bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3299: Salmonella commensal subspecies: a new model for the treatment of human cancer.
Authors: Ly Vy Khan , Viloria Edward , Saxena Priyanka , Sokhom Bossakara , McClelland Michael , Arrach Nabil 
Published: August 2014

Abstract
Salmonella can colonize and survive in both hypoxic and oxygenated regions of solid tumors. Avirulent Salmonella mutants have been investigated as anticancer agents in human clinical trials. The strains used, derived from Salmonella enterica subspecies I (sspI) strains, proved to be highly toxic. Salmonella non-subspecies I (nsspI) strains are known as commensals of cold-blooded species and rarely cause disease in humans. Therefore, nsspI strains could present a safer alternative for the treatment of human cancer. Here, we explore the potential of nsspI strains for use as an anticancer therapy. Strains representing the five nsspI subspecies were tested for virulence and tumor targeting in mice, and for their ability to invade and kill human breast, prostate, and colorectal cancer cell lines. We identified nsspI strains that were successful at tumor targeting and capable of invading and killing a variety of cancer cell lines in vitro while being incapable of causing disease in mice. The nsspI strains were engineered to express two key therapeutic enzymes: cytosine deaminase and uracil phosphoribosyltransferase. After invading cancer cells in culture, intracellular bacteria from all five nsspI classes caused significant cytotoxicity in the presence of 5-FC. We conclude that nsspI strains could serve as potential improved anticancer vectors, to be used in combination with a therapeutic gene, for the treatment of primary or metastatic tumors. Due to their safety profile, nsspI strains present an excellent alternative to conventional Salmonella sspI strains for the treatment of human cancer.
Citation Format: Vy Khan Ly, Edward Viloria, Priyanka Saxena, Bossakara Sokhom, Michael McClelland, Nabil Arrach. Salmonella commensal subspecies: a new model for the treatment of human cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3299. doi:10.1158/1538-7445.AM2013-3299
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3301: Guanidinium antisense oligonucleotides for cancer therapy.
Authors: Thomas Sufi M. , Ly Danith 
Published: August 2014

Abstract
Molecular targeted therapies are being tested in several clinical settings to target cancer. Most of the drugs being tested are small molecule inhibitors or antibodies that are specific to target proteins. Several of which have reduced target specificity or the tumor develops resistance to the drugs. This results in poor clinical outcomes. An approach that is highly specific and yet malleable enough to circumvent resistance mechanisms would be highly appealing. We have developed an antisense approach that can specifically bind to the mRNA of target proteins preventing translation and resulting in lower protein levels. In addition, unlike conventional antisense approaches, our antisense oligonucleotide carries a pseudo-peptide backbone with positively charged guanidinium residues rendering these resistant to nucleases and proteases. The oligomer binds nucleic acids with high sequence specificity and the hybridized complex is highly stable. As a proof of principle, we developed a 16 base antisense oligomer targeting the epidermal growth factor receptor (EGFR). EGFR is upregulated in several cancers and correlates with a poor prognosis. We tested the guanidinium-peptide nucleic acid (GPNA) EGFR antisense oligomer in tumors of the head and neck, lung and bladder. We carried out in vitro and in vivo studies including uptake and antitumor efficacy. Our data demonstrate that EGFR levels and cell survival are significantly reduced upon EGFRAS GPNA administration but not a scrambled control. Further, the EGFRAS GPNA effectively reduced levels of a constitutively active mutant EGFR (EGFRvIII). In vivo, EGFRAS GPNA had antitumor effects comparable to EGFR inhibitors that are under clinical testing namely erlotinib and cetuximab. Our data demonstrate that GPNA oligomers are an effective therapeutic approach against several tumor types.
Citation Format: Sufi M. Thomas, Danith Ly. Guanidinium antisense oligonucleotides for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3301. doi:10.1158/1538-7445.AM2013-3301
Abstract 3302: Antisense oligonucleotide depletion of the mitotic kinesin Eg5 by direct delivery to the brain could be a useful strategy for treating glioma tumors.
Authors: Krona Cecilia C. , Boubaker Jihane , Friedmann-Morvinski Dinorah , Wong Alex , McAlonis-Downes Melissa , Koller Erich , Kim Aneeza S. , Hung Gene , Rigo Frank , Chun Seung , Vitre Benjamin , Bennett Frank , Verma Inder , Cleveland Don W. 
Published: August 2014

Abstract
To date, all approved chemotherapeutic agents which target the mitotic cell division interfere with spindle microtubule dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are subject to resistance mechanisms and they are also associated with a variety of side effects, including neurotoxicity. Their use in treating nervous system tumors is therefore not warranted.
One strategy to target mitosis, without damaging microtubules in non-dividing neurons, would be to inhibit key mitotic components, such as the mitotic kinesin Eg5, which is required for establishing a normal bipolar mitotic spindle. We have shown that glioblastoma cells depleted for Eg5 arrest in the next mitosis. After a prolonged arrest, they may slip out and become multinucleated, which will likely prevent further successful divisions or they may go into apoptosis. Further, mitotic arrest and induction of apoptosis in Eg5 depleted glioblastoma cells occur independent of p53, Rb-signalling and the PI3K-pathway suggesting that Eg5 is a potential therapeutic target for glioblastoma patients with different underlying genetic abnormalities
We have also tested the clinical feasibility of using a cell cycle targeting antisense oligonucleotide based therapy delivered directly to the central nervous system (CNS) as a novel treatment for glioblastoma tumors.
This work has demonstrated that intraventricular administration of ASOs can efficiently target cells in the CNS and be delivered to glioma-initiating neural stem cells transplanted into the cortex of naïve mice as well as to glioblastoma tumors in a genetically predisposed mouse model. This strategy is therefore a potential route of administration for treating glioblastoma tumors which originate in the CNS. Direct targeting of mitotic components in the brain should have a limited toxicity to non-cycling neurons and as a benefit, as long as the blood-brain barrier is intact direct CNS delivery should have minimal dose-limiting toxicity outside of the CNS. Ongoing studies will determine the effect of Eg5 inhibition on glioblastoma growth in vivo.
Citation Format: Cecilia C. Krona, Jihane Boubaker, Dinorah Friedmann-Morvinski, Alex Wong, Melissa McAlonis-Downes, Erich Koller, Aneeza S. Kim, Gene Hung, Frank Rigo, Seung Chun, Benjamin Vitre, Frank Bennett, Inder Verma, Don W. Cleveland. Antisense oligonucleotide depletion of the mitotic kinesin Eg5 by direct delivery to the brain could be a useful strategy for treating glioma tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3302. doi:10.1158/1538-7445.AM2013-3302
Abstract 3309: T cell lymphoblastic leukemia in survivin TCR transgenic mice.
Authors: Cui Yongzhi , Onozawa Masahiro , Qin Haiying , Fry Terry , Aplan Peter , Mackall Crystal L. 
Published: August 2014

Abstract
Survivin has been considered a potential tumor antigen due to high expression in most cancers and limited expression in normal tissues. To explore whether survivin reactive TCRs mediate antitumor effects in mice, we generated TCR transgenic (Tg) mice with specificity for the H-2b restricted immunodominant epitope of survivin. Survivin reactive T cells were CD8+ and mediated immune reactivity toward survivin peptide pulsed targets. Some antitumor reactivity was observed, but it was not potent, and the survivin TCR Tg+ cells did not mediate objective tumor regression of survivin bearing tumors. Surprisingly, spontaneous T cell acute lymphoblastic leukemia (T-ALL) was observed beginning at 4-6 months of age in Tg+Rag+/- and Tg+Rag-/- mice. By one year of age, all survivin Tg+ mice succumbed to T-cell ALL. The leukemic cells were CD3+, survivin TCR+, and CD8+ or CD4-/CD8-Occurrence in 3 founders suggests that the transgene itself, rather than insertional mutagenesis, is causative. Given that survivin is expressed in the thymus, we postulated that the TCR-Tg serves as an oncogene via recognition of survivin peptides, which expands early thymic progenitors. In support of this, premalignant survivin TCR Tg+ thymi show expanded CD4-CD8-CD44-CD25- thymocytes and increased BrdU incorporation and leukemia incidence was significantly diminished TCR-Tg+β2m-/- mice. Subsequent to expansion of early thymic progenitors in response to TCR triggering, survivin TCR Tg+ cells acquire NOTCH mutations and upregulate CD25, implicating NOTCH signaling as a 2nd hit in this oncogenic process. At least one NOTCH1 mutation was found in all leukemias, with PEST (8/8), 5’ deletions (19/25) and heterodimerization mutations observed. T-ALL with NOTCH mutations was also observed at reduced frequencies, in TCR Tg mice with specificity to WT1 and gp100. We conclude that genetic engineering aimed at endowing hematopoietic or T lymphoid progenitors with the capacity to recognize tumor antigens expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis.
Citation Format: Yongzhi Cui, Masahiro Onozawa, Haiying Qin, Terry Fry, Peter Aplan, Crystal L. Mackall. T cell lymphoblastic leukemia in survivin TCR transgenic mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3309. doi:10.1158/1538-7445.AM2013-3309
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3310: Human artificial chromosome (HAC) vector with a conditional centromere for correction of human genetic deficiencies.
Authors: Kim Jung-Hyun , Kononenko Artem , Erliandri Indri , Kim Tae-Aug , Nakano Megumi , Iida Yuichi , Barrett J. Carl , Oshimura Mitsuo , Masumoto Hiroshi , Earnshaw William C. , Larionov Vladimir , Kouprina Natalay 
Published: August 2014

Abstract
Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. Due to their unique maintenance features and unlimited cloning capacity, HACs avoid the lack of copy number control and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are “cured” of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications.
Citation Format: Jung-Hyun Kim, Artem Kononenko, Indri Erliandri, Tae-Aug Kim, Megumi Nakano, Yuichi Iida, J. Carl Barrett, Mitsuo Oshimura, Hiroshi Masumoto, William C. Earnshaw, Vladimir Larionov, Natalay Kouprina. Human artificial chromosome (HAC) vector with a conditional centromere for correction of human genetic deficiencies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3310. doi:10.1158/1538-7445.AM2013-3310
Abstract 3311: In vivo selection of S. typhimurium A1-R enhanced tumor-targeting variants.
Authors: Uehara Fuminori , Zhang Yong , Tome Yasunori , Maehara Hiroki , Kanaya Fuminori , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
The S. typhimurium A1-R mutant (A1-R), which is auxotrophic for leu-arg, and selected for high antitumor virulence, has been previously shown to be effective as monotherapy against human breast, prostate, pancreatic, and fibrosarcoma tumors that have been orthotopically implanted in nude mice. In the present study, we generated an enhanced tumor-targeting S. typhimurium variant using in vivo selection. Dual-color murine mammary tumor (MMT) cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm were injected (1 × 106 cells) in both flanks of 4-week-old female nude mice. Seven days after tumor implantation, A1-R bacteria were injected (1 × 107 cfu iv). Five days after injection, the tumors were harvested and minced. The bacteria which invaded the tumor were isolated and seeded on LB agar. After overnight incubation, colonies were picked and purified and termed A1-R1. The procedure was repeated with A1-R1 to obtain A1-R2. To determine the efficacy of the new bacterial variants, MMT-dual cells were seeded onto the 6-well plates. After 48 hours incubation, A1-R, A1-R1, and A1-R2 (1 × 108 cfu/well) were added to each plate. After 0, 24, 48, 72, 96 hours incubation, each plate was observed by confocal microscopy. Compared with A1-R, the infection rate of cancer cells by A1-R1 and A1-R2 was increased. The A1-R1 and A1-R2 variant bacteria generated in vivo selection show promise for improved bacterial targeting in vivo.
Citation Format: Fuminori Uehara, Yong Zhang, Yasunori Tome, Hiroki Maehara, Fuminori Kanaya, Robert M. Hoffman, Ming Zhao. In vivo selection of S. typhimurium A1-R enhanced tumor-targeting variants. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3311. doi:10.1158/1538-7445.AM2013-3311
Abstract 3317: Efficacy of Salmonella typhimurium A1-R treatment on human patient pancreatic tumorgrafts.
Authors: Zhao Ming , Katz Matthew H.G. , Fleming Jason B. , Suetsugu Atsushi , Zhang Yong , Maawy Ali , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Hiroshima Yukihiko , Endo Itaru , Hoffman Robert M. 
Published: August 2014

Abstract
We have previously developed the genetically-modified Salmonella typhimurium A1-R (A1-R) strain that selectively targets tumors and demonstrated its efficacy for various types of cancer cell lines in nude mouse models. The aim of this study is to determine the efficacy A1-R treatment for human-patient pancreatic tumorgrafts. Pancreatic-cancer-patient tumor specimens were initially established subcutaneously in NOD/SCID mice immediately after surgery. The patient tumors were then harvested from NOD/SCID mice and passed orthotopically in transgenic nude mice, expressing fluorescent protein in order for the tumors to acquire fluorescent stroma for imaging. After confirmation of tumor growth by fluorescence imaging, the nude mice were treated in the following groups: (1) 5-fluorouracil (5FU) (10 mg/kg, ip); (2) cisplatin (CDDP) (10 mg/kg, ip); (3) gemcitabine (GEM) (150 mg/kg, ip); (4) A1-R (A1-R) (1.5x108 cfu/body, ip); and (5) PBS (vehicle/control) (ip). Control, 5FU, CDDP, GEM and A1-R injections were performed on a weekly basis from day-21 after tumor implantation for 4 weeks. Animals were sacrificed at 7 weeks, and tumors were harvested for analysis. Each treatment arm involved 5 tumor-bearing mice. No significant effects on body weight, morbidity, or severe toxicities were observed in any treatment arm. The tumor weight of each group was as follows: (1) 5FU, 0.044 ± 0.027g; (2) CDDP, 0.04 ± 0.032g; (3) GEM, 0.058 ± 0.051g; (4) A1-R, 0.106 ± 0.038g; and (5) PBS, 0.258 ± 0.209g. S. typhimurium A1-R treatment significantly reduced the tumor weight compared to control treatment (p = 0.011), as did the other treatments including 5FU (p = 0.005), CDDP (p = 0.004), and GEM (p = 0.001). S. typhimurium A1-R treatment was effective for human pancreatic tumorgrafts and could be a promising therapy for human pancreatic cancer.
Citation Format: Ming Zhao, Matthew H.G. Katz, Jason B. Fleming, Atsushi Suetsugu, Yong Zhang, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Yukihiko Hiroshima, Itaru Endo, Robert M. Hoffman. Efficacy of Salmonella typhimurium A1-R treatment on human patient pancreatic tumorgrafts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3317. doi:10.1158/1538-7445.AM2013-3317
Abstract 3318: Cytotoxic effect of photosensitive fluorescent protein KillerRed-expressing adenovirus against human cancer cells.
Authors: Takehara Kiyoto , Tazawa Hiroshi , Hashimoto Yuuri , Kishimoto Hiroyuki , Narii Nobuhiro , Mizuguchi Hiroyuki , Fujiwara Toshiyoshi 
Published: August 2014

Abstract
Photodynamic therapy (PDT) is an anticancer therapy to induce tumor-specific cytotoxicity by accumulation of photosensitizers (PSs) and following non-toxic light irradiation to tumor tissues. Non-toxic light irradiation induces the PS-mediated generation of reactive oxygen species (ROS) and subsequent cytotoxicity in tumor cells. For clinical application, some kinds of PSs, such as photofrin and laserphyrin, are intravenously injected before light irradiation in anticancer PDT. However, the lack of sufficient and continuous accumulation of PSs in tumor tissues makes difficult to eradicate tumor cells by PDT. Therefore, the development of novel PSs that accumulate to tumor tissues more efficiently and persistently is required to improve the antitumor effect of PDT. A bioengineered fluorescent protein KillerRed has been previously reported to generate ROS upon green light irradiation, suggesting a potential of KillerRed fluorescent protein as a novel PS. We recently confirmed that transient or stable transfection with KillerRed-expressing plasmid vector efficiently suppressed the cell viability through induction of ROS-mediated apoptosis in various types of human cancer cells when combined with light irradiation. In this study, we constructed non-replicative adenovirus expressing cytotoxic KillerRed (Ad-KillerRed) or non-cytotoxic red fluorescent protein Katushka (Ad-Katushka). The cytotoxic effect of these viruses was investigated in human cancer H1299, HCT116 and HT29 cells in combination with light irradiation. Infection with Ad-KillerRed or Ad-Katushka did not induce any cytotoxic effect in human cancer cells without light irradiation. When combined with light irradiation, human cancer cells infected with Ad-KillerRed, but not Ad-Katushka, showed morphological change like round-shape. However, the cell viability was not significantly suppressed in Ad-KillerRed-infected cancer cells after light irradiation. These results suggest that replication-competent adenovirus is necessary to efficiently induce KillerRed-mediated cytotoxic effect in human cancer cells in combination with light irradiation. Now we are planning to generate the replication-competent oncolytic adenovirus expressing KillerRed and investigate its antitumor effect on the in vitro and in vivo settings.
Citation Format: Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Toshiyoshi Fujiwara. Cytotoxic effect of photosensitive fluorescent protein KillerRed-expressing adenovirus against human cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3318. doi:10.1158/1538-7445.AM2013-3318
Abstract 3319: Salmonella typhimurium A1-R inhibits aggressive pancreatic tumor growth and prolongs survival.
Authors: Maawy Ali , Zhang Yong , Bouvet Michael , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
Salmonella typhimurium (A1-R) has been previously shown to target multiple tumor types. A1-R has been shown to prevent metastasis of the XPA-1 human pancreatic cancer cell line in nude mice. The aim of this study is the anti-tumor efficacy of A1-R against a more aggressive pancreatic cell line. Human MiaPaCa2 pancreatic cancer cells, expressing RFP, were cultured in vitro and subsequently infected with A1-R. Efficacy of infection was noted by intracellular bacteria with subsequent cell lysis and apoptosis. MiaPaCa2-RFP was implanted subcutaneously in nude mice. After tumor engraftment, the mice were subjected to intravenous therapy with A1-R (5×107 CFU) once a week for 3 weeks. The tumors were harvested and weighed after the treatment period. MiaPaCA2-RFP were subsequently surgically implanted orthotopically. Treatment was initiated 2 weeks later. Mice were treated with intravenous A1-R (5×107 CFU) once a week for 6 weeks, after which survival and tumor growth were recorded. In the subcutaneous tumor model, significant decreases in the rate of tumor growth (p = 0.049) and tumor size (p =0.004) were observed upon termination. In the orthotopic model, a significant decrease in the rate of tumor growth (p = 0.01) and increased survival was observed (p = 0.014). The mean survival of the treatment group and the control group was 49 days and 35 days, respectively. None of the mice showed any adverse events or weight loss from bacterial therapy. Further investigation will be expanded to other pancreatic cancer cell lines and human patient tumorgrafts in combination with chemotherapy with the goal of cure of pancreatic cancer.
Citation Format: Ali Maawy, Yong Zhang, Michael Bouvet, Robert M. Hoffman, Ming Zhao. Salmonella typhimurium A1-R inhibits aggressive pancreatic tumor growth and prolongs survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2013-3319