tbuckley/cabot-search huggingface dataset:
Abstract 1098: Delta-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem cells
Authors: Kazim Husain, Said M. Sebti, Mokenge P. Malafa
Journal: Cancer Research (2017)

Abstract Background: Pancreatic cancer, a lethal malignancy is the fourth leading cause of cancer-related deaths in the United States. The standard chemotherapy with gemcitabine is ineffective in patients with metastatic tumors. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the chemosensitization of pancreatic tumor metastasis by δ-tocotrienol to gemcitabine in vitro as well as in vivo. Methods: In vitro human metastatic pancreatic cancer cells L3.6pl and pancreatic cancer stem cells (PCSC) were treated with gemcitabine (5 μM) and δ-tocotrienol (50 μM) alone and in combination. Treated cells used for epithelial to mesenchymal transition (EMT), migration/invasion, microsphere/spheroid, and signaling markers assays. PCSC expressing luciferase was orthotopically implanted into pancreas of Athymic nude mice (n = 20) and after one week they were randomized into four groups: 1) vehicle control (ethanol extracted olive oil), 2) gemcitabine (100 mg/kg, IP, twice a week), 3) δ-tocotrienol (200 mg/kg, orally twice a day) and 4) gemcitabine + δ-tocotrienol. The treatment was continued for 4 weeks. The tumor volume, tumor weight, metastasis were recorded. Results: Gemcitabine slightly inhibited the growth, migration/invasion of L3.6pl and PCSC in vitro and PCSC tumor growth (tumor volume and weight) in vivo. δ-tocotrienol significantly inhibited the growth, microsphere/spheroid, migration/invasion, EMT(E-cadherin to vimentin), angiogenesis (VEGF), PCSC transcription factors (Nanog, Oct4, and Sox2), tumor growth and liver/lung metastasis compared to control. The combination of both drugs synergistically inhibited the cancer and stem cell growth, EMT, migration/invasion, microsphere/spheroid, metastasis, angiogenesis, and PCSC transcription factors in vitro as well as in vivo. Conclusion: Vitamin E δ-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell self-renewal, tumor growth and metastasis. Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Delta-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem 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 1098. doi:10.1158/1538-7445.AM2017-1098
Abstract 3829: TCIRG1, T-cell immune regulator 1, functions as a metastatic enhancing gene in liver tumorigenesis
Authors: Hee Doo Yang, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Sang Yean Kim, Suk Woo Nam
Journal: Cancer Research (2017)

Abstract Recurrence and metastasis are a major challenge in the management of hepatocellular carcinoma (HCC) patients after HCC resection. In order to identify metastatic molecular signature, we performed comparative gene expression profiling analysis with recurred HCC tissues from HCC patients who underwent partial or total hepatectomy and non-metastatic primary HCC. From this, we were able to recapitulate molecular signatures associate with HCC recurrence, and found that TCIRG1 (T-Cell Immune Regulator 1) was one of the aberrantly overexpressed gene elements in recurred HCC patients with total hepatectomy. We then observed that TCIRG1 is significantly overexpressed in TCGA-LIHC (Liver Hepatocellular Carcinoma Dataset of The Cancer Genome Atlas), and high expression of TCIRG1 was significantly associated with poor prognosis of HCC patients in 5-year disease-free. TCIRG1 knockdown suppressed tumor cell growth and proliferation in Huh7 and SNU475, liver cancer cell lines. From flow cytometric analysis for cell cycle analysis and cell death, we observed that TCIRG1 knockdown caused a significant increase of G1/S phase, and also induced programmed cell death processing in liver cancer cells. TCIRG1 knockdown also reduced the metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins, E-cadherin, N-cadherin, Vimentin, Fibronectin, Snail and Slug, in liver cancer cells. In addition, sustained expression of TCIRG1 in liver cancer cell line reduced tumor growth rate in mouse xenograft model. Moreover, targeted-disruption of TCIRG1 significantly attenuated the metastatic potential of ras-transformed NIH-3T3 cells in vitro and in vivo. In conclusion, our findings suggest that TCIRG1 functions as metastatic enhancing gene by modulating cellular growth, death, and EMT in liver cancer cells providing TCIRG1 as a therapeutic target for the treatment of liver malignancy and metastasis. Citation Format: Hee Doo Yang, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Sang Yean Kim, Suk Woo Nam. TCIRG1, T-cell immune regulator 1, functions as a metastatic enhancing gene in liver tumorigenesis [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 3829. doi:10.1158/1538-7445.AM2017-3829
Abstract 3188: ER-stress induced translational regulation by RGS2 leads to tumor-promoting microenvironment and chemoresistance
Authors: Hye-Young Min, Shin-Hyung Park, Ho Jin Lee, Jaebeom Cho, Myungkyung Noh, Seung Yeob Hyun, Ho-Young Lee
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of the cancer-related death worldwide. Despite extensive efforts for the cure of lung cancer, the effectiveness of currently available therapeutic regimens has been marginal and limited, and recurrence is still an inevitable consequence of anticancer therapies. Therefore, mechanistic understanding on the progression and relapse of lung cancer and finding out relevant targets are essential for development of efficacious therapeutic strategies. We have investigated mechanisms of chemoresistance by using subsets of lung cancer cell lines carrying acquired resistance to chemotherapies. These chemoresistant sublines of NSCLC cells exhibited a prominent downregulation of in vitro tumor activities, including proliferation, metabolism, and protein synthesis, but displayed increased tumor growth in vivo. Additional studies revealed that the chemoresistant sublines experienced increased secretion of various soluble factors that led to increases in proliferation and stemness of drug-naïve cancer cells and recruitment of macrophages, establishing tumor microenvironment (TME) prone to tumor recurrence. We further demonstrate a pivotal role of regulator of G protein signaling 2 (RGS2) in tumor-promoting cell-cell communications, ultimately leading to chemoresistance. RGS2 disrupted chemotherapy-induced apoptosis and secretion of soluble factors involved in cellular communications in TME by regulating unfolded protein responses, a typical cellular event associated with downregulation of protein synthesis. Mechanistically, RGS2 induced proteasome-mediated protein degradation of a component of eukaryotic translation initiation factor complexes through direct interaction, resulting in blockade of the CAP-dependent protein translation. RGS2 expression was elevated in tumors derived from patients with lung cancer compared with normal counterparts and significantly associated with poor clinical outcomes. These findings suggest that RGS2 is a novel biomarker responsible for chemoresistance by establishing tumor-promoting TME and can be a potential therapeutic target for the treatment of lung cancer with chemoresistance. Citation Format: Hye-Young Min, Shin-Hyung Park, Ho Jin Lee, Jaebeom Cho, Myungkyung Noh, Seung Yeob Hyun, Ho-Young Lee. ER-stress induced translational regulation by RGS2 leads to tumor-promoting microenvironment and chemoresistance [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 3188. doi:10.1158/1538-7445.AM2017-3188
Abstract 3907: Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer models
Authors: Guillaume Vares, Yannick Saintigny, Sei Sai, Hirotaka Sugawara, Tetsuo Nakajima
Journal: Cancer Research (2017)

Abstract Remarkable progress has been made in the understanding and treatment of human cancer, resulting in greatly improved survival for many patients. However, such achievements remain incomplete or out of reach for some hard-to-treat cancers, such as pancreatic cancer or triple-negative breast cancer. Chondrosarcoma is resistant to conventional radiation therapy and to chemotherapy. Innovative approaches focusing on those challenging cancer models are therefore highly expected. There is now wide acknowledgment that tumors are generally heterogeneous and that cancer treatment failure, relapse or metastasis may be related a small population of stem-like cells that are capable of self-renewing and of causing the different lineage of cancer cells comprising a tumor. These cancer stem cells (CSCs) are more radio-resistant than their non-CSC counterparts and have a distinct molecular signature. CSCs and differentiated cancer cells seem to coexist in a dynamic equilibrium influenced by the micro-environment and by specific micro-RNA expression patterns. The development of new therapeutic strategies (such as micro-RNA modulating strategies) that selectively target CSCs is currently receiving increasing attention. Particle radiation therapy (such as carbon-ion therapy) is effective at treating various radioresistant tumors and has already achieved promising results. Approaches combining high-LET radiation therapy and targeted-therapy have been suggested for tumors with bad prognosis.We have described a new molecular pathway in basal-like breast cells, resulting in the generation of breast CSCs. Maintenance of the CSC phenotype required the downregulation of miR-29 expression and the upregulation of Klf4 expression. Restoring miR-29 with mimic administration might therefore improve breast cancer therapy efficiency by targeting CSCs. For those reasons, we have evaluated the ability of several microRNA-modulating treatments to reverse CSC phenotype in three experimental in vitro models (pancreatic cancer, chondrosarcoma, triple-negative breast cancer), in combination with exposure spread-out Bragg peak (SOBP) carbon-ion beam (at the HIMAC medical accelerator). In triple-negative breast cells, miR-29 mimic administration increased radiation-induced cell death and decreased the proportion of CSCs. We identified several other microRNA mimic treatments capable of improving carbon-ion therapy efficiency by targeting radioresistant CSCs in those experimental models. Citation Format: Guillaume Vares, Yannick Saintigny, Sei Sai, Hirotaka Sugawara, Tetsuo Nakajima. Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer 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 3907. doi:10.1158/1538-7445.AM2017-3907
Abstract 4832: Establishment of lung cancer organoid lines as a new preclinical model for lung cancer
Authors: Minsuh Kim, Sung-Min Chun, Hyemin Mun, Young-Ah Suh, Se jin Jang
Journal: Cancer Research (2017)

Abstract Human cancers are composed of genetically and phenotypically heterogeneous subpopulations organized into a hierarchy of tumor initiating stem cells and various differentiated tumor cell. Cancer organoids seem to be more suitable in vitro models for targeting tumor heterogeneity than cell lines. We established cancer organoid lines from lung cancer patient tissues, recapitulating histology of human cancers in three dimensional culture conditions. Thirteen organoid lines from various lung cancer subtypes including adenocarcinoma, squamous cell carcinoma and small cell carcinoma were compared with their original human tumors in histologic features and genetic profiles. In the IHC staining, it revealed that organoids of adenocarcinomas have typical glandulo-papillary structures or mucin-containing tumor cells. Organoids of squamous cell carcinomas showed keratinization and intercellular bridges. Organoids of small cell carcinoma displayed typical neuroendocrine morphology. Using NGS cancer panel sequencing, the organoid lines maintained genetic characteristics of the original human tumors in major driver genes including EGFR, TP53, and RB mutation. In xenograft experiments, the organoid lines revealed stronger tumorigenesity than direct graft of human tumor tissues. Cancer organoids showed resistance to various anticancer drug treatments. In conclusion, our lung cancer organoid lines are alternative cancer model for preclinical researches recapitulating genotypic and phenotypic heterogeneity of original human tumors. Note: This abstract was not presented at the meeting. Citation Format: Minsuh Kim, Sung-Min Chun, Hyemin Mun, Young-Ah Suh, Se jin Jang. Establishment of lung cancer organoid lines as a new preclinical model for lung 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 4832. doi:10.1158/1538-7445.AM2017-4832
Abstract CT134: Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
Authors: Glen J. Weiss, Jordan Waypa, Jessica Coats, Lisa Blaydorn, Kayla McGahey, Ashish Sangal, Robert P. Whitehead, Vivek Khemka
Journal: Cancer Research (2017)

Abstract Background: Pembrolizumab (P) is a checkpoint inhibitor that blocks the interaction between programmed cell death protein 1 on T-cells and PD-L1 and PD-L2 on tumor cells. We conducted a single center phase Ib/II study of gemcitabine, nab-paclitaxel, and P (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) (NCT02331251). Methods: PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% were eligible and received gemcitabine and nab-paclitaxel on days 1 and 8 and P 2 mg/kg on day 1 every 21 days until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Results: 17 pts with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Any grade drug-related treatment adverse events (AEs) occurred in 100% of patients; the most common (&amp;gt;20% pts) were anemia, thrombocytopenia, hypoalbuminemia, ALT and ALK elevation, fatigue, rash, nausea, vomiting, diarrhea, fever, insomnia, and edema in limbs. Grade 3 events (&amp;gt;10% pts) were hyponatremia, thrombocytopenia, and neutropenia (2 case each, 11.8%). Dose-limiting toxicities occurred only in previously treated PDAC (grade 3 thrombocytopenia; grade 3 fatigue and thrombocytopenia) and the cohort was subsequently divided into chemo naïve and previously treated pts. The recommended phase II dose (RP2D) for chemo naïve PDAC was gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. Of the 8 evaluable chemo naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 2 PR on treatment for ~11 and 15 months and there are 3 pts still too early to assess. The primary endpoint of &amp;gt;15% complete response was not met. The best response for previously treated pts was SD. For chemo naïve and previously treated PDAC, the 6-month survival rate is 89% (with 3 pts still on study less than 3 months) and 40%, respectively. The median PFS and OS is 5 and 10.3 months and 2.1 and 4.1 months for chemo naïve and previously treated pts, respectively. Conclusions: GNP can be safely given to chemo naïve PDAC pts. Efficacy appears to be similar to slightly improved over previously reported results for standard weekly x 3 every 28 day gemcitabine and nab-paclitaxel dosing. Citation Format: Glen J. Weiss, Jordan Waypa, Jessica Coats, Lisa Blaydorn, Kayla McGahey, Ashish Sangal, Robert P. Whitehead, Vivek Khemka. Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma [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 CT134. doi:10.1158/1538-7445.AM2017-CT134
Abstract 3310: Atg7 overexpression promotes bladder cancer invasion <i>via</i> autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability <i>in vitro</i> and <i>in vivo</i>
Authors: Junlan Zhu, Yang Li, Chuanshu Huang, Haishan Huang
Journal: Cancer Research (2017)

Abstract Autophagy is the basic catabolic mechanism regulating degradation of unnecessary or dysfunctional cellular components and is regulated by the autophagy-related gene 7 (Atg7). Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is of tremendous importance for potentially reducing the mortality of this disease. In the present study, we for the first time found that the Atg7 was remarkably upregulated in human BC cell lines and the BBN-induced mouse invasive BCs, which is consistent with our most recent finding in human BCs. The knockdown of Atg7 in human BC cells dramatically inhibited cancer cell invasion, suggesting that Atg7 is a key player in regulation of BC invasion. Mechanistic studies revealed that Atg7 overexpression was mediated by miR-190, which was highly upregulated at transcriptional level in BC tissues and cell lines, and was able to bind to 3’-UTR of atg7 mRNA for its stabilization. Moreover, Atg7-mediated autophagic mechanism could remove AUF1 protein and in turn reduced AUF1 interaction with rhogdi2 mRNA, resulting in elevation of rhogdi2 mRNA stability, and subsequently leading to BC cell invasion. Remarkably, inhibition of Atg7-mediated autophagy led to AUF1 protein accumulation, RhoGDI2 downregulation and BC cell invasion attenuation. Collectively, our results demonstrate that overexpressed Atg7 mediates BC cell autophagy, which removes AUF1 protein, thereby reducing its binding with rhogdi2 mRNA and subsequently leading to elevation of rhogdi2 mRNA stability and protein expression, further promoting BC invasion. The identification of miR-190/Atg7 autophagic mechanism regulating AUF1/RhoGDI2 expression provides a significant insight into understanding the nature of BC invasion, and is also highly potential for developing autophagy-based-specific therapeutic strategy for treatment of human BC patients. Citation Format: Junlan Zhu, Yang Li, Chuanshu Huang, Haishan Huang. Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo [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 3310. doi:10.1158/1538-7445.AM2017-3310
An introduction to patient decision aids
Journal: BMJ (2013)

Patient decision aids are a means of helping people make informed choices about healthcare that take into account their personal values and preferences. Decision aids are a part of a shared decision making process, encouraging active participation by patients in healthcare decisions.1 2 Decision aids are relevant in many common healthcare decisions. They have been developed to make it easier for patients and healthcare professionals to discuss treatment options. Here, we give an overview of the rationale for the use of patient decision aids, what they contain, the evidence of their efficacy, and examples of their current and potential uses.

Shared decision making is a process in which clinicians and patients work together to decide about interventions based on clinical evidence and the patient’s informed preferences.2 It involves the provision of evidence based information about options, benefits, risks, and uncertainties, together with decision support counselling and a system for recording and implementing patients’ informed preferences. There is evidence that patients want to take part in decision making. A recent systematic review of peer reviewed journal articles found that, in 63% of articles most patients expressed a wish to actively participate in decisions around their treatment.3 Also, the wish to participate appears to have increased over time. In studies published before 2000, only around 50% of articles found that most patients wished to be active partners in their treatment decisions, whereas from 2000, the percentage rose to 71%.3 This was especially clear for cancer patients, where most patients in 85% of the 27 studies published since 2000 wished to be involved in treatment decisions. However, patients’ preferences for involvement in decision making are variable and are affected by factors such as age, sex, and education.4

Shared decision making is appropriate for many types of healthcare decisions, …