tbuckley/cabot-search huggingface dataset:
Abstract 675: The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication
Authors: Ho Jung An, Tae-Jung Kim, Young Jo Sa, Chang Suk Kang
Journal: Cancer Research (2017)

Abstract Introduction: The Hedgehog (Hh) signaling plays essential role in transcription regulation and embryonic development. In many cancers including lung cancer, it is related to carcinogenesis and poor prognosis. This signaling also mediates epithelial to mesenchymal transition (EMT) by paracrine mechanism in various diseases. We aim to study the interaction between Hedgehog and EMT pathway and its clinical implication in non-small cell lung cancer (NSCLC). Method: Total 271 cases of NSCLC who received surgical resection in Yeouido St. Mary’s Hospital between 1997 and 2011 were included. For immunohistochemical analysis of Hh and EMT related proteins, 4um sections were sliced from tissue microarray. Hh signaling proteins including Sonig hedgehog (Shh), Patched (Ptch), Smoothened (Smo), Glioma-associated oncogene (Gli-1) and Suppressor of fused (Sufu), and EMT associated molecules including E-cadherin and vimentin were analyzed. Staining intensity (IS) was estimated as follows 0 (no staining), +1 (weak), +2 (distinct), +3 (strong). Intensity score (IS) ≥1 was defined as positive. Medical record was retrospectively reviewed. The study was approved by the institutional review board the hospital. Result: The median age was 63 (18-84) years, and 65.3% were male. Squamous cell carcinoma was diagnosed in 113 (41.7%), adenocarcinoma in 153 (56.5%), and mixed type in 153 (56.5%). Stage 1 and 2 were 46.9% and 30.6%, respectively, and 8 cases had distant metastasis. The Hh proteins showed positive correlation each other. For EMT, the expressions of Hh protein was significantly correlated with tumoral and stromal positivity of vimentin, and inversely with positivity of E-cadherin (P = 0.002 and P = 0.028, respectively). The expression of Hh proteins were significantly associated with lymph node metastasis along with large tumor size (P = 0.021 and P = 0.035, respectively). In survival analysis, expressions of Shh and Gli1 were independent predictor of disease free survival and cancer-specific survival (P = 0.007 and P = 0.025, respectively). Conclusion: Expression of Hh protein is associated with epithelial-mesenchymal transition and associated with poor prognosis in NSCLC. Citation Format: Ho Jung An, Tae-Jung Kim, Young Jo Sa, Chang Suk Kang. The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication [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 675. doi:10.1158/1538-7445.AM2017-675
Allografting for indolent lymphoid neoplasms
Authors: C.L. Toze, J.D. Shepherd, J.M. Connors, N.J. Voss, R.D. Gascoyne, D.E. Hogge, H.G. Klingemann, S.H. Nantel, T.J. Nevill, G.L. Phillips, D.E. Reece, H.J. Sutherland, E.A. Conneally, M.J. Barnett
Journal: Annals of Oncology (2000)
Abstract 4001: Infiltration of neutrophils in the tumor was associated with poor prognosis of patients with gastric cancer
Authors: Hiroaki Tanaka, Soichiro Hiramatsu, Tatsuro Tamura, Hisashi Nagahara, Kenjiro Kimura, Masatsune Shibutani, Go Ohira, Takahiro Toyokawa, Sadaaki Yamazoe, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2017)

Abstract Background:Recent evidence shows that neutrophils often migrate into the tumor and are associated with tumor progression. These tumor associated neutrophils (TANs) neutrophils have potential to induce angiogenesis, lymphangiogensesis and immunosuppression by inhibiting cytotoxic T lymphocytes. Immune status is one of the important prognostic factor of gastric cancer. We previously reported that lymphangiogenesis was augmented in the primary tumor of gastric carcinoma. Aim:The aim of this study was to investigate the correlation between CD15+ TANs and clinicopatological features of patients with gastric cancer. Materials and Methods: We investigated the association of the density of TANs in primary tumor with clinicopathological features by immunohistochemistry. We used specimens from a total of 143 primary tumor and 497 lymph nodes from 120 patients underwent gastrectomy between 2007 and 2008 in our department. We examined prognostic value of TANs identified as positive CD15 cells in both of the primary tumor and tumor draining lymph nodes. Results:The median number of TANs in primary tumor and tumor draining lymph nodes were 18.4 and 23 cells/HPF, respectively. High TANs in both of the primary tumor and lymph nodes had correlation with depth of invasion (primary tumor P&amp;lt;0.001, lymph nodes P=0.036) and lymph nodes metastasis (primary tumor P&amp;lt;0.001, lymph nodes P=0.002). Kaplan-Meier analysis showed that patients with high TANs in both primary tumor and lymph nodes had worse prognosis than patients with a low TANs (primary tumor P=0.031, lymph nodes P=0.014). Multivariate analysis revealed that high TANs in lymph nodes were independent prognostic factors. (P=0.038) Conclusion: Our results showed that patients with high CD15+TANs infiltration in gastric cancer tissues had poorer prognosis because of increasing lymph nodes metastasis. These findings suggested the TANs might have important role of tumor lymphangiogenesis in microenvironment of gastric carcinoma. Citation Format: Hiroaki Tanaka, Soichiro Hiramatsu, Tatsuro Tamura, Hisashi Nagahara, Kenjiro Kimura, Masatsune Shibutani, Go Ohira, Takahiro Toyokawa, Sadaaki Yamazoe, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Infiltration of neutrophils in the tumor was associated with poor prognosis of patients with gastric 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 4001. doi:10.1158/1538-7445.AM2017-4001
Abstract 1880: Bulk lung cancer cell migration is more common than single cell migration and regulated by different genes
Authors: Helmut H. Popper, Sylvia Eidenhammer
Journal: Cancer Research (2017)

Abstract Introduction: There are two different forms how tumor cells migrate: single cell or small cell cluster movement as it is seen in small cell carcinoma, and movement by large clusters of organized cells as seen most often in adenocarcinoma or squamous cell carcinoma. This latter migration form is not understood. Drosophila border cells forming wings migrate in large cell complexes similar to what is seen in the carcinomas and the genes identified in these cells might regulate the same process in carcinomas. Methods: 30 cases of pulmonary squamous cell and adenocarcinomas were selected based on the identification of large tumor cell clusters visible within the stroma as well as in blood vessels. Immunohistochemistry was done for receptor of activated C kinase (Rack1), brinker (brk), mother against dpp (mad), and saxophone (sax), proteins shown to be responsible for bulk cell movement in drosophila development. In addition immunohistochemistry was also done for Src-kinase, Twist, Snail, and TGFβ1 Tyrosine kinase substrate 5 (Tks5), E-cadherin, SARI (suppressor of AP-1), and vimentin, all known to be associated with epithelial-to-mesenchymal transition (EMT) and formation of invadopodia. Results and Conclusion: Most well differentiated pulmonary carcinomas migrate in large cell clusters, for example acinar adenocarcinomas form nicely structured acini deep within the stroma and even within blood vessels. These carcinomas do not undergo classical EMT. Proteins expressed by the four genes (Rack1, brk, mad, and sax) associated with border cell movement in drosophila could also be identified in pulmonary carcinomas and might coordinate bulk cell movement. Other members of TGF-beta signaling cascade were identified. Inhibition of Src by Rack1 may be important for border cell migration and cluster cohesion maintenance. Proteins usually seen in single tumor cell migration, such as vimentin (a sign of EMT) could not be proven in the tumor cell clusters. Findings of this study show that similar mechanisms are working in pulmonary carcinomas and that bulk cell migration is probably another way of metastasis. Further investigation using cell culture system and genetically designed adenocarcinomas expressing these genes should prove our findings and contribute in understanding migration of carcinoma bulk complexes. Citation Format: Helmut H. Popper, Sylvia Eidenhammer. Bulk lung cancer cell migration is more common than single cell migration and regulated by different 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 1880. doi:10.1158/1538-7445.AM2017-1880
Abstract 437: Stromal support of pancreatic tumor metabolism
Authors: Costas A. Lyssiotis
Journal: Cancer Research (2017)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive disease characterized by a prominent desmoplastic stromal reaction and deregulated metabolism. The role of stroma in PDAC biology is complex and has been shown to play critical roles that may differ depending on the biological context. The intense stromal reaction also impacts the vasculature, leading to a highly hypoxic and nutrient poor environment. As such, these tumors must adapt how nutrients are captured and utilized to support their metabolic needs. In this talk, I will describe how stromal-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncovered an undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel sources decreases the dependence on glucose and serum-derived nutrients, which are limiting in the pancreatic tumor microenvironment. Moreover, we demonstrated that PSC alanine secretion is dependent on PSC autophagy, a process stimulated by the cancer cells. Thus, our results demonstrate a novel metabolic crosstalk between PSCs and cancer cells, with PSC-derived alanine as an alternative carbon source, and highlight a previously unappreciated metabolic network within pancreatic tumors where diverse fuel sources are utilized to promote growth in an austere tumor microenvironment. Citation Format: Costas A. Lyssiotis. Stromal support of pancreatic tumor metabolism [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 437. doi:10.1158/1538-7445.AM2017-437
Abstract 2239: Establishment of lung cancer CTCs competent for lung metastasis
Authors: Zujun Que, Bin Luo, Qihui Shi, Jianhui Tian
Journal: Cancer Research (2017)

Abstract Circulating tumor cells (CTCs) have been implicated as a population of cells that may seed metastasis, which led to the 90% of dead in cancer patients. Though the detection technologies has been developing swiftly, how to culture the cells successfully and established a permanent cell line are the bottleneck in the research of metastasis mechanism. Here, we report, for the first time, the establishment of permanent cell line from CTCs of one Non-small cell lung cancer patient and identifying the biological characterization. The cell line designated CTC-0430 has been cultured for more than one and half years, and the cells have been characterized at the genome, proliferation, drug resistance, the expression of surface marker, cytokine secretion level and the characterization of tumor formation in vivo by immunohistochemisty and immunofluorescence. This thorough analysis showed that CTC-0430 cells display a stable phenotype characterized by an intermediate epithelial/mesenchymal phenotype, stem-cell like properties and the drug sensitivity test indicating stronger drug resistance compared to A549 and 95-D. When compare with A549 and 95-D cells, CTC-0430 cells high expression of ICAM-1 and ICAM-3, low expression of CX3CL1 and CXCL1. Functional studies showed that CTC-0430 cells induced rapidly in vivo tumors after subcutaneous transplantation in immunodeficient mice, and the lung metastasis were found after six months later. Besides, three months after we injected the cells into the caudal vein of NOD/SCID mice, the lung metastasis were formed. And then the metastasis lung tissue were used to make IHC and IF, which indicated that the biological characterizations of this cell line are different from A549. The establishment stable cell line of lung cancer CTCs can provide in vivo research platform for the intervention study of postoperative metastasis of lung cancer. Citation Format: Zujun Que, Bin Luo, Qihui Shi, Jianhui Tian. Establishment of lung cancer CTCs competent for lung 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 2239. doi:10.1158/1538-7445.AM2017-2239
Use of Adjuvant Pharmacotherapy in Type 1 Diabetes: International Comparison of 49,996 Individuals in the Prospective Diabetes Follow-up and T1D Exchange Registries
Authors: Sarah K. Lyons, Julia M. Hermann, Kellee M. Miller, Sabine E. Hofer, Nicole C. Foster, Birgit M. Rami-Merhar, Grazia Aleppo, Jochen Seufert, Linda A. DiMeglio, Thomas Danne, David M. Maahs, Reinhard W. Holl
Journal: Diabetes Care (2017)

The majority of those with type 1 diabetes (T1D) have suboptimal glycemic control (1–4); therefore, use of adjunctive pharmacotherapy to improve control has been of clinical interest. While noninsulin medications approved for type 2 diabetes have been reported in T1D research and clinical practice (5), little is known about their frequency of use. The T1D Exchange (T1DX) registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria are two large consortia of diabetes centers; thus, they provide a rich data set to address this question.

For the analysis, 49,996 pediatric and adult patients with diabetes duration ≥1 year and a registry update from 1 April 2015 to 1 July 2016 were included (19,298 individuals from 73 T1DX sites and 30,698 individuals from 354 DPV sites). Adjuvant medication use (metformin, glucagon-like peptide 1 [GLP-1] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT2] inhibitors, and other noninsulin diabetes medications including pramlintide) was extracted from …
Abstract 3290: Cancer mortality by antiarrhythmic drug use in a population-based cohort of Finnish men
Authors: Kalle J. Kaapu, Teemu Murtola, Kirsi Talala, Kimmo Taari, Teuvo Tammela, Anssi Auvinen
Journal: Cancer Research (2017)

Abstract Introduction: In-vitro studies have suggested that antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. A non-selective beta-blocker sotalol has similar effect on K+-channels. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. Materials and methods: The study population consists of 78,615 men originally identified for the Finnish Randomized Study for Screening of Prostate Cancer. Men were 55-69 years old at baseline. Prevalent prostate cancer cases were excluded; no exclusions were made based on other cancer types. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used Cox regression method to analyze the overall cancer mortality and individually mortality from the most common causes of cancer death. Results: A total of 8,064 men (10.3%) had used antiarrhythmic drugs. Of these 5,668 had used digoxin and 2,540 had used sotalol. During the median follow-up of 16.9 years after baseline 26,790 (34.1%) men died, of these 8,225 (30.7% of deaths) due to cancer. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.25, 95% CI 1.12-1.40). Similar results were observed for digoxin (HR 1.44, 95% CI 1.26-1.63) but not for sotalol (HR 0.92, 95% CI 0.68-1.24). Furthermore, the antiarrhythmic drug use was associated with elevated risk of lung-cancer death (HR 1.76 95% CI 1.46-2.14). However, the risk associations disappeared in long-term use. When we restricted the analysis to cancer cases only, no differences were observed in survival after the cancer diagnosis for any cancer type. Conclusion: Cancer mortality was elevated among users of antiarrhythmic drugs compared to non-users. This association is probably due to the differences between users and non-users as it was related to short-term use, and disappeared in long-term use. Use of digoxin or sotalol was not associated with improved cancer-specific survival. Citation Format: Kalle J. Kaapu, Teemu Murtola, Kirsi Talala, Kimmo Taari, Teuvo Tammela, Anssi Auvinen. Cancer mortality by antiarrhythmic drug use in a population-based cohort of Finnish men [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 3290. doi:10.1158/1538-7445.AM2017-3290
Abstract 5544: New technologies to probe the systems glycobiology of cancer
Authors: Pauline M. Rudd, Mark Hilliard, Mohankumar Muniyappa, Roisin O'Flaherty, Radka Saldova
Journal: Cancer Research (2017)

Abstract A robotic 384 well based platform was developed to release and label the human serum N-glycome. Improved separation of the glycan pool, based on hydrophilic interaction UPLC chromatography combined with mass spectrometry (Waters Corporation) and computer assisted data interpretation (NIBRT Glycobase) enabled us to build a database after assigning the detailed structures of more than 170 N-glycans. The aim of the project was to use these technologies and databases to link glycosylation changes in individual patients’ serum with features of cancer and with changes in a range of other –omics data acquired from the same patients. Alterations in glycosylation in various breast cancers were mapped to changes in the serum glycomes and aligned with genetic, transcriptomic and proteomic data. Pathway analysis showed strong associations between these glycan changes and the –omics data. This revealed that many of the glycan changes are directly associated with pathways involved in cancer metastasis. Our next aim was to demonstrate the feasibility of collecting personalised data from individual patients from each of the –omics analyses to build up a dataset of the changing glycosylation over time. This opens up the possibility of linking these data to explore pathways of disease and, in particular, nodal points where the patient can no longer compensate for the effects of an altered pathway that is leading to disease. To this end, single glycoproteins from 8 controls and 26 ovarian cancer patients were sequentially purified from 5ul of serum on affinity plates and the released glycans were analysed. Rather than the conventional way of looking at markers which compare a patients’ data with averages, the control can now be the blood of the patient themselves taken at an earlier time point. The automation, sensitivity, quantitation and resolution of the new technology platforms coupled with dedicated software open up new possibilities for precision medicine and early intervention based on the biochemical profile of the patient. References: Association of N-glycosylation with breast carcinoma and systemic features using high-resolution quantitative UPLC. Saldova R, Asadi Shehni A, Haakensen VD, Steinfeld I, Hilliard M, Kifer I, Helland A, Yakhini Z, Børresen-Dale AL, Rudd PM. J Proteome Res. 2014 May 2;13(5):2314-27. Serum N-glycan analysis in breast cancer patients–Relation to tumour biology and clinical outcome. Haakensen VD, Steinfeld I, Saldova R, Shehni AA, Kifer I, Naume B, Rudd PM, Børresen-Dale AL,Yakhini Z. Mol Oncol. 2016 Jan;10(1):59-72. Citation Format: Pauline M. Rudd, Mark Hilliard, Mohankumar Muniyappa, Roisin O'Flaherty, Radka Saldova. New technologies to probe the systems glycobiology of 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 5544. doi:10.1158/1538-7445.AM2017-5544
Abstract 4198: Highly potent and selective DNA-PK inhibitor M3814 with sustainable anti-tumor activity in combination with radiotherapy
Authors: Thomas Fuchss, Werner W. Mederski, Ulrich Emde, Hans-Peter Buchstallter, Frank Zenke, Astrid Zimmermann, Christian Sirrenberg, Lubo Vassilev, Lars Damstrup, Klaus Urbahns, Andree Blaukat
Journal: Cancer Research (2017)

Abstract Physical or chemical agents that damage DNA such as ionizing radiation are among the most widely used classes of cancer therapeutics today. Double strand breaks (dsb) generated in DNA by radiation induce a multitude of cellular responses, including DNA repair, cell cycle arrest or cell death once the damage is left unrepaired. A complex set of molecular events are responsible for DNA repair mediated by two major repair mechanisms - homologous recombination (HR) or non-homologous end joining (NHEJ). DNA-PKcs together with its regulatory protein subunits Ku70 &amp; Ku80, is an integral component of the NHEJ process and considered an attractive intervention point to inhibit DNA dsb repair. We have developed an orally bioavailable, highly potent &amp; selective inhibitor of DNA-PK, M3814, for cancer therapy in combination with DNA damaging modalities such as radiation &amp; radio-chemotherapy. Here, we present the optimization of initial hit matter &amp; its structure-activity relationships leading to M3814, its chemical structure (first-time disclosure) &amp; preclinical characterization using biochemical, cellular &amp; human tumor xenograft models. M3814 sensitized multiple tumor cell lines to radiation therapy in vitro and strongly enhanced the anti-tumor activity of ionizing radiation in vivo with complete tumor regression by applying a clinically relevant fractionated radiation regimen. These effects are due to inhibition of DNA-PK protein kinase activity as demonstrated by the levels of DNA-PK autophosphorylation in human tumor cell lines &amp; xenograft tumors. M3814 is currently being investigated in PhI/II clinical trials. Citation Format: Thomas Fuchss, Werner W. Mederski, Ulrich Emde, Hans-Peter Buchstallter, Frank Zenke, Astrid Zimmermann, Christian Sirrenberg, Lubo Vassilev, Lars Damstrup, Klaus Urbahns, Andree Blaukat. Highly potent and selective DNA-PK inhibitor M3814 with sustainable anti-tumor activity in combination with radiotherapy [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 4198. doi:10.1158/1538-7445.AM2017-4198