tbuckley/cabot-search huggingface dataset:
Abstract 4701: Blocking FSTL1 ameliorates immunity against osteosarcoma
Authors: Chie Kudo-Saito, Yamato Ogiwara, Kazunori Aoki
Journal: Cancer Research (2017)

Abstract Purposes: Osteosarcoma is a rare malignant tumor of bone in children and young adults, and it is very hard to successfully control the systemic metastases and life-threatening health problems more than a decade after the completion of the care due to the intensiveness of the conventional treatments including surgical resection of the primary tumor and chemotherapy. Therefore, non/low-toxic but advanced treatments have been expected for a long while. We recently found that a BMP family FSTL1 is highly and functionally expressed in murine and human osteosarcoma cell lines, and systemically expands pluripotent mesenchymal stem/stromal cells (MSCs), which play a central role in amplification of tumor heterogeneity that is consequence of reciprocal evolution together with the tumor microenvironment, including induction of immune suppression and dysfunction, desmoplasia, and angiogenesis. FSTL1 and its induced MSCs also directly confer higher invasive and metastatic properties on tumor cells leading to further cancer progression. In this study, we evaluated antitumor efficacy induced by anti-FSTL1 mAb on murine osteosarcoma models, and also compared the therapeutic efficacy with those induced by immune checkpoint inhibitory mAbs (ICIs). Results: We used two syngeneic tumor models that were subcutaneously implanted with murine osteosarcoma NHOS cells in BALB/c mice, or LM3 cells in C3H mice. These mice were intraperitoneally injected with anti-FSTL1 mAbs (10mg/kg) twice on day 5 and day 8 after tumor implantation, and were sacrificed for immunological analysis of tumor-infiltrating cells, spleen cells and bone marrow cells on day 15. In both osteosarcoma models, CD45- MSCs as well as other immunosuppressive CD4+Foxp3+ Tregs and CD11b+Gr1+ MDSCs systemically increased, indicating impairment of antitumor immunity in the mice. Treatment with the anti-FSTL1 mAb significantly induced potent tumor-specific CTLs through reduction of MSCs, resulting in tumor-free in some of the treated mice. Although the antitumor efficacy was similar to those induced by ICIs, the mode of action was totally distinct because MSCs and the MSC-inducible exhausted CD8+PD1+Tim3+ T cells were reduced only in the anti-FSTL1-treated mice, but not in the ICI-treated mice. Conclusions: These results suggest that blocking FSTL1 properly reprograms immunity toward elimination of osteosarcoma by reducing the tumor-supportive MSCs. Anti-FSTL1 mAb may be a promising drug for treating osteosarcoma more moderately but effectively in clinical settings. Citation Format: Chie Kudo-Saito, Yamato Ogiwara, Kazunori Aoki. Blocking FSTL1 ameliorates immunity against 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 4701. doi:10.1158/1538-7445.AM2017-4701
Linking Stress and Infertility: A Novel Role for Ghrelin
Authors: Luba Sominsky, Deborah M Hodgson, Eileen A McLaughlin, Roger Smith, Hannah M Wall, Sarah J Spencer
Journal: Endocrine Reviews (2017)

Infertility affects a remarkable one in four couples in developing countries. Psychological stress is a ubiquitous facet of life, and although stress affects us all at some point, prolonged or unmanageable stress may become harmful for some individuals, negatively impacting on their health, including fertility. For instance, women who struggle to conceive are twice as likely to suffer from emotional distress than fertile women. Assisted reproductive technology treatments place an additional physical, emotional, and financial burden of stress, particularly on women, who are often exposed to invasive techniques associated with treatment. Stress-reduction interventions can reduce negative affect and in some cases to improve in vitro fertilization outcomes. Although it has been well-established that stress negatively affects fertility in animal models, human research remains inconsistent due to individual differences and methodological flaws. Attempts to isolate single causal links between stress and infertility have not yet been successful due to their multifaceted etiologies. In this review, we will discuss the current literature in the field of stress-induced reproductive dysfunction based on animal and human models, and introduce a recently unexplored link between stress and infertility, the gut-derived hormone, ghrelin. We also present evidence from recent seminal studies demonstrating that ghrelin has a principal role in the stress response and reward processing, as well as in regulating reproductive function, and that these roles are tightly interlinked. Collectively, these data support the hypothesis that stress may negatively impact upon fertility at least in part by stimulating a dysregulation in ghrelin signaling.
Abstract 449: Reduced argininosuccinate synthetase expression in refractory sarcomas: impacts on therapeutic potential and drug resistance
Authors: Eisuke Kobayashi, Youngji Kim, Daisuke Kubota, Yoshiyuki Suehara, Akira Kawai, Shigehisa Kitano
Journal: Cancer Research (2017)

Abstract Introduction: Treating drug-resistant sarcomas remain a major challenge. The present study aimed to identify a novel therapy for drug-resistant sarcomas based on a metabolic errors involving argininosuccinate synthetase1 (ASS1). Methods: We assessed the expression of ASS1 and P-glycoprotein (P-gp) in osteosarcoma (KHOS), doxorubicin (Dox)-resistant osteosarcoma (KHOSR2), epithelioid sarcomas (ES-X and VAESBJ), alveolar soft part sarcoma (ASPS-KY), and each clinical specimen. Each cell was cultured in arginine-containing and arginine-free media. Cell growth was assessed using an XTT assay and flow cytometry. We analyzed the induction of autophagy in arginine-free medium. Moreover, we assessed the expression of P-gp in after suppressing ASS1 in Dox-sensitive cells (MCF-7, KHOS) and in after transfecting the ASS1 into Dox-resistant cells (ES-X, VAESBJ, ASPS-KY and KHOSR2). Results: The expression of ASS1 was reduced in Dox-resistant sarcoma cells. Immunohistochemistry (IHC) and real-time PCR showed that there was interestingly an inverse relationship between the expression of ASS1 and the expression of P-gp. The inhibition of cellular proliferation with G1-arrest was shown to lead to autophagy with arginine deprivation. In addition, the combination of autophagy inhibitor plus arginine deprivation was more effective than arginine deprivation alone. In cells in which the expression of ASS1 was suppressed, the expression of P-gp was upregulated in comparison to negative controls. Discussion: These results indicate that the reduced expression of ASS1 expression in Dox-resistant sarcomas may contribute to drug resistance. ASS1 deficiency is a potential target for novel drug therapies. The combination of arginine deprivation therapy and an autophagy inhibitor may have anti-tumor effects in refractory sarcomas. Significance: As the induction of autophagy by the deprivation arginine may have a pro-survival role in patients with ASS1-deficient sarcomas, the combination of arginine deprivation therapy with autophagy modulators might potentiate anti-tumor effects in patients with drug-resistant sarcomas. Citation Format: Eisuke Kobayashi, Youngji Kim, Daisuke Kubota, Yoshiyuki Suehara, Akira Kawai, Shigehisa Kitano. Reduced argininosuccinate synthetase expression in refractory sarcomas: impacts on therapeutic potential and drug resistance [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 449. doi:10.1158/1538-7445.AM2017-449
A theoretical model for exercise progressions as part of a complex rehabilitation programme design
Authors: Sam Blanchard, Philip Glasgow
Journal: British Journal of Sports Medicine (2017)

Clear clinical reasoning relating to appropriate progression and regression of rehabilitation is essential to achieve positive clinical outcomes. A theoretical model to assist practitioners in this respect has previously been described.1 This model (figure 1) provides a visual means for clinicians to represent modification of rehabilitation stimuli with regard to progression of a single exercise.



Figure 1 
A theoretical model to describe progressions and regressions for exercise rehabilitation.1



In brief, the model encourages clinicians to regress modifiable variables within an exercise (eg, sets, reps, speed) to facilitate effective introduction of external stimuli or a change of environment. While useful as a reference for clinicians on progression of single exercises, the original model is limited in its ability to describe progressions within a multidimensional rehabilitation programme. The model suggests that a patient must be able to fully execute each stage of an exercise progression before the reintroduction of previously learnt components. In practice, rehabilitation is rarely linear with many …
Abstract 1552: Integrative bioinformatics analyses of ChIP seq and RNA seq data reveals a complex regulatory landscape of NRF1 network involved in the pathogenesis of breast cancer
Authors: Jairo Ramos, Deodutta Roy
Journal: Cancer Research (2017)

Abstract The expression of redox sensitive transcription factor -nuclear respiratory factor 1 (NRF1) expression significantly correlates with histological grades and prognosis of breast cancer. However, the molecular mechanism by which NRF1 may contribute in the development of breast cancer is not clear. In this study we examined whether NRF1 is a molecular risk factor of breast cancer. We also identified regulatory landscape of NRF1 network involved in the pathogenesis of breast cancer. Steps followed for the investigation included the selection of mRNA microarray dataset from TCGA and Metabric, selection and analysis of ChIP-Seq datasets from different breast cancer cell lines to identify NRF1 target genes possibly involved in breast cancer through Molecular Pathway, Gene Ontology and statistical analysis. Analysis of mRNA expression in breast cancer patients showed that NRF1 was significantly overexpressed in breast cancer tissues compared to normal tissues. ChIP-Seq analysis of two different breast cancer cell line - MCF7 and T7D showed that there are more than 8,000 genes, which contain NRF1 binding DNA motif(s). The NRF1 binding to ChIP DNA sequences of target gene is cell context dependent. High percentage of known breast cancer (~50%) susceptibility genes are transcriptional targets of NRF1. Network analysis revealed that NRF1 regulates genes, which are key regulators of epithelial-mesenchymal transition (EMT), stemness, cell apoptosis, cell cycle regulation, chromosomal integrity, and DNA damage and repair. Furthermore, we observed that NRF1 regulates target genes of both breast cancer and cancer KEGG pathways. Many of the MicroRNAs involved in cancer and genes of signaling pathways involved in cancer initiation and progression such as MAPK, PI3K/AKT and Notch signaling are also transcriptional targets of NRF1. In summary, this study reveals a complex regulatory landscape of NRF1 network involved in the pathogenesis of breast cancer. Dysregulation of NRF1 signaling pathways may contribute in the development of breast cancer. Clinical confirmation of our study will have significant impact on our understanding of the role of NRF1 as a valuable biomarker for breast cancer diagnosis and prognosis and will provide strong rationale for the future studies to further develop NRF1 for breast cancer therapeutic target. This work was in part supported by a VA MERIT Review (VA BX001463) grant to DR. Citation Format: Jairo Ramos, Deodutta Roy. Integrative bioinformatics analyses of ChIP seq and RNA seq data reveals a complex regulatory landscape of NRF1 network involved in the pathogenesis of breast cancer [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 1552. doi:10.1158/1538-7445.AM2017-1552
Abstract 838: Effect of tumor treating fields on cell proliferation and synergistic antitumor efficacy in combination with ionizing radiation
Authors: Eun Ho Kim, Yunhui Jo, Jiwon Sung, Hyo Sook Song, Myonggeun Yoon
Journal: Cancer Research (2017)

Abstract Alternating electric fields at an intermediate frequency (100~300 kHz), called tumor treating fields (TTFs), are reported to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the presence of an antimitotic effect of TTFs has been widely reported, the efficacy of TTFs is still controversial issue among medical experts. To resolve this controversial issue, the comparison study between the effects of TTFs and the effect of other conventional cancer treatment techniques need to be carried out. In this study, experimental evidence of the synergistic antimitotic effect of TTFs in combination with ionizing radiation (IR) is reported. For these experiments, aggressive brain cancer cells, glioblastoma multiforme (GBM) cells (U373 and U87), were treated either with TTFs alone, with IR alone or with TTFs followed by ionizing radiation (IR). The percentages of cell apoptosis, DNA damage, and mitotic abnormalities were increased by the application of TTFs alone and its quantity was markedly increased when TTFs were combined with IR. Our results also suggested that radiotherapy together with TTFs may be clinically beneficial since the combination treatment seemed to synergistically suppress both cell migration and invasion, based on the inhibition of MMP-9 and vimentin. Citation Format: Eun Ho Kim, Yunhui Jo, Jiwon Sung, Hyo Sook Song, Myonggeun Yoon. Effect of tumor treating fields on cell proliferation and synergistic antitumor efficacy in combination with ionizing radiation [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 838. doi:10.1158/1538-7445.AM2017-838
Abstract 5011: Tumor associated macrophages promote malignant phenotypes of disseminated human gastric cancer cells in intraperitoneal cancer immune microenvironment
Authors: Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Tetsuya Kagawa, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2017)

Abstract Gastric cancer is the third leading cause of cancer-related death, and peritoneal dissemination is one of the most frequent site of recurrence. Although the role of tumor microenvironment is recognized, it is still unclear how intraperitoneal cancer-immune microenvironment contributes to peritoneal metastasis. Thus, we investigated the interaction between intraperitoneal cancer and immune cells, especially focusing on tumor-associated macrophages (TAM) in the peritoneal cavity. The peritoneal wash from gastric cancer patients was subjected to conventional cytology, flow cytometry, and immuno-fluorescent assay using antibodies against CD45 (leukocytes), CD14 (monocytes), CD80/163 (M1/M2 macrophages, respectively), in combination with genetically engineered cancer-imaging viral agent ‘TelomeScan’ which specifically expresses GFP in telomerase-positive cells. In cytology-positive samples, CD163-positive macrophages could be detected in approximately 70% of intraperitoneal macrophages with TelomeScan-positive cancer cells, while cytology negative samples contained few CD163-positive macrophages. In addition, peripheral blood mononuclear cells (PBMCs) from healthy volunteers were induced to differentiate into CD163-positive M2 macrophages (TAM-like macrophages), and co-cultured with gastric cancer cells to examine the effect on their malignant phenotype such as migration and invasion. We found that PBMCs-derived CD163-positive M2 macrophages significantly potentiated the ability of migration and invasion in gastric cancer cells. In case of existence of free cancer cells in peritoneal cavity, intraperitoneal macrophages appeared to differentiate into TAM and they potentially accelerate malignant phenotypes of gastric cancer cells. These results suggested that intraperitoneal cancer-immune microenvironment may play an important role to promote peritoneal disseminations in gastric cancer. Citation Format: Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Tetsuya Kagawa, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara. Tumor associated macrophages promote malignant phenotypes of disseminated human gastric cancer cells in intraperitoneal cancer immune microenvironment [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 5011. doi:10.1158/1538-7445.AM2017-5011
Abstract 68: Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models
Authors: Emily M. King, Ronit Mazor, Ira Pastan
Journal: Cancer Research (2017)

Abstract Recombinant immunotoxins (rITs) are composed of a tumor antigen-targeting antibody fragment fused to a portion of Pseudomonas exotoxin A. rITs have been effective in clinical trials for patients with hematologic malignancies. The CD22 targeting rIT Moxetumomab Pasudotox has achieved overall response rates of 86% and complete remission rates of 46% in patients with relapsed-refractory Hairy Cell Leukemia. However, the therapeutic efficacy of rITs against solid tumors is limited by their immunogenicity in immune-competent patients. In clinical trials to treat mesothelioma patients with SS1P, a rIT targeting mesothelin, 90% of patients developed neutralizing antibodies against SS1P after one cycle of treatment. When immunosuppressive chemotherapy and SS1P were combined, more cycles of rIT could be given and several patients with advanced chemo-refractory mesothelioma had striking tumor regressions. This implicates high therapeutic potential for rITs against solid tumors once immunogenicity is surmounted. Methotrexate (MTX) is a folate antagonist which interferes with purine biosynthesis, and is used to treat osteosarcomas and other cancers. MTX also interferes with T cell responses and is used to treat autoimmune diseases. Based on its immunosuppressive properties, Joly et al. demonstrated that low-dose MTX prevented the formation of ADAs against recombinant human alglucosidase alfa in mice in an antigen-specific manner. We hypothesized that MTX would similarly prevent the formation of ADAs against rITs in an antigen-specific manner. To test our hypotheses, mice were treated with the mesothelin-targeting rIT RG7787 with or without MTX given 0, 24, and 48 hours after RG7787 treatment. Serum was collected and anti-RG7787 ADAs were measured by direct ELISA. We found that six doses of RG7787 combined with low dose MTX (1 mg/kg) inhibited the formation of ADAs against RG7787. This inhibition was sustained through six challenges with RG7787 without additional MTX. Further, we found that immunization with RG7787 plus MTX induced RG7787-specific tolerance, and had no effect on the ADA response against a second protein, ovalbumin. We conclude that combination of MTX and RG7787 is effective at preventing primary immune responses in a durable, antigen-specific manner. We propose to combine this agent in immune-competent cancer patients receiving rIT therapy to prevent rIT immunogenicity. Citation Format: Emily M. King, Ronit Mazor, Ira Pastan. Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models [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 68. doi:10.1158/1538-7445.AM2017-68
Abstract 1220: Coordinated chemical-genetics approach identifies PTP4A3-mediated regulation of colon cancer cell migration and extracellular matrix interactions
Authors: Kelley E. McQueeney, Joseph M. Salamoun, Isabella K. Blanco, Paula Pekic, Jennifer Ahn, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo
Journal: Cancer Research (2017)

Abstract Aberrant regulation of protein phosphorylation is an exceedingly common driver of human cancers. It is notable that we understand much less about the role of protein tyrosine phosphatases in human malignancies compared to tyrosine kinases. The membrane-associated, intracellular, protein tyrosine PTP4A3 is highly overexpressed in multiple tumor types including colorectal cancer and has been associated with tumor metastases. We have, therefore, investigated the role of PTP4A3 in colon cancer migration and invasion. The Ptp4a3 gene was expunged from colon tumor cells derived from Ptp4a3flox/flox mice and the resulting cells exhibited impaired migration, invasion, and colony formation compared to the wildtype isogenic cells. We characterized a potent, selective, and noncompetitive small molecule inhibitor of PTP4A3, JMS-631-053, which also disrupted colon cancer cell migration, invasion, and colony formation. PTP4A3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. Expression of these extracellular matrix genes is mutually exclusive with PTP4A3 expression in tumors derived from patients with colorectal cancer. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support continued efforts to pharmacologically target PTP4A3 for cancer therapy. Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Isabella K. Blanco, Paula Pekic, Jennifer Ahn, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. Coordinated chemical-genetics approach identifies PTP4A3-mediated regulation of colon cancer cell migration and extracellular matrix interactions [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 1220. doi:10.1158/1538-7445.AM2017-1220