tbuckley/cabot-search huggingface dataset:
Abstract 4570: Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression
Authors: Kazunori Aoki, Chihiro Shibasaki, Hisayoshi Hashimoto, Kenta Narumi, Chie Kudo
Journal: Cancer Research (2017)

Abstract Type I interferon (IFN) is a pleiotropic cytokine regulating the cancer cell death and immune response. IFN-α can effectively induce an antitumor immunity by the activation of tumor-specific T cells and maturation of dendritic cells in various animal models. It is widely known that an induction of tolerance by the tumor is one of the critical mechanisms involved in tumor progression and resistance for immune therapy. Extensive studies have shown that CD4+Foxp3+ regulatory T cells (Tregs) are critical in controlling antitumor immune responses in the tumor microenvironment. Since the effect of type I IFN on an immunotolerant microenvironment is unknown, we investigated the immunological effects of intratumoral IFN-α gene transfer on tumor-infiltrating Tregs in a mouse model. Here, to examine whether the expression of IFN-α affects the immunotolerant microenvironment in tumors, CT26 murine colon cancer tumors were directly injected once with 1 x 108 PFU of IFN-α-expressing adenovirus (Ad-mIFN). The injection of Ad-mIFN significantly suppressed the tumor growth. We found that intratumoral IFN-α gene transfer significantly decreased the frequency of Tregs per CD4+ T cells in tumors compared with control vector injection. We hypothesized that Treg-homing cytokines such as CCL17 and CCL22 cytokines are involved in the reduction of tumor-infiltrating Tregs by the Ad-mIFN injection. The IFN-α expression significantly suppressed of CCL17 and CCL22 expression of tumors, and the expression of CCR4 and CCR5 expression on Tregs was not changed. IFN-α protein significantly suppressed CCL17 of CT26 cells in vitro in a dose-dependent manner. Then, we constructed CCL17 shRNA-transduced CT26 cells (CT26shCCL17) to examine the immunological role of CCL17 in vivo. The frequency of Tregs per CD4+ T cells was significantly reduced in subcutaneous tumors of CT26shCCL17 cells (25.9 %), and tumor growth was inhibited compared with that of control shRNA-transduced CT26 cells (39.4%), suggesting CCL17 has an important role to migrate Tregs into tumors. The study demonstrated that IFN-α gene delivery creates an environment strongly supporting the enhancement of antitumor immunity through the suppression of Tregs. Citation Format: Kazunori Aoki, Chihiro Shibasaki, Hisayoshi Hashimoto, Kenta Narumi, Chie Kudo. Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2017-4570
Abstract 4741: Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in pediatric osteosarcoma
Authors: Manjula Nakka, Wendy Allen-Rhoades, Yiting Li, Aaron Kelly, Jianhe Shen, Aaron Taylor, Donald A. Barkauskas, Jason Yustein, Irene Andrulis, Jay Wunder, Richard Gorlick, Paul Meltzer, Ching Lau, Tsz-Kwong Man
Journal: Cancer Research (2017)

Abstract Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of surgery and multi-agent chemotherapy, osteosarcoma patients who respond poorly towards chemotherapy or develop relapses have a dismal outcome. Identification of biomarkers for active disease may help to monitor tumor burden, detect early relapses, and predict prognosis in these patients, so that they can be treated as early as possible to improve their survival. In this study, we examined if circulating microRNAs (miRNAs) can be used as biomarkers in osteosarcoma patients. We performed genome-wide miRNA profiling on a discovery cohort of OS plasma samples (n=32) collected from the Texas Children’s Hospital. A total of 56 miRNAs were upregulated and 164 miRNAs were downregulated in osteosarcoma samples when compared to normal plasma samples (n=8). miRNA-21, miR-221 and miRNA-106a were selected for further validation based on their known biological importance. We showed that all three circulating miRNAs were expressed significantly higher in OS samples (n=29) than normal samples (n=17) in an independent cohort obtained from the Children’s Oncology Group. Furthermore, we demonstrated that miR-21 was expressed significantly higher in osteosarcoma tumors (n=89) compared with normal bone controls. More importantly, lower expressions of miR-21 and miR-221, but not miR-106a, significantly correlated with a poor outcome. In conclusion, our results indicate that miR-21, miR-221 and miR-106a are elevated in the circulation of osteosarcoma patients, whereas tumor expressions of miR-21 and miR-221 are prognostically significant. Further investigation of the miRNAs may lead to a better prognostic method and potential miRNA therapeutics for osteosarcoma. Citation Format: Manjula Nakka, Wendy Allen-Rhoades, Yiting Li, Aaron Kelly, Jianhe Shen, Aaron Taylor, Donald A. Barkauskas, Jason Yustein, Irene Andrulis, Jay Wunder, Richard Gorlick, Paul Meltzer, Ching Lau, Tsz-Kwong Man. Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2017-4741
Abstract 3055: A permanent lung imaging window reveals, for the first time, the steps of extravasation, seeding and growth of early metastatic dissemination
Authors: Sonia E. Voiculescu, Yarong Wang, Maja Oktay, John Condeelis, David Entenberg
Journal: Cancer Research (2017)

Abstract Metastatic disease is the major cause of cancer mortality and is responsible for over 1/2 million deaths each year in the U.S. alone. Of the three most common sites of metastasis observed clinically (bone, lung and liver), the most difficult to study using intravital microscopy is the lung; a delicate organ in perpetual motion. We have recently developed and validated an implantable, permanent, lung imaging window which allows high-resolution multiphoton imaging of the intact, breathing (without ventilation), murine lung over days to weeks of repeated imaging. This window does not use vacuum to immobilize the lung tissue thereby avoiding well know artifacts associated with vacuum lung windows. Using our new window, we have been able to visualize, with single cell resolution, the steps of metastasis in a clinically relevant, spontaneously-metastasizing murine breast cancer model. We present the first direct visualization of tumor cell arrival, extravasation, and progression to micro-metastases. Further, we have observed, for the first time, the activity of the tripartite structure called Tumor MicroEnvironment of Metastasis (TMEM) in metastatic lung lesions directly demonstrating the mechanism of dissemination from metastatic lung tumors. Using this approach to imaging live lung tissue serially, within a single animal, we are investigating the mechanisms underlying the fate of tumor cells arriving in the lung with the ultimate goal of directly identifying signals behind seeding and survival of metastatic tumor cells and their responses to interventions in real time. Citation Format: Sonia E. Voiculescu, Yarong Wang, Maja Oktay, John Condeelis, David Entenberg. A permanent lung imaging window reveals, for the first time, the steps of extravasation, seeding and growth of early metastatic dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3055. doi:10.1158/1538-7445.AM2017-3055
Abstract 2880: GANT61-mediated constraint of Fibulin-5/prorenin receptor/BMI1 signaling impacts nasopharyngeal carcinoma stemness and metastasis
Authors: Hsin-Ting Tasi, Chang-Han Chen
Journal: Cancer Research (2017)

Abstract Background: Cancer stem cells (CSCs) of NPC exhibit higher tumorigenesis and metastatic potential. Novel therapies based on molecular targets of CSCs have become the focus to cure NPC. GANT61, a GLI1 inhibitor, has been reported to exhibit potent anticancer effect on many cancers; here, we evaluated whether GANT61 has inhibitory effects on NPC-CSCs and further explored the possible mechanism. Methods: Condition medium was used to enrich NPC stem-like cells. The NPC stem-like cells characteristics were examined by Q-RT-PCR, Western blotting, MTT, BudU, colony formation, sphere formation, and subcutaneous and metastatic xenograft models. Genetic, pharmacological and biochemical approaches were applied in NPC stem-like cells to investigate molecular signals, to assess the efficacies under the inhibitors treatment, and to examine the correlation among the molecules in vitro, in vivo and NPC specimens. Results: In the present study, we had demonstrated that NPC tumorsphere cells (NPC-TCs) possess CSC properties. The proliferation, colony formation, spheroid formation, migration, and invasion of NPC-TCs were dramatic prevented in the presence of GANT61 in vitro and in vivo. ChIP reveals that Gli1 preferentially binds to the Fibulin-5 promoter, and Fibulin-5 transcriptional/post-transcriptional levels in NPC-TCs were regulated upon GANT61 treatment. However, ectopic expression of Fibulin-5 in NPC-TCs not only enhanced self-renewal and ALDH1 expression, but also reduced the effects of GANT61-eilicted anti-tumor in vitro and in vivo. We further identified that a novel signaling, prorenin receptor/BMI1 pathway was modulated by Fibulin-5 and involved in Fibulin-5-raised self-renewal capacity of NPC-TCs in vitro and in vivo. Notably, GANT61 inhibited NPC-TCs phenotypes was associated with suppression of Fibulin-5/prorenin receptor/BMI1 signaling. Finally, a significant correlation was observed among GLI1, Fibulin-5, AT1R and BMI1 in the specimens of NPC. Conclusions: Our data highlight that Fibulin-5/prorenin receptor/BMI1 signaling has critical role in maintaining stem-like properties of NPC-CSCs and can be efficiently targeted by GANT61 representing a preclinical therapeutic strategy to repress NPC-CSCs. Note: This abstract was not presented at the meeting. Citation Format: Hsin-Ting Tasi, Chang-Han Chen. GANT61-mediated constraint of Fibulin-5/prorenin receptor/BMI1 signaling impacts nasopharyngeal carcinoma stemness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2880. doi:10.1158/1538-7445.AM2017-2880
Abstract 4265: Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes
Authors: Kara N. Maxwell, Thomas Paul Slavin, Jenna M. Lilyquist, Joseph Vijai, Susan L. Neuhausen, Steven N. Hart, Vignesh Ravichandran, Tinu Thomas, Ann Maria, Kasmintan A. Schrader, Raymond Moore, Chunling Hu, Brad Wubbenhorst, Brandon M. Wenz, Kurt D'Andrea, Susan M. Domchek, Mark E. Robson, Paulo Peterlongo, Paolo Radice, James M. Ford, Judy E. Garber, Csilla Szabo, Kenneth Offit, Katherine L. Nathanson, Fergus J. Couch, Jeffrey N. Weitzel
Journal: Cancer Research (2017)

Abstract A better understanding of gene-specific risks for development of breast cancer will lead to improved screening, prevention, and therapeutic strategies for individuals identified to carry germline mutations. We performed targeted massively-parallel sequencing to identify mutations and large genomic rearrangements in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA-negative women with familial breast cancer (FBC). A case-control analysis was performed comparing the frequency of internally classified mutations identified in FBC cases to that in non-Finnish European controls from the Exome Aggregation Consortium (ExAC) excluding samples from The Cancer Genome Atlas. Including large genomic rearrangements, mutations were identified in 8.2% of FBC cases compared to 6.2% of ExAC controls, including mutations in high-penetrance genes (0.6% in cases vs. 0.1% in controls), moderate-penetrance genes (3.7% vs 1.7%), and seven cases with two mutations (0.3%). The remainder of FBC cases and ExAC controls had mutations in proposed breast cancer genes (1.6% of cases vs 2.4% of controls), Lynch syndrome genes (0.5% vs. 0.5%) or were heterozygous MUTYH carriers (1.5% vs. 1.5%). Case-control analysis demonstrated significant associations with FBC for ATM, PALB2, and TP53 mutations (OR&amp;gt;3.0, p&amp;lt;10-4), BARD1 mutations (OR=3.2, p=0.012), and CHEK2 truncating mutations (OR=1.6, p=0.041). Our results therefore demonstrate that only approximately 4% of BRCA1/2 negative FBC patients have mutations in genes definitively associated with breast cancer at this time. Large case-control studies are needed to fully evaluate the breast cancer risks associated with moderate penetrance and proposed breast cancer susceptibility genes. Citation Format: Kara N. Maxwell, Thomas Paul Slavin, Jenna M. Lilyquist, Joseph Vijai, Susan L. Neuhausen, Steven N. Hart, Vignesh Ravichandran, Tinu Thomas, Ann Maria, Kasmintan A. Schrader, Raymond Moore, Chunling Hu, Brad Wubbenhorst, Brandon M. Wenz, Kurt D'Andrea, Susan M. Domchek, Mark E. Robson, Paulo Peterlongo, Paolo Radice, James M. Ford, Judy E. Garber, Csilla Szabo, Kenneth Offit, Katherine L. Nathanson, Fergus J. Couch, Jeffrey N. Weitzel. Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2017-4265
Abstract 4656: Assessment of BCL-2, BCL-xL and MCL-1 in bone marrow biopsy samples using VENTANA BenchMark XT automated slide stainer
Authors: Ashley Streator, Eneida C. Villanueva, Burton F. Holmes, Liping Zhang
Journal: Cancer Research (2017)

Abstract Immunophenotyping is essential for diagnosis and classification of most hematopoietic malignancies, and often followed by ancillary studies to understand the predictive and prognostic value of biomarkers. Immunohistochemistry (IHC) provides in-situ coupling of antigen expression with morphology of precursor B- from precursor T-lymphoblastic leukemia/lymphoma. The number of different IHC antibodies that can be applied to bone marrow (BM) biopsies is increasing concurrently with development of flow cytometry and molecular diagnostic methods. IHC detects scattered tumor cells in Hodgkin’s Lymphoma, Multiple Myeloma (MM) and Acute Myelogenous Leukemia (AML), where key biomarkers may not be detectable by current flow cytometry methods. The goal of this study was to detect BCL-2, Bcl-xL and MCL-1 that are able to predict pre-clinical sensitivity to the drug Venetoclax. We examined the expression of these biomarkers in MM bone samples decalcified using commercially available reagents to determine whether decalcification methods impact BCL-2 family IHC Staining. Results: MM bone samples (n=59) decalcified in Decal STAT® for 20 min, stained for BCL-2 (124) and Bcl-xL (54H6). MM bone samples (n=7) decalcified in Decal STAT® for 60 min stained for BCL-2 and Bcl-xL. Finally, eleven MM bone samples decalcified in Richard Allan Decal Solution® stained for BCL-2 and Bcl-xL. MCL-1 stained poorly with commercially available decalcification solutions. For MCL-1 to be used, additional staining optimization is required. Conclusion: BCL-2 and BCL-xL proteins can be detected in MM bone samples decalcified with commercially available solutions. With these preliminary results, future studies will pursue the potential for sensitivity to "Venetoclax (ABT-199/GDC-0199)". Citation Format: Ashley Streator, Eneida C. Villanueva, Burton F. Holmes, Liping Zhang. Assessment of BCL-2, BCL-xL and MCL-1 in bone marrow biopsy samples using VENTANA BenchMark XT automated slide stainer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4656. doi:10.1158/1538-7445.AM2017-4656
TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study
Authors: Yasutoshi Kuboki, Tomohiro Nishina, Eiji Shinozaki, Kentaro Yamazaki, Kohei Shitara, Wataru Okamoto, Takeshi Kajiwara, Toshihiko Matsumoto, Takahiro Tsushima, Nobuo Mochizuki, Shogo Nomura, Toshihiko Doi, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino
Journal: The Lancet Oncology (2017)
Invited commentary: methodological issues in the design and analysis of randomised trials
Authors: Mohammad Ali Mansournia, Douglas G Altman
Journal: British Journal of Sports Medicine (2017)

Randomised trials are widely considered the ‘gold standard’ for causal inference, because on average randomisation balances covariates between treatment groups, even if those covariates are unobserved. However, trials are not immune to random confounding, as well as selection bias and measurement bias. Therefore, special care is needed in the design and analysis stages of randomised trials. Here, we review some important methodological aspects of randomised controlled trials in the context of a recently published paper, which assessed the effect of McKenzie method of mechanical diagnosis and therapy on pain and disability in patients with chronic, non-specific, low back pain using a randomised placebo-controlled trial.1 

Garcia et al state that they randomly assigned 148 participants to two groups of similar sizes, that is, 74 patients per group using simple randomisation. However, simple (unrestricted) randomisation, equivalent to repeated fair coin tossing, can lead to treatment groups of markedly different sizes in small trials and thus imprecise effect estimates. In fact, the authors were very fortunate, as the probability of complete balance in their study is just 6.5%, and the probability of imbalances equal or greater than 10 (ie, 79 vs 69) is non-negligible (46.0%). Balanced block randomisation with, say, 37 blocks of size 4, would have insured balance in the number of patients being allocated to intervention or placebo in this study, although its sequence is more predictable than simple randomisation (to fix the latter problem, one can use larger block sizes, and randomly varying the block size). More importantly, balanced blocking prevents from substantial periodic imbalance and thus is often recommended for assignment in randomised trials.2 Successful randomisation also depends on allocation concealment, which authors achieved by use of sealed, opaque, numbered envelopes. Failure to conceal the …
Abstract 426: Targeted genome profiling in patients with advanced hepatocellular carcinoma treated with sorafenib
Authors: Wonseok Kang, Kyung Kim, Joon Hyeok Lee, Ho Yeong Lim, Woong-Yang Park, Jeeyun Lee, Yong Han Paik
Journal: Cancer Research (2017)

Abstract Background/Objectives: Sorafenib is the only approved targeted agent as first-line treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, many HCC patients are initially not responsive to sorafenib. Due to anatomic limitations and underlying liver dysfunction, genomic studies of HCC patients have not been actively pursued yet compared to other solid tumors; especially, in sorafenib-treated subset. In this study, we have retrospectively identified advanced HCC patients who had archival tumor tissues available for targeted genomic sequencing and who had been treated with sorafenib. Methods: We performed targeted genomic profiling for 381 cancer-related genes from 42 HCC (32 hepatitis B virus-related, 1 alcohol-related, 7 unknown) patients treated with sorafenib at Samsung Medical Center, Seoul, Korea from July 2008 to October 2013. We excluded 2 patients who were lost to follow up for evaluation of treatment response to sorafenib. Results: Of the 40 patients, there were 5 confirmed PRs, 7 SDs, and 28 PDs. In 40 patients, there were 6 CDKN2B amplifications, 4 NTRK1 amplifications, 2 MET amplifications, 2 FGF19 amplifications, 2 CCND1 amplifications, 1 EGFR amplification, 1 FGF23 amplification and 1 CCNE1 amplification. In cell cycle-related genes, those patients with aberrations were less likely to respond to sorafenib. Of note, two patients whose tumor had CCND1 amplifications had de novo resistance to sorafenib. Conclusions: Our study demonstrates inter-patient heterogeneity in advanced HCC patients and the role of cell cycle-associated genes in resistance mechanism to sorafenib is being investigated. Citation Format: Wonseok Kang, Kyung Kim, Joon Hyeok Lee, Ho Yeong Lim, Woong-Yang Park, Jeeyun Lee, Yong Han Paik. Targeted genome profiling in patients with advanced hepatocellular carcinoma treated with sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 426. doi:10.1158/1538-7445.AM2017-426
Abstract 5272: Chemopreventive activities of a polyphenol rich purified extract from olive oil processing on colon cancer cells
Authors: Barbara Bassani, Teresa Rossi, Daniela De Stefano, Daniele Pizzichini, Paola Corradino, Antonino Bruno, Douglas M. Noonan, Adriana Albini
Journal: Cancer Research (2017)

Abstract Epidemiological studies showed that diet can play a relevant role in reducing the risk of developing colon cancer (CC) and lower rate of CC insurgence has been observed amongst populations living within the Mediterranean basin. Olive oil, a major component of the Mediterranean diet, is an abundant source of phenolic compounds. Olive oil production is associated with the generation of waste material, termed ‘olive mill wastewaters’ (OMWW), that have been reported to be enriched in polyphenols as well. Given the beneficial activity of polyphenols on human health, we investigated whether the use of different batches of purified extracts from OMWW, termed A009, might be effective in exerting chemopreventive activities in vitro and in vivo, on CC cell lines. Cell proliferation and survival were evaluated on A009 treated cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while the induction of apoptosis was assessed by flow cytometry. Further, functional studies to investigate the ability of A009 to interfere with CC cell line adhesion, migration, sprouting and invasion were performed. Finally, the ability of A009 to interfere with CT-26 CRC tumour cell growth was assessed in vivo. Purified hydroxytyrosol, the major component in the A009 extracts, was used as a control. A009 inhibited cell proliferation, migration, invasion, adhesion and sprouting of CC cells along with the release of pro-angiogenic and pro- inflammatory cytokines (VEGF, IL-8) similar to hydroxytyrosol alone. In vivo, A009 inhibited CT-26 tumour growth in a significant manner over that of hydroxytyrosol alone. Our results show that A009 extracts exert promising chemopreventive properties, suggesting that different polyphenols act synergistically, improving their single component effects in CC cell lines. Finally, our results support the idea of repositioning a waste derived material for nutraceutical employment, with environmental and industrial cost management benefits. Citation Format: Barbara Bassani, Teresa Rossi, Daniela De Stefano, Daniele Pizzichini, Paola Corradino, Antonino Bruno, Douglas M. Noonan, Adriana Albini. Chemopreventive activities of a polyphenol rich purified extract from olive oil processing on colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5272. doi:10.1158/1538-7445.AM2017-5272