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      1. Author :
        O'Connor, A. E.; Mc Gee, M. M.; Likar, Y.; Ponomarev, V.; Callanan, J. J.; O'Shea D, F.; Byrne, A. T.; Gallagher, W. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Int J Cancer
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-D3H1, MDA-MB-231-luc-D3H1, IVIS, Bioware, Breast Cancer
      12. Abstract :
        Photodynamic therapy (PDT) is an established treatment modality for cancer. ADPM06 is an emerging non-porphyrin PDT agent which has been specifically designed for therapeutic application. Recently, we have demonstrated that ADPM06-PDT is well tolerated in vivo and elicits impressive complete response rates in various models of cancer when a short drug-light interval is applied. Herein, the mechanism of action of ADPM06-PDT in vitro and in vivo is outlined. Using a drug and light combination that reduces the clonogenicity of MDA-MB-231 cells by >90%, we detected a well-orchestrated apoptotic response accompanied by the activation of various caspases in vitro. The generation of reactive oxygen species (ROS) upon photosensitizer irradiation was found to be the key instigator in the observed apoptotic response, with the endoplasmic reticulum (ER) found to be the intracellular site of initial PDT damage, as determined by induction of a rapid ER stress response post-PDT. PDT-induced apoptosis was also found to be independent of p53 tumor suppressor status. A robust therapeutic response in vivo was demonstrated, with a substantial reduction in tumor proliferation observed, as well as a rapid induction of apoptosis and initiation of ER stress, mirroring numerous aspects of the mechanism of action of ADPM06 in vitro. Finally, using a combination of (18) F-labeled 3'-deoxy-3'-fluorothymidine ((18) F-FLT) nuclear and optical imaging, a considerable decrease in tumor proliferation over 24-hr in two models of human cancer was observed. Taken together, this data clearly establishes ADPM06 as an exciting novel PDT agent with significant potential for further translational development.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21413012
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10516
      1. Author :
        Oashi, K.; Furukawa, H.; Nishihara, H.; Ozaki, M.; Oyama, A.; Funayama, E.; Hayashi, T.; Kuge, Y.; Yamamoto, Y.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Invest Dermatol
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        B16-F10-luc2, Melanoma, B16F10-luc2, IVIS
      12. Abstract :
        In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.274.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22951727
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10501
      1. Author :
        Ogunniyi, A. D.; Paton, J. C.; Kirby, A. C.; McCullers, J. A.; Cook, J.; Hyodo, M.; Hayakawa, Y.; Karaolis, D. K.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Vaccine
      6. Products :
      7. Volume :
        26
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        Cyclic diguanylate (c-di-GMP) is a unique bacterial intracellular signaling molecule capable of stimulating enhanced protective innate immunity against various bacterial infections. The effects of intranasal pretreatment with c-di-GMP, or intraperitoneal coadministration of c-di-GMP with the pneumolysin toxoid (PdB) or pneumococcal surface protein A (PspA) before pneumococcal challenge, were investigated in mice. We found that c-di-GMP had no significant direct short-term effect on the growth rate of Streptococcus pneumoniae either in vitro or in vivo. However, intranasal pretreatment of mice with c-di-GMP resulted in a significant decrease in bacterial load in lungs and blood after serotypes 2 and 3 challenge, and a significant decrease in lung titers after serotype 4 challenge. Potential cellular mediators of these enhanced protective responses were identified in lungs and draining lymph nodes. Intraperitoneal coadministration of c-di-GMP with PdB or PspA before challenge resulted in significantly higher antigen-specific antibody titers and increased survival of mice, compared to that obtained with alum adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive pneumococcal disease. We propose that c-di-GMP can be used as an effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases.
      13. URL :
        http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18640167
      14. Call Number :
        141772
      15. Serial :
        5663
      1. Author :
        Ohlsen, Knut; Lorenz, Udo
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Future microbiology
      6. Products :
      7. Volume :
        2
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Anti-Bacterial Agents; Bioware; Community-Acquired Infections; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        Multiple resistant staphylococci that cause significant morbidity and mortality are the leading cause of nosocomial infections. Meanwhile, methicillin-resistant Staphylococcus aureus (MRSA) also spreads in the community, where highly virulent strains infect children and young adults who have no predisposing risk factors. Although some treatment options remain, the search for new antibacterial targets and lead compounds is urgently required to ensure that staphylococcal infections can be effectively treated in the future. Promising targets for new antibacterials are gene products that are involved in essential cell functions. In addition to antibacterials, active and passive immunization strategies are being developed that target surface components of staphylococci such as cell wall-linked adhesins, teichoic acids and capsule or immunodominant antigens.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18041906
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9049
      1. Author :
        Okuda, Tomoyuki; Kawaguchi, Yasuhisa; Okamoto, Hirokazu
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Current topics in medicinal chemistry
      6. Products :
      7. Volume :
        9
      8. Issue :
        12
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Bioware; Gene Silencing; PC-3M-luc; Peptides; Proteins; RNA Interference; Transfection
      12. Abstract :
        RNA interference (RNAi) is an attractive phenomenon for practical use that specifically inhibits gene expression and is carried out by small double-stranded RNAs (dsRNAs) including small interfering RNA (siRNA) or short hairpin RNA (shRNA). In addition, RNAi is of great interest for clinical use to cure refractory diseases related to the expression of a specific gene. To achieve gene silencing in the body, a sufficient amount of dsRNA must be delivered and internalized into target cells. However, dsRNAs have a large molecular weight and net negative charge, which limits their membrane-permeating ability. Moreover, dsRNAs are rapidly degraded by endonucleses in the body. Therefore, for the efficient delivery of dsRNAs, many approaches based on drug delivery systems have been carried out. In this review, we focus on recent reports about the application of functional peptides and proteins designed for the efficient delivery of dsRNAs.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19860710
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8962
      1. Author :
        Orihuela, C. J.; Radin, J. N.; Sublett, J. E.; Gao, G.; Kaushal, D.; Tuomanen, E. I.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        72
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen7, Xen35
      12. Abstract :
        Streptococcus pneumoniae is a leading cause of invasive bacterial disease. This is the first study to examine the expression of S. pneumoniae genes in vivo by using whole-genome microarrays available from The Institute for Genomic Research. Total RNA was collected from pneumococci isolated from infected blood, infected cerebrospinal fluid, and bacteria attached to a pharyngeal epithelial cell line in vitro. Microarray analysis of pneumococcal genes expressed in these models identified body site-specific patterns of expression for virulence factors, transporters, transcription factors, translation-associated proteins, metabolism, and genes with unknown function. Contributions to virulence predicted for several unknown genes with enhanced expression in vivo were confirmed by insertion duplication mutagenesis and challenge of mice with the mutants. Finally, we cross-referenced our results with previous studies that used signature-tagged mutagenesis and differential fluorescence induction to identify genes that are potentially required by a broad range of pneumococcal strains for invasive disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15385455
      14. Call Number :
        141856
      15. Serial :
        6874
      1. Author :
        Orihuela, Carlos J; Gao, Geli; Francis, Kevin P; Yu, Jun; Tuomanen, Elaine I
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        The Journal of infectious diseases
      6. Products :
      7. Volume :
        190
      8. Issue :
        9
      9. Page Numbers :
        1661-1669
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bacteremia; Bacterial Proteins; Cerebrospinal Fluid; Disease Models, Animal; Female; Lung; Meningitis, Pneumococcal; Mice; Mice, Inbred BALB C; Mutation; N-Acetylmuramoyl-L-alanine Amidase; Nasopharynx; Neuraminidase; Pneumococcal Infections; Pneumonia, Pneumococcal; Pyruvate Oxidase; Streptococcus pneumoniae; Streptolysins; Virulence Factors; Xen7
      12. Abstract :
        We assessed the ability of Streptococcus pneumoniae mutants deficient in either choline binding protein A (CbpA), pneumolysin (Pln), pyruvate oxidase (SpxB), autolysin (LytA), pneumococcal surface protein A, or neuraminidase A (NanA) to replicate in distinct anatomical sites and translocate from one site to the next. Intranasal, intratracheal, and intravenous models of disease were assessed in 4-week-old BALB/cJ mice by quantitation of bacterial titers in the relevant organs. Mice were also observed by use of real-time bioluminescent imaging (BLI). BLI allowed visualization of the bacteria in sites not tested by sampling. All mutants were created in D39 Xen7, a fully virulent derivative of capsular type 2 strain D39 that contains an optimized luxABCDE cassette. NanA, SpxB, and, to a lesser extent, CbpA contributed to prolonged nasopharyngeal colonization, whereas CbpA and NanA contributed to the transition to the lower respiratory tract. Once lung infection was established, Pln, SpxB, and LytA contributed to bacterial replication in the lungs and translocation to the bloodstream. In the bloodstream, only Pln and LytA were required for high-titer replication, whereas CbpA was required for invasion of the cerebrospinal fluid. We conclude that transitions between body sites require virulence determinants distinct from those involved in organ-specific replication.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15478073
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        10002
      1. Author :
        Orihuela, Carlos J; Gao, Geli; McGee, Mackenzie; Yu, Jun; Francis, Kevin P; Tuomanen, Elaine
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2003
      5. Publication :
        Scandinavian journal of infectious diseases
      6. Products :
      7. Volume :
        35
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Disease Models, Animal; Female; Lung; Mice; Mice, Inbred BALB C; Pneumococcal Infections; pXen-5; Serotyping; Streptococcus pneumoniae, Xen10, Xen7, Xen35
      12. Abstract :
        The variability of the course of infection by Streptococcus pneumoniae is well known but poorly understood. Most animal models of pneumonia, sepsis or meningitis have been forced to use site-specific bacterial inoculation to mimic localized human infection. This study examined the differences in the progression of disease-causing strains D39 (serotype 2), A66.1 (serotype 3) and TIGR4 (serotype 4) using isolates transformed with the Gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r). Expression of the lux operon results in bioluminescence, permitting the detection of the bacteria within a living animal while using a CCD camera. Mice infected intranasally with A66.1 developed only pneumonia, those challenged with D39 experienced high-grade sepsis, while TIGR4 infection resulted in low-grade pneumonia and bacteremia ultimately progressing to meningitis. Quantitative analysis of bacterial titers confirmed these patterns, which were consistent across different lineages of mice. Mice anesthetized with ketamine and xylazine developed more severe forms of the disease compared with isoflurane. These studies unambiguously characterize 3 distinct models of the natural course of pneumococcal infection. Mapping these models provides a framework for detailed molecular modeling of pneumococcal virulence determinants at specific stages of disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/14620149
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9026
      1. Author :
        Palma, Joann P; Wang, Yi-Chun; Rodriguez, Luis E; Montgomery, Debra; Ellis, Paul A; Bukofzer, Gail; Niquette, Amanda; Liu, Xuesong; Shi, Yan; Lasko, Loren; Zhu, Gui-Dong; Penning, Thomas D; Giranda, Vincent L; Rosenberg, Saul H; Frost, David J; Donawho, Cherrie K
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Clinical cancer research: an official journal of the American Association for Cancer Research
      6. Products :
      7. Volume :
        15
      8. Issue :
        23
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bioware; Dacarbazine; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; MDA-MB-231-D3H2LN cells; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Suppressor Proteins
      12. Abstract :
        PURPOSE ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ. EXPERIMENTAL DESIGN ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT). RESULTS Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ. CONCLUSIONS Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19934293
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8954