tbuckley/cabot-search huggingface dataset:
Abstract 2506: Preclinical characterization of LV305, a lentiviral vector targeting tumors expressing NY-ESO-1
Authors: Tina C. Albershardt, David J. Campbell, Andrea J. Parsons, Jan H. ter Meulen, Peter Berglund
Journal: Cancer Research (2015)

Abstract The cancer-testis antigen, NY-ESO-1, is an attractive tumor antigen target for cancer immunotherapy, because it is expressed in numerous cancer types (e.g., melanoma, breast cancer, sarcoma, lung cancer) but not in normal adult tissues except the testis or placenta. Although recent studies using various NY-ESO-1 formulations show promising results, an optimal immunotherapeutic strategy to generate T cell responses for controlling tumor growth is still lacking. Lentiviral vectors (LVs) are proven tools for delivering nucleic acid payloads into cells due to their ability to transduce not only dividing cells but also quiescent cells, such as dendritic cells (DCs). Because DCs are essential for the initiation of T cell responses, we have engineered LV305 (a product candidate from ZVex™, our LV-based discovery platform) to selectively deliver the antigen-encoding NY-ESO-1 gene to human DCs in vivo. To develop tools to evaluate LV305 in a preclinical setting, we 1) generated a cell line, CIN.23, which is a CT26 murine colon cancer cell line that stably expresses human NY-ESO-1 protein; and 2) mapped and confirmed NY-ESO-1 CD8 and CD4 T cell epitopes recognized by H2d. Mice immunized with LV305 developed strong, dose-dependent, poly-functional, and cytotoxic NY-ESO-1-specific CD8 T cells within 14 days post-immunization and could be boosted with LV305 at least three times to recall peak-level CD8 T cell responses. Immunization with LV305 protected mice against CIN.23 tumor challenge, which was abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, together with CD4 T cells or NK cells, from LV305-immunized donor mice to tumor-bearing mice conferred significant protection against metastatic tumor growth. This protection was not observed when CD8 T cells alone were adoptively transferred. Taken together, these findings suggest that CD8 T cells are required but not sufficient for mediating LV305-induced anti-tumor efficacy. We have demonstrated the anti-tumor therapeutic potential of LV305-mediated in vivo DC immunization in murine models and are currently investigating LV305 in a phase I clinical trial in cancer patients with tumors expressing NY-ESO-1. Citation Format: Tina C. Albershardt, David J. Campbell, Andrea J. Parsons, Jan H. ter Meulen, Peter Berglund. Preclinical characterization of LV305, a lentiviral vector targeting tumors expressing NY-ESO-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2506. doi:10.1158/1538-7445.AM2015-2506
Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial
Authors: Abdel-Rahmène Azzouzi, Sébastien Vincendeau, Eric Barret, Antony Cicco, François Kleinclauss, Henk G van der Poel, Christian G Stief, Jens Rassweiler, Georg Salomon, Eduardo Solsona, Antonio Alcaraz, Teuvo T Tammela, Derek J Rosario, Francisco Gomez-Veiga, Göran Ahlgren, Fawzi Benzaghou, Bertrand Gaillac, Billy Amzal, Frans M J Debruyne, Gaëlle Fromont, Christian Gratzke, Mark Emberton
Journal: The Lancet Oncology (2016)
Cocaine-Induced Endothelial Dysfunction: Role of RhoA/Rho Kinase Pathway Activation.
Authors: Jaime Pereira, Claudia G Saez, Julio Pallavicini, Karla Pereira-Flores, Camila Mendoza, Romina Hernández, Ulises Novoa, María Paz Ocaranza, Teresa Massardo, Diego Mezzano, Jorge Jalil
Journal: Blood (2012)
Favorable short‐term outcome of hepatitis C virus–positive liver graft with bridging fibrosis: A plea for very early viral eradication
Authors: Silvia Martini, Mauro Salizzoni, Ezio David, Francesco Tandoi, Paolo Fonio, Luisa Delsedime, Silvia Strona, Dominic Dell Olio, Giorgio Maria Saracco, Renato Romagnoli
Journal: Hepatology (2016)

Martini, Silvia; Salizzoni, Mauro; David, Ezio; Tandoi, Francesco; Fonio, Paolo; Delsedime, Luisa; Strona, Silvia; Dell Olio, Dominic; Saracco, Giorgio Maria; Romagnoli, Renato Author Information
364. Impact of Injection Volume on Hydrodynamic Delivery To the Liver in Mice
Authors: Tsutomu Kanefuji, Takeshi Yokoo, Takeshi Suda, Kunihiko Sawada, Yoshinori Arai, Hiroyuki Abe, Kenya Kamimura, Dexi Liu, Shuji Terai
Journal: Molecular Therapy (2015)

Hydrodynamic gene delivery is a widely prevailed method for gene delivery to the liver especially in rodents, because of its efficiency and simplicity. A transient enlargement of the liver derived from physical force, which is generated by a rapid injection of a large amount of solution through the tail vein of a mouse, plays an important role for the gene transfer. We previously demonstrated that the expansion speed of the liver is a primary determinant for gene transfer efficiency, because the liver volume at the end of the injection (final volume) was not significantly different between hydrodynamic (5 sec) and slow (60 sec) injections, as long as the same amount of volume of 9% of body weight (BW) was injected (kanefuji, et al. Mol Ther Methods Clin Deve 1;14029). However, the relationship between the injection volume and final volume has not been clarified. The present study aimed to evaluate volume-dependent physical impacts on the liver in hydrodynamic injection. Physical impacts to the liver were quantified in mice by measuring the final volume using a cone beam computed tomography (CBCT) and serum concentration of alanine aminotransferase (ALT). Hydrodynamic (9% of BW/5 sec), half-hydrodynamic (5% of BW/5 sec), and half-slow (5% of BW/60 sec) injections were performed with contrast medium including 300 mg/ml of iodine through the tail vein of mice. Just after the injections, CBCT studies were performed without any surgical intervention to collect volume data of the liver, and the final volumes were shown as the relative volume of that of control mice. Blood samples were collected for the assay of serum concentration of ALT at the time points of 1, 4, 24, 48, and 168 hours after the injections. The average final volumes were 125.8±11.5 and 119.7±4.8% in half-hydrodynamic and half-slow injections, and were not significantly different from each other, while they were significantly lower than that of 173.1±10.4% in hydrodynamic injection (p>0.99 and <0.05, respectively, Kruskal-Wallis followed by Dunn's Multiple Comparison test). The average levels of ALT 4 hours after the injections were 82.6±72.4 U/L and 1582±701.5 U/L in half-hydrodynamic and hydrodynamic injections, which were significantly different from each other (p<0.01, Mann-Whitney test), and returned to the normal level within 48 hours after the injections. These results clearly indicate that the final volume evidently depends on the injection volume but not speed in both hydrodynamic and half-hydrodynamic injections. Furthermore, the reduction of the injection volume markedly suppressed the elevation of liver enzyme in serum after the injection. From a safety viewpoint, there is no doubt that an injection with less volume is advisable as far as sufficient gene delivery is guaranteed. A further study is on going to make the efficacy of half-hydrodynamic injection comparable with that of hydrodynamic injection.
Abstract 3415: PAICS is the prognostic marker in colorectal cancer patients with stage III
Authors: Yusuke Kobayashi, Kensuke Kumamoto, Yoshiko Matsumoto, Motonobu Saito, Tatsuo Shimura, Seiichi Takenoshita
Journal: Cancer Research (2015)

Abstract PAICS (Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase) is an important bifunctional enzyme in de novo purine biosynthesis. It could be an attractive target for anticancer drug design, since rapidly dividing cancer cells rely on the purine through de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the salvage pathway. Previous reports demonstrated that PAICS expression was up-regulated in ALL, lung cancer, and glioblastoma. In the present study, we first performed the comparison of PAICS mRNA expression between cancer tissue and normal colonic mucosa in 83 colorectal cancer (CRC) patients by realtime RT-PCR. We further investigated PAICS expression by immunohistochemical staining in 258 CRC patients and analyzed the association between PAICS expression and clinicopathological factors and prognosis. To understand the biological significance of PAICS expresssion, knockdown experiments of PAICS expression were performed by a siRNA method using the colon cancer cell line, HCT116. We analyzed the relationship between PAICS mRNA expression and genetic status and prognosis using several databases. PAICS mRNA expression in CRC tissue was significantly enhanced when compared to that in normal tissue. In immunohistochemical examination, PAICS expression was observed in cytoplasm of cancer cells. PAICS expression was detected in 55% cases of colorectal cancer patients. There were significant association between PAICS expression and histology (p = 0.049). There was not significant correlation between PAICS expression and overall survival in CRC patients. Regarding CRC patients with stage III, patients with positive expression of PAICS had significantly good prognosis as compared to those with negative expression (p = 0.015). Knockdown of PAICS expression acquired the ability of cellular invasion using colon cancer cell lines, HCT116 and SW480. In all CRC databases we analyzed, stage III patients with high expression of PAICS had good prognosis as compared to those with low expression of PAICS. We concluded that PAICS expression was up-regulated in approximately 55% CRC, and higher level of PAICS expression might serve as a good prognostic marker in advanced CRC patients. Citation Format: Yusuke Kobayashi, Kensuke Kumamoto, Yoshiko Matsumoto, Motonobu Saito, Tatsuo Shimura, Seiichi Takenoshita. PAICS is the prognostic marker in colorectal cancer patients with stage III. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2015-3415
Abstract 4699: Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer
Authors: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2015)

Abstract Increased phosphoinositide 3-kinase (PI3K) pathway activity is commonly observed in human prostate cancer and constitutes a potential target for therapeutic intervention. AZD5363 is a potent pan-AKT kinase inhibitor that is currently being investigated in phase 1 and 2 clinical trials in solid cancers including prostate. AZD5363 has demonstrated strong anti-tumor activity against human prostate cancer cells in vitro and in vivo. Genetically engineered mouse models mimic the genetic and biological evolution of human prostate cancer and address deficiencies encountered with xenograft models. In the present study, we examined in vivo target validation, pharmacodynamics, and antitumor responses of AZD5363 monotherapy in a PTEN-deficient mouse model of prostate cancer, and show the survival benefit in an advanced prostate cancer model driven by PTEN/P53 inactivation. Downstream targets of AKT were inhibited in a dose-dependent manner and activity of AZD5363 at was observed up to 8 hours after a single dose of 100 mg/kg. Tumor cell proliferation and the induction of apoptosis paralleled the activity of AZD5363. Compared to vehicle treated mice, chronic administration of AZD5363 at 100 mg/kg B.I.D. 5 times per week for 4 weeks inhibited growth of castration-naïve and castration-resistant prostate cancers by 15.9% ±4.3 and 20.2% ±4.4, respectively. Inhibition of S6 phosphorylation was effectively maintained the after chronic administration of AZD5363 and was accompanied by decreased proliferation rates and increase in apoptosis. Furthermore, in a long-term survival study of PTEN/P53 double knockout mice, treatment with AZD5363 significantly improved survival rates from 24 to 37 days, P&amp;lt;0.011. In conclusion, our findings indicate that AZD5363 is effective against autochthonous models of mouse prostate cancer and support further investigation of the AKT inhibitor for the treatment of PTEN-deficient prostate cancer. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4699. doi:10.1158/1538-7445.AM2015-4699
Body mass index (BMI) as a prognostic and predictive factor in stage II/III colon cancer: An analysis of the ACCENT database.
Authors: F. Sinicrope, N. R. Foster, G. A. Yothers, A. B. Benson, D. G. Haller, J. Seitz, R. Labianca, J. Benedetti, R. M. Goldberg, A. De Gramont, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

e21126 Background: Obesity is an established risk factor for developing colon cancer. We determined the impact of body mass index (BMI) upon prognosis and treatment benefit using the Adjuvant Colon Cancer Endpoints (ACCENT) database. Methods: BMI (kg/m2) was categorized at baseline in patients (pts) with TNM stage II and III colon carcinomas (n= 23,315) enrolled in 20 randomized trials of 5-fluorouracil-based adjuvant therapy. Cox models were used to determine the association of BMI with time-to-recurrence (TTR), disease-free (DFS) and overall survival (OS). Results: Among colon cancer pts, 4194 (18%) were obese (BMI ≥30 kg/m2), 8347 (35.8%) overweight (BMI 25-29.9 kg/m2), 9062 (38.9%) normal weight (BMI 20-24.9 kg/m2), and 1712 (7.3%) underweight (BMI < 20 kg/m2). Obese vs normal weight pts were more likely to be younger (median age 60 vs 61 yr; p=0.0006), have distal tumors (57% vs 55%; p=0.0066), and be stage III vs II (68% vs 64%; p<0.0001). In univariate analyses, obese [HR 1.13 (1.06, 1.20), p=0.0003] and underweight [HR 1.12 (1.02, 1.23), p=0.0145] pts had poorer OS compared to normal weight pts. Analysis by gender demonstrated that underweight men [HR 1.26 (1.09, 1.47), p=0.0022], but not women (HR=1.09, p=0.13), had a worse OS vs normal weight pts. Similar results were found for DFS and OS; TTR was weaker among underweight pts. BMI category was not predictive of treatment benefit. Conclusions: Obese and underweight colon cancer survivors have a statistically significant, but clinically modest, worse prognosis. Obesity does not predict chemotherapy benefit. Studies to determine if weight loss can attenuate the adverse prognostic impact of obesity are warranted. BMI Category TTR HR (95% CI) 5-yr TTR Rate (95% CI) P-value OS HR (95% CI) 5-yr OS Rate (95% CI) P-value Obese 1.07 (1.01, 1.14) 67.5% (66.0-68.9) 0.0357 1.11 (1.04, 1.18) 72.6% (71.3-74.0) 0.0024 Overweight 1.01 (0.96, 1.06) 69.5% (68.5-70.5) 0.7856 0.99 (0.94, 1.05) 74.5% (73.6-75.5) 0.7141 Normal* 1.0 69.9% (69.0-70.9) NA 1.0 74.9% (74.0-75.8) NA Underweight 1.13 (1.03, 1.24) 67.0% (64.8-69.4) 0.0080 1.22 (1.11, 1.33) 72.6% (70.5-74.8) <0.0001 Adjusted for age, stage, treatment, and gender.*Reference group.
Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study.
Authors: Bertrand Godeau, Olivier Fain, Raphael Porcher, Francois Lefrere, Pierre Fenaux, Stephane Cheze, Anne Vekhoff, Marie-Paule Chauveheid, Jerome Stirnemann, Lionel Galicier, Emmanuelle Bourgeois, Stephanie Haiat, Bruno Varet, Michel Leporrier, Thomas Papo, Marc Michel, Philippe Bierling
Journal: Blood (2006)
Abstract 145: HOTTIP, an oncogenic long non-coding RNA, is frequently up-regulated in hepatocellular carcinoma and is negatively regulated by tumor suppressive microRNA miR-125b
Authors: Felice H. Tsang, Sandy L. Au, Lai Wei, Dorothy N. Fan, Joyce M. Lee, Carmen C. Wong, Irene O. Ng, Chun-Ming Wong
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is one of the most common human cancers. Due to the lack of early diagnostic and effective treatment modalities, the mortality of HCC is high. The development and progression of HCC is a multistep process driven by the accumulation of genetic and epigenetic alterations. Recently, emerging evidence has suggested the role of long non-coding RNAs (lncRNAs) in human carcinogenesis. Herein, by profiling the expression of 88 well-annotated lncRNAs, we identified that HOTTIP was the most significantly up-regulated lncRNA (81%, 57/70) in human HCCs, even in early stage of HCC formation. Functionally, knockdown of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumorigenicity in vivo. In addition, knockdown of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lncRNA mapped to the distal end of the HOXA gene cluster. Knockdown of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR-125b as a post-transcriptional regulator of HOTTIP. Ectopic expression of miR-125b abolished HOTTIP-coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR-125b. In Summary, our findings suggest that HOTTIP is a novel oncogenic lncRNA, with miR-125b being its negative regulator. It contributes to hepatocarcinogenesis by regulating the expression of its neighboring protein-coding genes. Citation Format: Felice H. Tsang, Sandy L. Au, Lai Wei, Dorothy N. Fan, Joyce M. Lee, Carmen C. Wong, Irene O. Ng, Chun-Ming Wong. HOTTIP, an oncogenic long non-coding RNA, is frequently up-regulated in hepatocellular carcinoma and is negatively regulated by tumor suppressive microRNA miR-125b. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 145. doi:10.1158/1538-7445.AM2015-145
Second Opinions From Medical Oncologists for Early-Stage Breast Cancer
Authors: Allison W. Kurian, Christopher R. Friese, Irina Bondarenko, Reshma Jagsi, Yun Li, Ann S. Hamilton, Kevin C. Ward, Steven J. Katz
Journal: JAMA Oncology (2016)

Advances in the evaluation and treatment of breast cancer have made the clinical decision-making context much more complex. A second opinion from a medical oncologist may facilitate decision making for women with breast cancer, yet little is known about second opinion use.
Abstract 4378: Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro
Authors: Thomas M. Bodenstine, Grace S. Chandler, Naira V. Margaryan, Luigi Strizzi, Alina Gilgur, Elisabeth A. Seftor, Richard E B Seftor, Zhila Khalkhali-Ellis, Andrey Ugolkov, Andrew P. Mazar, Mary J C Hendrix
Journal: Cancer Research (2015)

Abstract Triple negative breast cancer represents an aggressive malignancy for which few targeted therapies exist. The embryonic morphogen Nodal is re-expressed in highly aggressive breast cancers and reduction of Nodal signaling decreases tumor cell metastatic characteristics. This represents a potential avenue for the development of therapeutics aimed at inhibiting the Nodal pathway. To explore this further, we evaluated Nodal expression in breast cancer cells following chemotherapy. In vitro treatment of MDA-MB-231 and MDA-MB-468 human breast cancer cell lines with Doxorubicin, a chemotherapy commonly used for the treatment of malignant breast cancer, resulted in the generation of surviving subpopulations that retained Nodal expression (&amp;gt;80%) and remained viable. To validate these findings in vivo, we analyzed Doxorubicin treated metastatic patient derived breast cancer xenografts (PDX) which displayed a residual population of Nodal positive cells when analyzed by immunohistochemistry. Based on these findings, we hypothesize that targeting Nodal in a combinatorial approach with chemotherapy will lead to a reduction in remaining viable populations of cancer cells. When we utilized an anti-Nodal neutralizing antibody to inhibit Nodal signaling, antibody treatment reduced cell proliferation, attachment and increased rates of apoptosis in Doxorubicin treated breast cancer cell lines. Decreases in phosphorylation of Histone 3, a marker of cellular proliferation, and increases in the cleavage of PARP, correlating to induction of apoptosis, were noted in response to antibody treatment. These data suggest that Nodal signaling plays a critical role in the growth of metastatic breast cancer cells and targeting Nodal may improve therapeutic outcome in malignancies such as triple negative breast cancer. The initial results highlight translational potential for the development of humanized antibodies capable of inhibiting Nodal function. Citation Format: Thomas M. Bodenstine, Grace S. Chandler, Naira V. Margaryan, Luigi Strizzi, Alina Gilgur, Elisabeth A. Seftor, Richard E B Seftor, Zhila Khalkhali-Ellis, Andrey Ugolkov, Andrew P. Mazar, Mary J C Hendrix. Targeting the embryonic morphogen Nodal reduces viability of doxorubicin-treated breast cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2015-4378
A Role for NFAT in Innate Immunity: Neutrophil Effector Functions in Patients after Allogeneic Hematopoietic Stem Cell Transplantation Under Cyclosporine Α Treatment
Authors: Katharina Plein, Daniel Teschner, Christian Michel, Eva-Maria Wagner, Pamela Stein, Matthias Theobald, Hansjoerg Schild, Markus Radsak
Journal: Blood (2014)