tbuckley/cabot-search huggingface dataset:
Abstract 5227: Suppressive role of elevated estrogen on endometrial carcinogenesis
Authors: Ryoichi Asaka, Tsutomu Miyamoto, Koichi Ida, Hodaka Takeuchi, Hirofumi Ando, Yasushi Yamada, David Hamisi Mvunta, Hisanori Kobara, Hiroyasu Kashima, Tanri Shiozawa
Journal: Cancer Research (2018)

Abstract Background: Although estrogen has been regarded as a risk factor for endometrial carcinoma, its concentration-dependent carcinogenetic effects remain unclear, because most endometrial carcinomas occur in post-menopausal women, whose serum estrogen levels are relatively low. Because impaired mismatch repair (MMR) was reportedly crucial in the early stages of endometrial carcinogenesis, we focused on the relationship between various estrogen concentration and MMR activity in normal and malignant endometrial glandular cells. In those cells, we reported that the protein and mRNA expression of both hMLH1 and hMSH2, the key factors of MMR, were up-regulated by estrogen stimulation. In addition, we demonstrated that the estrogen stimulation enhanced the MMR activity in those cells using in vitro MMR assay with the M13mp2 phage heteroduplex DNAs and that the proliferating cells without hMLH1/hMSH2 expressions implying “high risk” cells were more frequently observed under relative-low estrogen concentrations. In this study, to further confirm the role of E2 in vivo, we employed a mouse endometrial carcinoma model induced by intra-uterine injection of a carcinogen, N-methyl-N-nitrosourea (MNU) under various E2 concentrations. Methods: MNU was injected into the uterine cavity of 29 CD-1 mice at 6 weeks of age, and E2 was administered by pellets or orally. Uteri were removed for histological examinations 24 weeks later, and serum E2 levels were measured. The immunohistochemical expression of MMR proteins in uterine epithelia was investigated. Results: Of 29 mice, 8, 8, 8, and 5 showed atrophic, normal, hyperplastic, and carcinomatous endometria, respectively. The mean E2 levels of each group were 0.2pg/ml, 3.8pg/ml, 190.0pg/ml, and 6.7pg/ml, with significant differences. The expression of the MMR proteins was stronger in mice with elevated E2. Conclusions: Elevated E2 levels preferentially induced endometrial hyperplasia rather than carcinoma, and this may be mediated by MMR proteins. These results indicate that modest E2 is needed, whereas elevated E2 levels are not necessarily advantageous for carcinogenesis, suggesting the importance of low-chronic (un-opposed) estrogen in human endometrial carcinogenesis. Citation Format: Ryoichi Asaka, Tsutomu Miyamoto, Koichi Ida, Hodaka Takeuchi, Hirofumi Ando, Yasushi Yamada, David Hamisi Mvunta, Hisanori Kobara, Hiroyasu Kashima, Tanri Shiozawa. Suppressive role of elevated estrogen on endometrial carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5227.
Abstract 4488: Osteosarcoma cells interact with bronchial cells in lung to drive production of pro-metastatic cytokines
Authors: John M. Hinckley, Amy Gross, Ryan Roberts
Journal: Cancer Research (2018)

Abstract The survival rate for patients diagnosed with osteosarcoma (OS) drops from 70% to an abysmal 20% when diagnosed with lung metastasis. We have shown that metastatic colonization of lungs by OS cells depends on the production of IL6 and CXCL8 by tumor cells, which seems to increase within the metastatic niche of the lung. Identification of key tumor-host interactions that drive this phenomenon will facilitate the development of novel therapies aimed at prevention of metastases in patients diagnosed with OS. We hypothesized that OS cells interact with lung tissues in ways that establish paracrine signal amplification loops, where IL6 and CXCL8 stimulate lung-resident cells to produce secondary signaling molecules that, in turn, further stimulate tumor cell production of IL6 and CXCL8 in a feed-forward mechanism. Co-culture experiments have identified strong interactions between OS cells and primary cultures of bronchial epithelial cells and lung smooth muscle cells. Exposure of OS cells to conditioned supernatants from the primary cell cultures show that these interactions result from exchange of soluble mediators secreted by each cell type. Proteomic profiling of bronchial cell supernatants following incubation with OS conditioned media identified a number of intriguing candidate mediators, which might facilitate the growth and survival of OS cells within the microenviroment of the lung. Some of those same candidate mediators trigger expression of IL6 and CXCL8 in OS cell cultures. These results suggest a paracrine loop mechanism, where OS cells trigger a response from lung stromal cells that promotes survival and proliferation of the OS cells, establishing a favorable niche for the development of metastasis. Citation Format: John M. Hinckley, Amy Gross, Ryan Roberts. Osteosarcoma cells interact with bronchial cells in lung to drive production of pro-metastatic cytokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4488.
Abstract 4177: An IL13Rα2 peptide inhibits colorectal cancer metastatic progression
Authors: Ignacio Casal, Marta Jaén, Rubén A. Bartolomé
Journal: Cancer Research (2018)

Abstract Interleukin 13 receptor α2 (IL13Rα2) is an excellent tumoral marker for metastatic colorectal cancer and glioblastoma. Our goal was to block IL-13 binding to IL13Rα2 by using IL13Rα2 synthetic peptides in order to delay or suppress metastatic spread and progression. Peptides were selected from the D1 binding region. Synthetic peptides were synthesized using solid phase chemistry. Two metastatic colorectal cancer cell lines (KM12SM and SW620) plus two glioblastoma cell lines were used for testing proliferation, adhesion, migration and invasion. We used Biacore assays to demonstrate direct interaction between the peptides and IL-13. In vivo experiments with nude mice were performed to study mice survival to metastasis after peptide treatment. Peptides containing the highly preserved WKTIITKN motif of the D1 binding domain of IL13Rα2 demonstrated a strong capacity to inhibit migration, invasion and proliferation in metastatic colorectal cancer and glioblastoma cells. Alanine scanning experiments indicated that, at least, residues 82K, 83T, 85I and 86T were essential for IL-13 binding to IL13Rα2. IL13Rα2 D1 peptide inhibited IL-13-mediated cell signaling through FAK, Src, AKT and ERK1/2 in colorectal cancer and glioblastoma cell lines. Moreover, the D1 peptide abolished ligand-mediated receptor internalization and degradation. To improve bioavailability and resistance to proteolytic digestion for in vivo administration, we prepared the D enantiomer version of the peptide. Mice inoculated with metastatic colorectal cancer cells and treated with the enantiomer version of the D1 peptide showed a remarkable increase in survival. In conclusion, the D1 enantiomer peptide blocked the IL-13/IL13Rα2 binding, paving the way to develop novel and promising therapeutic strategies to inhibit metastatic progression in colorectal cancer and other solid tumors, including glioblastoma. Citation Format: Ignacio Casal, Marta Jaén, Rubén A. Bartolomé. An IL13Rα2 peptide inhibits colorectal cancer metastatic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4177.
Abstract 2417: eIF4E phosphorylation licenses Myc-driven metabolic and stress reprogramming
Authors: Hang Ruan, Xiangyun Li, Brian Leibowitz, Jingshan Tong, Xinghua Lu, Nahum Sonenberg, Xiang Xu, Lin Zhang, Jian Yu
Journal: Cancer Research (2018)

Abstract eIF4E, Eukaryotic Translation Initiation Factor 4E, regulates the rate limiting cap-binding step in mRNA translation. Oncogenic pathways converge to increase eIF4E expression, as well as phosphorylation of eIF4E (S209) and its inhibitor 4EBPs, which are believed to facilitate the translation of “weak'' mRNAs including cell type-specific and oncogenic targets. eIF4E phosphorylation, but not eIF4E, is dispensable for normal development. Pharmacologic inhibition of either p-eIF4E or p-4EBP has limited antitumor efficacy. Our current study aims to better define the role of p-eIF4E in colon cancer. We find that p-eIF4E, not eIF4E transcript or protein is elevated in human colon tumors and precursors. Knockin (KI) of phosphorylation-defective eIF4E mutant allele (4ES209A) in human colon cancer cells strongly suppresses Myc translation and cell growth under stress or in mice, while minimally impacting Cap binding or global translation. Surprisingly, p-eIF4E is found to be required to maintain p-4EBP1 levels, dissociate eIF4E from 4E-BP1, and stimulate glutamine metabolism via integrated stress response (ISR). Further, p-eIF4E and p-4EBP1 are highly elevated in the polyps in APC min/+ mice compared to adjacent normal intestinal crypts, and 4ES209A KI significantly inhibits intestinal polyposis and glutamine metabolism gene signatures. Finally, p-eIF4E renders CRC cells addicted to glutamine and glutaminolysis by preventing Myc- and ISR-driven metabolic crisis and cell death. In summary, we demonstrate that eIF4E phosphorylation is central to oncogenic translation, and is required to license Myc-driven metabolic adaptation and addiction via ISR-dependent transcriptional programs in colon cancer. These novel findings help reconcile the long-standing and context-dependent roles of ISR in cancer cell growth, death, plasticity and heterogeneity, and provide new ways for its therapeutic exploitation. Citation Format: Hang Ruan, Xiangyun Li, Brian Leibowitz, Jingshan Tong, Xinghua Lu, Nahum Sonenberg, Xiang Xu, Lin Zhang, Jian Yu. eIF4E phosphorylation licenses Myc-driven metabolic and stress reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2417.
Abstract 15871: Trends in Myocardial Infarction as a Secondary Discharge Diagnosis
Authors: Emily B Levitan, Paul Muntner, Ligong Chen, George Howard, Meredith L Kilgore, Todd M Brown, Monika M Safford
Journal: Circulation (2015)

Background: Little research has focused on myocardial infarctions (MIs) that are not the primary illness, and thus MI is listed as a secondary hospital discharge diagnosis. Objective: We examined secular trends in the proportion of MI hospitalizations where MI was a secondary diagnosis and changes in the primary reasons for hospitalization associated with secondary diagnosis of MI. Methods: Using data from the Medicare national 5% sample for 1999-2011, we identified MI hospitalizations as inpatient claims with primary or secondary discharge diagnoses of International Classification of Diseases, Ninth Revision, Clinical Modification, 410.xx, excluding 410.x2 which represents subsequent episodes of care. This approach has previously been validated. For each year, we calculated the proportion of MI hospitalizations where the MI diagnosis appeared in a secondary position. For hospitalizations with MI as a secondary diagnosis, we examined the trends in the most common primary diagnoses. Results: The number of MI hospitalizations ranged from 20,821 in 2003 to 17,640 in 2011 among Medicare beneficiaries in the 5% sample. In 1999, 21% of MI diagnoses were secondary diagnoses, and by 2011, this proportion had risen to 36% (Figure). Over this time period, the proportion of MI hospitalizations with congestive heart failure and coronary atherosclerosis as primary diagnoses declined (16% to 9%, and 11% to 3%, respectively) and the proportion with septicemia as the primary diagnosis increased (3% to 17%). Conclusions: Our results suggest that a growing number and percentage of MI diagnoses are occurring among patients hospitalized for other reasons. The causes of this increase require further investigation. Because individuals whose primary illness is not MI are underrepresented in research studies, the appropriateness and effectiveness of secondary prevention of cardiovascular disease in this patient population are not well described.
Serum homocysteine, folate and vitamin B<sub>12</sub>levels in patients with psoriasis: a systematic review and meta‐analysis
Authors: T.‐Y. Tsai, H. Yen, Y.‐C. Huang
Journal: British Journal of Dermatology (2018)

Patients with psoriasis are at increased risk for cardiovascular comorbidities. Previous studies examined the possible contribution of serum homocysteine, folate and vitamin B12 to cardiovascular risks in patients with psoriasis but had conflicting conclusions. To perform a systematic review and meta‐analysis of studies on serum homocysteine, folate and vitamin B12 levels in patients with psoriasis. Online databases were searched on 15 February 2018 to include studies comparing serum homocysteine, folate and vitamin B12 levels between patients with psoriasis and controls. A random effects model was adopted to estimate odds ratios for dichotomous data and standardized mean differences (SMDs) for continuous data. A comprehensive literature search identified 24 studies eligible for inclusion. Compared with controls, patients with psoriasis had a significantly higher serum homocysteine level [SMD 0·41, 95% confidence interval (CI) 0·21–0·61; I2 = 76·7%, 18 studies], a higher prevalence of hyperhomocysteinaemia (odds ratio 3·48, 95% CI 2·08–5·83; I2 = 41·1%, seven studies) and a lower serum folate level (SMD −0·94, 95% CI −1·49 to −0·40; I2 = 95·6%, 14 studies). However, there was no difference in serum vitamin B12 levels between patients with psoriasis and the control group (SMD 0·004, 95% CI −0·49 to 0·50; I2 = 92%, 11 studies). Metaregression analysis revealed a significant inverse correlation between the SMD of homocysteine levels and folate levels. Patients with psoriasis might have higher serum homocysteine and lower folate levels than control patients without psoriasis. However, due to significant heterogeneity and other limitations, the associations require further examinations in more studies.
Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial
Authors: Hong Yang, Hui Liu, Yuping Chen, Chengchu Zhu, Wentao Fang, Zhentao Yu, Weimin Mao, Jiaqing Xiang, Yongtao Han, Zhijian Chen, Haihua Yang, Jiaming Wang, Qingsong Pang, Xiao Zheng, Huanjun Yang, Tao Li, Florian Lordick, Xavier Benoit D’Journo, Robert J. Cerfolio, Robert J. Korst, Nuria M. Novoa, Scott J. Swanson, Alessandro Brunelli, Mahmoud Ismail, Hiran C. Fernando, Xu Zhang, Qun Li, Geng Wang, Baofu Chen, Teng Mao, Min Kong, Xufeng Guo, Ting Lin, Mengzhong Liu, Jianhua Fu
Journal: Journal of Clinical Oncology (2018)

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.
Abstract 4867: Treating hepatocellular carcinoma metastasis and overcoming chemoresistance through inhibiting the MDM2 oncogene
Authors: Wei Wang, Bo Hu, Jiang-Jiang Qin, Jianwen Cheng, Xin Li, Ming Hu, John Buolamwini, Xin-Rong Yang, Jia Fan, Ruiwen Zhang
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) poses a major health problem worldwide and novel, effective therapeutic approaches are urgently needed. The MDM2 oncogene is amplified and overexpressed in HCC and associated with its initiation, progression, metastasis, and chemoresistence. MDM2 has been demonstrated to be as a promising therapeutic target for the treatment of HCC. However, most of the current MDM2 inhibitors have been designed to block the binding between MDM2 and p53, and have limited efficacy against tumors with mutant or deficient p53. We recently performed a high-throughput virtual and cell-based screening, yielding a novel MDM2 inhibitor, termed SP141. The present study was designed to evaluate the anti-HCC activity of SP141, its potential to chemosensitize HCC cells to other anticancer agents, and to determine the underlying mechanism(s) of action of SP141 in various in vitro and in vivo models with different backgrounds of p53 (wildtype, mutant or null). Our results demonstrated that SP141 inhibited cell growth and prevented cell migration and invasion, independent of p53. Mechanistically, SP141 directly bound to the MDM2 protein and promoted MDM2 degradation. The inhibition of MDM2 by SP141 also increased the sensitivity of HCC cells to sorafenib. In addition, in orthotopic and patient-derived xenograft (PDX) models, SP141 inhibited MDM2 expression and suppressed tumor growth and metastasis, without any host toxicity. Furthermore, mechanistic study demonstrated that the inhibition of MDM2 by SP141 was essential for its anti-HCC activities. In conclusion, MDM2 inhibition by SP141 resulted in the inhibition of HCC tumor growth and metastasis and sensitization of HCC cells to chemotherapy, regardless of their p53 status. These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC. (Supported by NIH R01 CA186662 and R01CA214019 and ACS RSG-15-009-01-CDD.) Citation Format: Wei Wang, Bo Hu, Jiang-Jiang Qin, Jianwen Cheng, Xin Li, Ming Hu, John Buolamwini, Xin-Rong Yang, Jia Fan, Ruiwen Zhang. Treating hepatocellular carcinoma metastasis and overcoming chemoresistance through inhibiting the MDM2 oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4867.
Abstract 19872: 30-day Readmission Rate and Center Variability for US Children Hospitalized With Heart Failure
Authors: Christopher S Almond, David N Rosenthal, Matthew Wood, Joseph W Rossano, Jack F Price, Kevin P Daly, Esther Liu, Chealsea Nather, Kristin Jensen, Andrew Y Shin
Journal: Circulation (2015)

Background: The 30-day readmission rate is a well-established performance benchmark for adult heart failure programs. Little is known about the 30-day readmission rate for pediatric heart failure programs or the variability among centers. We sought to determine the 30-day readmission rate for children admitted with acute decompensated heart failure (ADHF) to support benchmarking efforts in pediatrics. Methods: The Pediatric Health Information System (PHIS) database was queried to identify all children ≤21 years of age admitted between January 2009 and March 2014 with a primary or secondary diagnosis of heart failure. All-cause 30-day readmission rates were calculated, as was mean length of stay. Results: Over the 5-year study period, a total of 39,150 hospitalizations at 47 children’s hospitals met the inclusion criteria. Overall, 56% were infants, 25% age 1-12 years, 9% adolescents, and 9% adults, 48% were female, 72% had congenital heart disease, 28% had cardiomyopathy/myocarditis. The mean hospital length of stay was 25 days (range 11,41 days; SD 7 days). In-hospital mortality was 8.4%. Overall 30-day readmission rate was 20% (range 10%, 30%; SD 5%) and varied considerably by center (Figure). Conclusion: A substantial portion of children (one in five) admitted to the hospital for heart failure is re-admitted within 30 days. There is considerable center-based variation in re-admission rates. The mean hospital length of stay exceeds 3 week and also varies considerably by center.
Therapeutic Impact of Follistatin-Like 1 on Myocardial Ischemic Injury in Preclinical Models
Authors: YasuhiroOgura, NoriyukiOuchi, KojiOhashi, ReiShibata, YoshiyukiKataoka, TakahiroKambara, TetsutaroKito, SonomiMaruyama, DaisukeYuasa, KazuhiroMatsuo, TakashiEnomoto, YusukeUemura, MegumiMiyabe, MasakazuIshii, TakashiYamamoto, YuukiShimizu, KennethWalsh, ToyoakiMurohara
Journal: Circulation (2012)

Background—Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism. Methods and Results—Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion–injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischem...