tbuckley/cabot-search huggingface dataset:
Abstract 3429: Evidence chronic inflammation is a risk factor for histiocytic sarcoma in Bernese mountain dogs - implications for human histiocytic sarcoma
Authors: Audrey Ruple-Czerniak, Paul S. Morley
Journal: Cancer Research (2016)

Abstract The purpose of this study was to evaluate exposure variables associated with development of histiocytic sarcoma (HS), a rare but aggressive malignancy, using the canine spontaneous tumor model. The domestic dog has been shown to be an excellent model to investigate risk of occurrence of complex diseases in humans, especially cancers. This is due in part to the limited genetic heterogeneity within specific dog breeds. HS, though rare in most breeds of dogs, is a common malignancy in Bernese mountain dogs (BMD) with up to 25% of the population of dogs being diagnosed with HS during their lifetime. The frequency of HS diagnosis in BMDs is thought to be due to a heritable mutation in a single gene region analogous to the human chromosome 9p21. For this study, owners of BMDs registered with a non-profit breed registry, the Berner-Garde Foundation, were recruited for participation in an internet-based cross-sectional survey. Data were collected for a total of 216 BMDs. Of the total population of BMDs enrolled in the study 118 dogs were sibling-sets representing a case and a non-case that originated from the same litter. Mixed effects logistic regression (MELR) and conditional logistic regression (CLR) were used in parallel to examine associations between potential risk factors and the occurrence of HS. When controlling for litter of origin (as a marker of relatedness), dogs diagnosed with orthopedic conditions were found to be more likely to develop HS (MELR, OR: 2.5, 95% CI: 1.5, 5.2; CLR, OR: 2.81, 95% CI: 1.1, 7.3), while dogs receiving prescription anti-inflammatory medications were found to be at a considerably lower risk of developing this disease (MELR, OR: 0.43, 95% CI: 0.2, 0.8; CLR, OR: 0.32, 95% CI: 0.1, 0.8). These data suggest inflammation may be a modifiable risk factor for the development of HS. Therefore, identification and treatment of conditions that promote inflammatory mechanisms may reduce future risk of developing HS in dogs and people. Results of logistic regression models examining risk factors associated with development of histiocyRisk factorCategoryOdds ratio (MELR), n = 21695% CIP-ValueOdds ratio (CLR), n = 11895% CIP-ValueOrthopedic conditionYes2.491.21, 5.140.0142.811.08, 7.260.034NoReferenceReferenceNon-prescription medication useYes2.101.05, 4.180.0362.881.04, 7.900.041NoReferenceReferenceLong-term prescription medication useYes0.430.22, 0.810.0100.320.12, 0.830.020NoReferenceReference Citation Format: Audrey Ruple-Czerniak, Paul S. Morley. Evidence chronic inflammation is a risk factor for histiocytic sarcoma in Bernese mountain dogs - implications for human histiocytic sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3429.
Resistant Hypertension: Diagnosis, Evaluation, and Treatment
Authors: David A. Calhoun, Daniel Jones, Stephen Textor, David C. Goff, Timothy P. Murphy, Robert D. Toto, Anthony White, William C. Cushman, William White, Domenic Sica, Keith Ferdinand, Thomas D. Giles, Bonita Falkner, Robert M. Carey
Journal: Circulation (2008)

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.
Abstract 110: Molecular profiling of Tudor domain-containing proteins identifies PHF20L1 as a candidate oncogene in breast cancer
Authors: Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Zeng-Quan Yang
Journal: Cancer Research (2016)

Abstract Tudor domain-containing proteins (TDRDs), which recognize and bind to methyl-lysine/arginine residues on histones and non-histone proteins, play critical roles in regulating chromatin architecture, transcription, genomic stability, and RNA metabolism. Dysregulation of several TDRDs have been observed in various types of cancer. However, neither the genomic landscape nor clinical significance of TDRDs in breast cancer has been explored comprehensively. Here, we performed an integrated genomic and transcriptomic analysis of 41 TDRD genes in breast cancer (TCGA and METABRIC datasets) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. Among seven TDRDs (PHF20L1, ARID4B, SETDB1, LBR, TDRKH, TDRD10, and TDRD5) that had the highest frequency (&amp;gt;10%) of gene amplification, the plant homeodomain finger protein 20-like 1 (PHF20L1) was the most commonly amplified (17.62%) TDRD gene in TCGA breast cancers. Different subtypes of breast cancer had different patterns of copy number and expression for each TDRD. Notably, amplification and overexpression of PHF20L1 were more prevalent in aggressive basal-like and Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. Furthermore, knockdown of PHF20L1 inhibited cell proliferation in PHF20L1-amplified breast cancer cell lines. PHF20L1 protein contains N-terminal Tudor and C-terminal plant homeodomain domains. Detailed characterization of PHF20L1 in breast cancer revealed that the Tudor domain likely plays a critical role in promoting cancer. Mechanistically, PHF20L1 might participate in regulating DNA methylation by stabilizing DNA methyltransferase 1 (DNMT1) protein in breast cancer. Thus, our results demonstrated the oncogenic potential of PHF20L1 and its association with poor prognostic parameters in breast cancer. Furthermore, our findings provide strong foundations for further research and therapeutic targeting of PHF20L1 or other TDRDs in breast cancer. Citation Format: Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Zeng-Quan Yang. Molecular profiling of Tudor domain-containing proteins identifies PHF20L1 as a candidate oncogene in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 110.
Abstract LB-038: Constitutive activation of mTORC1 in endothelial cells leads to the development and progression of lymphangiosarcoma through VEGF autocrine signaling
Authors: Shaogang Sun, Song Chen, Fei Liu, Haige Wu, Jonathan McHugh, Ingrid Bergin, Anita Gupta, Denise Adams, Jun-Lin Guan
Journal: Cancer Research (2016)

Abstract Angiosarcoma/ lymphangiosarcoma is a rare malignancy with poor prognosis, for which animal models with a defined molecular pathogenesis are lacking. Here, we generated a new mouse model with an inducible endothelial cell specific deletion of Tsc1 to examine the potential role of abnormal activation of mTORC1 signaling in lymphangiosarcoma. We found that loss of Tsc1 increased EC proliferation and retinal angiogenesis in neonates. In adult mice, Tsc1 deletion led to a spectrum of endothelial proliferative lesions, ranging from vascular malformations to vascular tumors. Studies using rapamycin indicated that sustained mTORC1 signaling is required for both the development and maintenance of lymphangiosarcomas. Further analysis showed increased VEGF expression through increased activity of HIF1α and c-Myc transcription factors in tumor cells, and that blockade of autocrine VEGF signaling decreased proliferation of these cells both in vitro and in vivo. Lastly, we found significant correlations between mTORC1 activation and expression of VEGF, HIF1α and c-Myc in human angiosarcoma samples. Together, these studies demonstrate critical mechanisms of aberrant mTORC1 activation in the development of lymphangiosarcoma, and validate Tsc1iΔEC mice as a valuable novel model of lymphangiosarcoma with known molecular underpinnings for further study. Citation Format: Shaogang Sun, Song Chen, Fei Liu, Haige Wu, Jonathan McHugh, Ingrid Bergin, Anita Gupta, Denise Adams, Jun-Lin Guan. Constitutive activation of mTORC1 in endothelial cells leads to the development and progression of lymphangiosarcoma through VEGF autocrine signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-038.
Nationwide genomic screening network for the development of novel targeted therapies in advanced non-small cell lung cancer (LC-SCRUM-Japan).
Authors: Shingo Matsumoto, Kiyotaka Yoh, Takashi Seto, Takuma Yokoyama, Haruyasu Murakami, Eiji Iwama, Shunichi Sugawara, Yuichiro Ohe, Koji Takeda, Makoto Nishio, Miyako Satouchi, Masato Shingyoji, Daijiro Harada, Takako Okuyama, Norio Okamoto, Takashi Kohno, Koji Tsuta, Genichiro Ishii, Katsuya Tsuchihara, Koichi Goto
Journal: Journal of Clinical Oncology (2015)

8093 Background: Various driver gene alterations have emerged as critical targets for molecular therapies in non-small cell lung cancer (NSCLC), but these alterations other than EGFR mutations occur in rare populations. A nationwide genomic screening network in Japan (LC-SCRUM-Japan) was established in February 2013 for the development of novel targeted therapies against advanced NSCLCs harboring these rare alterations. Methods: Advanced non-squamous NSCLCs without EGFR mutations were eligible for inclusion in LC-SCRUM-Japan. The tumors were analyzed for ALK/RET/ROS1 fusions using RT-PCR, and detected fusions were confirmed by FISH. Between November 2013 and March 2014, fusion-negative tumors were further examined for other driver gene mutations using a next-generation sequencing (NGS) system (Ion PGM with Ion Torrent AmpliSeq Cancer Hotspot Panel, version 2), enabling the simultaneous analysis of 50 cancer-related genes. Results: As of December 26, 2014, a total of 188 institutions across Japan were participating and 1347 patients had been enrolled in LC-SCRUM-Japan. Among 1271 available samples, ALK/RET/ROS1 fusions were detected in 24 (2%)/31 (3%)/55 (4%) cases, respectively. The NGS analysis was performed in 201 cases without the fusions, and 82 cases (41%) had driver mutations, including 45 KRAS mutations (22%), 10 BRAF mutations (5%), 9 ERBB2 mutations (4%), 2 PIK3CA mutations (1%), and 1 NRAS mutation (0.5%). MET and ERBB2 amplifications were also detected by the NGS in 4 (2%) and 2 (1%) cases, respectively. Among a total of 198 cases harboring targetable gene alterations, 16 with RET fusions, 26 with ROS1 fusions, and 2 with BRAF mutations were enrolled in clinical trials for vandetanib (LURET study, Japan), crizotinib (OO12-01, East Asia), and dabrafenib (BRF113928), respectively. Conclusions: This nationwide and population enrichment screening system enabled various rare driver gene alterations to be efficiently detected in advanced NSCLC, thereby contributing to the rapid accrual of matched patients in clinical trials for targeted therapies.
Abstract 1230: BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models
Authors: Zhiyu Tang, Yong Liu, Beibei Jiang, Yajuan Gao, Wenfeng Gong, Xing Wang, Dan Su, Fenglong Yu, Ye Liu, Min Wei, Lai Wang
Journal: Cancer Research (2016)

Abstract Liver cancer has the third highest mortality rate among all cancers in China and hepatocellular carcinoma (HCC) is the most common type of liver cancer. The mitogen-activated protein kinase (MAPK) signaling pathway is often constitutively active in HCC. The growth of HCC requires the formation of new blood vessels. and VEGF is critical in this process. Sorafenib, a multikinase inhibitor that targets both RAF and VEGF receptor, is to date the only approved drug to treat advanced stages of HCC. Despite sorafenib extended the survival in patients with HCC, its clinical benefits remain modest and drug resistance is common. BGB283 is a second generation RAF inhibitor with unique RAF dimer and VEGFR inhibition activity. Thus, there is good rationale to test BGB-283 in HCC. In this study, we compared the in vitro and in vivo activities of BGB-283 and sorafinib in human HCC cell lines and patient derived HCC xenograft models. In the biochemical assays, BGB-283 demonstrated great potency for BRAF-V600E, BRAF-WT, CRAF(IC50 = 32, 69 and 6.5 nM, respectively) and for VEGFR family enzymes, VEGFR1, VEGFR2 and VEGFR3 (IC50 = 25, 14 and 58 nM, respectively). In the cellular assays, the anti-proliferative effect of BGB-283 and sorafinib was evaluated in several HCC cell lines. A head-to-head comparison of in vivo anti-tumor activities of BGB-283 and sorafinib were also evaluated in human primary HCC xenograft mouse models. The patient derived xenograft (PDX) HCC models were established in house using HCC patient surgical samples. Sorafinib was not active in 2 out of 7 models. Oral administration of BGB-283 resulted in significant tumor growth inhibition in all 7 models and was significantly more efficacious than sorafinib in 4 models and similar in the other 3 models. In conclusion, BGB-283 is a unique RAF dimer inhibitor with VEGFR inhibition activity. BGB-283 has also demonstrated better anti-tumor activity than sorafinib in HCC PDX models, suggesting BGB-283 could be a promising drug candidate for treating HCC patients. Citation Format: Zhiyu Tang, Yong Liu, Beibei Jiang, Yajuan Gao, Wenfeng Gong, Xing Wang, Dan Su, Fenglong Yu, Ye Liu, Min Wei, Lai Wang. BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1230.
Abstract 4070: Carcinogen 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis is accelerated in Smad3 heterozygous mice compared to Smad3 wild type mice
Authors: Zhengxue Liu, Tanima R. Kundu, Isao Matsuura, Guannan Wang, Yong Lin, You-Rong Lou, Nicola J. Barnard, Xiao-Fan Wang, Mou-Tuan Huang, Nanjoo Suh, Fang Liu
Journal: Cancer Research (2016)

Abstract Smad3 plays an important role in inhibiting cell proliferation and promoting apoptosis. Previous studies based on cell culture and xenograft animal models suggest that Smad3 has tumor suppressor function for breast cancer during early stages of tumorigenesis. Here we show that DMBA (7,12-dimethylbenz[a]anthracene), a chemical carcinogen, induces mammary tumor formation at a significantly higher frequency in the Smad3 heterozygous mice than in the Smad3 wild type mice. This is the first genetic evidence showing that Smad3 inhibits mammary tumorigenesis in a mouse model. Our findings provide strong support that Smad3 has important tumor suppressor function for breast cancer. Citation Format: Zhengxue Liu, Tanima R. Kundu, Isao Matsuura, Guannan Wang, Yong Lin, You-Rong Lou, Nicola J. Barnard, Xiao-Fan Wang, Mou-Tuan Huang, Nanjoo Suh, Fang Liu. Carcinogen 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis is accelerated in Smad3 heterozygous mice compared to Smad3 wild type mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4070.
Abstract 2239: Isolation and characterization of circulating tumor cells (CTCs) in non small cell lung carcinoma
Authors: Marianna Scrima, Donatella Malanga, Carmela De Marco, Giuseppe Viglietto
Journal: Cancer Research (2016)

Abstract Purpose: Lung cancer is the most common cause of cancer-related deaths that frequently metastasizes prior to disease diagnosis. Circulating tumor cells (CTCs) are of great clinical interest in terms of prognosis and therapy intervention and may provide important prognostic and predictive information in non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate diagnostic performance of a non-invasive method based on filtration-based technology (ISET) using cytomorphologic criteria in patients undergoing surgery comparing with histologic features of corresponding primary lesions. Materials and Methods: The CTCs analysis was performed through the following steps: isolation by ISET filtration method (ScreenCell®) from 5 ml of peripheral blood of 36 patients with NSCLC and 23 with benign lung lesions; classification of CTCs with haematoxylin and eosin (H&amp;E) staining; identification of cell marker with co-immunostaining for epithelial and mesenchymal markers (Vimentin and Cytocheratin). CTCs were classified as tumor cells if: (i) they have a large (≥12 μm), hyperchromatic, irregular-shaped nuclei; (ii) high nuclear-cytoplasmic ratio (&amp;gt;0.5). Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from histological or cytological analysis. Results: CTCs were detected in 27 of 36 (75%) NSCLC patients and in 2 of 23 (9%) negative control patients (p = 0.001). No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. A test sensitivity and specificity for diagnosing lung cancer was 75% and 91% respectively. After co-immunostaining (Cytocheratin, Vimentin, CD45) CTCs showed positivity (14/15, 93%) only to vimentin (mesenchymal marker) and completely absence of cytocheratin signal (epithelial marker). Conclusions: The performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer showed by high test sensitivity and specificity. The vimentin high expression in CTCs showed both that is a possible marker to CTCs identification and isolation and the importance of EMT mechanism transition in CTCs. Citation Format: Marianna Scrima, Donatella Malanga, Carmela De Marco, Giuseppe Viglietto. Isolation and characterization of circulating tumor cells (CTCs) in non small cell lung carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2239.
How compression therapy could be alleviating chemotherapy-induced peripheral neuropathy: A study of skin microcirculation homeostasis across all CIPN grades.
Authors: Tsuyoshi Ohno, Charles de Kerckhove, Takashi Mine, Hiroki Yoshioka, Mikiko Kosaka, Kazuyuki Matsuda, Maiko de Kerckhove, Yoshihiro Mori, Shigetoshi Matsuo, Takashi Azuma, Takehiro Mishima, Satoshi Inoue, Takashi Hamada, Susumu Eguchi
Journal: Journal of Clinical Oncology (2015)

e20670 Background: We previously reported that compression and medication therapies applied to breast cancer patients 1) control chemotherapy-induced peripheral neuropathy (CIPN) grades, and 2) increase skin perfusion; however, it is not fully clear at the microcirculation level how our 3S Approach of stockings, sleeves, and selected prophylactic medications appears to alleviate CIPN symptoms. In light of vasomotion research relating tissue-fluid exchange to skin microcirculation homeostasis, quantified by Stability Index [SI] for Total Blood Flow [TBF], we investigated compression therapy’s effect on skin microcirculation homeostasis across all CIPN grades. Methods: Compression stockings were applied for 24 hours on 22 3S-adopting, nab-PTX–treated breast cancer patients (44 lower limb samples) just before IV, and on 25 female healthy volunteers (n = 50). Measurements before and after application were by laser Doppler blood flow meter. The nab-PTX group was subdivided by CIPN grade for subsequent analysis (n = 12 for Grade 0, n = 20 for Grade 1, and n = 12 for Grades 2 and 3 combined). SI is derived by [TBF Standard Deviation] / [Mean TBF], where low SI values indicate normal, stable blood flow and high values indicate impairment. Results: Before applying stockings, SI [mean, %] was 11.6 ± 6.3 in the 44 patient samples and 8.3 ± 4.9 in the 50 volunteer samples. Applying the stockings significantly lowered patient SI to 8.7 ± 3.4 (p < 0.01) and volunteer SI to 6.5 ± 2.5 (p < 0.05). By patient subgroup, Grade 0 SI lowered from 14.1 ± 5.4 to 11.3 ± 3.9, p = 0.085; Grade 1, 11.9 ± 8.0 to 8.4 ± 3.2, p = 0.043 [significant]; Grades 2+3, 9.2 ± 3.3 to 6.6 ± 1.2, p = 0.012 [significant]. Conclusions: Our study suggests that the skin microcirculation homeostasis of nab-PTX patients appears to be 1) poor compared to the healthy population and 2) improved by compression therapy across every CIPN grade, including high grades. Such apparent effectiveness may relate to previous 3S findings of improved CIPN grade control, increased skin perfusion, and potentially improved drug clearance at the skin level and may support continuing compression therapy even for high grade patients.
The metalloproteinase ADAMTS-5 is present in the vasculature and its expression is related to proteoglycan turnover and lipoprotein retention in atherosclerosis
Authors: Athanasios Didangelos, Ursula Mayr, Xiaoke Yin, Christin Stegemann, J. Shalhoub, A. H. Davies, C. Monaco, Manuel Mayr
Journal: Cardiovascular Research (2012)