CuZnSOD), and GPX-1, and lower levels of catalase and PRX-3 in BEAS/NNK cells compared to BEAS cells. Interestingly, among three enzymes that catalyze the reaction from hydrogen peroxide to water, only GPX-1 was upregulated in BEAS/NNK cells. Quantitative analyses showed that superoxide generation in the early passages of BEAS/NNK cells was higher than in BEAS cells, and eventually decreased to the basal level, most likely due to the upregulation of SODs during the adaptation in culture. Hydrogen peroxide in BEAS/NNK cells was lower than in BEAS cells, likely due to high expression of GPX-1. Nuclear factor-kappaB (NF-kB), a cell survival transcription factor known to affect radiosensitivity, was activated in BEAS/NNK cells, as demonstrated by electrophoretic mobility shift assay (EMSA). Our results suggest that BEAS/NNK cells acquired overexpression of SODs and GPX-1 during the carcinogenesis process, and that this increase in antioxidant enzymes to eliminate ROS may be an important mechanism by which cells become resistant to IR. Constitutive activation of NF-kB may provide an additional survival mechanism for BEAS/NNK cells to resist IR.
Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation
Authors: Michihito Kono, Shinsuke Yasuda, Richard L. Stevens, Hideyuki Koide, Takashi Kurita, Yuka Shimizu, Yusaku Kanetsuka, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tomohiro Shimizu, Tokifumi Majima, Takao Koike, Tatsuya Atsumi
Journal: Arthritis & Rheumatology (2014)

Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis.Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP-4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease.Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats.RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction.
Recombinant Methionyl Human Stem Cell Factor and Filgrastim for Peripheral Blood Progenitor Cell Mobilization and Transplantation in Non-Hodgkin's Lymphoma Patients — Results of a Phase I/II Trial
Authors: Craig H. Moskowitz, Patrick Stiff, Michael S. Gordon, Ian McNiece, Anthony D. Ho, John J. Costa, E. Randolf Broun, Robert A. Bayer, Melody Wyres, Jerome Hill, Kathy Jelaca-Maxwell, Craig R. Nichols, Sherri L. Brown, Stephen D. Nimer, Janice Gabrilove
Journal: Blood (1997)
Can medicine prevent war?
Authors: S. Yusuf, S. Anand, G. MacQueen
Journal: BMJ (1998)

War is one of the world's most serious threats to health. The recent global burden of disease report has indicated that war will be one of the top 10 causes of disability adjusted life years lost by the year 2020.1 For every combatant killed in war, one non-combatant is also killed directly, 14-15 civilians lose their lives from loss of shelter, food, and water or epidemics—and several times these numbers are physically or psychologically wounded. What can healthcare workers do about this threat?

In a provocative article Dudley Herschbach, a Nobel laureate in chemistry, reflects on what it might be like if human beings could speak to dolphins.2 He imagines a fruitful interaction between humans and dolphins that would derive its force from the fact that the two species come from different habitats, face different problems, and have evolved different ways of communicating among themselves. He fantasises that a genuinely creative relationship would lead to the solution of many problems humans had thought intractable. He applies the parable to our human situation: “Each academic species has evolved its own language, so interdisciplinary …