bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sudden cardiac death in adults with congenitally corrected transposition of the great arteries
Authors: McCombe A , Touma F , Jackson D , Canniffe C , Choudhary P , Pressley L , Tanous D , Robinson Peter J , Celermajer D 
Published: July 2016

BackgroundCongenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart disease. There have been only few reports of sudden cardiac death (SCD) in patients with ccTGA and reasonable ventricular function.MethodsA retrospective review of the medical records of all patients attending our adult congenital heart centre, with known ccTGA.ResultsFrom a database of over 3500 adult patients with congenital heart disease, we identified 39 (∼1%) with ccTGA and ‘two-ventricle’ circulations. 65% were male. The mean age at diagnosis was 12.4±11.4 years and the mean age at last time of review was 34.3±11.3 years. 24 patients (56%) had a history of surgical intervention. 8 (19%) had had pacemaker implantation and 2 had had a defibrillator implanted for non-sustained ventricular tachycardia (NSVT). In 544 years of patient follow-up, there had been five cases of SCD in our population; 1 death per 109 patient-years. Two of these patients had had previously documented supraventricular or NSVT. However, they were all classified as New York Heart Association (NYHA) class I or II, and systemic (right) ventricular function had been recorded as normal, mildly or mildly–moderately impaired, at most recent follow-up.ConclusionsOur experience suggests the need for improved risk stratification and/or surveillance for malignant arrhythmia in adults with ccTGA, even in those with reasonable functional class on ventricular function.
Coronary sinus-based percutaneous annuloplasty as treatment for functional mitral regurgitation: the TITAN II trial
Authors: Lipiecki Janusz , Siminiak Tomasz , Sievert Horst , Müller-Ehmsen Jochen , Degen Hubertus , Wu Justina C , Schandrin Christian , Kalmucki Piotr , Hofmann Ilona , Reuter David , Goldberg Steven L , Haude Michael 
Published: July 2016

ObjectiveFunctional (or secondary) mitral regurgitation (FMR) is associated with greater morbidity and worse outcomes in patients with congestive heart failure (CHF) and cardiomyopathy. The Carillon® Mitral Contour System® is a coronary sinus-based percutaneous therapy to reduce FMR. We evaluated the safety and efficacy of a modified version of the Carillon device in the treatment of patients with cardiomyopathy and FMR.Methods36 patients with CHF, depressed left ventricular function (ejection fraction <40%) and at least moderate FMR underwent the Carillon device implant.ResultsThere was 1 major adverse event within 30 days—a death (not device related)—occurring 17 days after the implant. Reductions in FMR and improvements in functional class and 6 min walk tests were seen, similar to prior studies. Device fractures in the high strain region of the proximal anchor (seen in prior studies) were not seen in this study.ConclusionsThe modified Carillon device was associated with improvements in clinical and echocardiographic parameters in treating patients with FMR, while successfully addressing the issue of anchor fracture. This version of the Carillon device will be used in a blinded randomised trial of symptomatic patients with FMR.
Study of
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Sr transport through a column filled with crushed granite in the presence of bentonite colloids
Authors: Kolomá Kateřina , Červinka Radek 
Published: July 2016

Abstract

The present work is focused on the study of strontium transport through crushed granite in the presence of bentonite colloids under dynamic arrangement. The aim of the experiments was to investigate the effect of bentonite colloids on strontium migration in crushed granite. The tracer behaviour was studied in a column set-up under aerobic conditions with a continuous inlet of the liquid phase of a constant tracer concentration (activity) and flow rate. Defined volumes of liquid phase were sampled at periodic time intervals at the column outlet for the measurements of tracer concentrations (activity). The transport was described by breakthrough curves. The stepwise approach included these steps: (1) an evaluation of the hydrodynamic column properties by the non-sorbing tracer
3
H; (2) a column experiment with bentonite colloids in deionized water was performed; (3) migration of
85
Sr solution in two liquid phases (deionized and synthetic granitic water); and (4) the transport of a radiocolloid suspension in deionized water was studied. Results showed different behaviour of bentonite colloids and strontium in the column. Bentonite colloids behaved as a non-sorbing tracer: conversely, strontium showed strong sorption on granitic material. The strontium transport in the presence of bentonite colloids differed from strontium transport itself. The strontium transport in the presence of colloids was faster than transport without the bentonite colloids. The observed retention of strontium on granite suggests a higher affinity of strontium towards granitic rock than towards bentonite colloids, and showed the reversibility of the sorption of strontium on bentonite colloids.
Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure
Authors: Cedervall Jessica , Zhang Yanyu , Olsson Anna-Karin 
Published: July 2016

Abstract
A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as a mechanism by which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of protein-arginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis. Cancer Res; 76(15); 4311–5. ©2016 AACR.
RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression
Authors: Meng Xuan , Tackmann Nicole R. , Liu Shijie , Yang Jing , Dong Jiahong , Wu Congying , Cox Adrienne D. , Zhang Yanping 
Published: July 2016

Abstract
The ribosomal protein (RP)–MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC–induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad antioncogenic mechanism, we crossed mice bearing an MDM2C305F mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic HrasG12V transgene. Interestingly, the MDM2C305F-mutant mice, which are hypersensitive to c-MYC–induced tumorigenesis, are not hypersensitive to oncogenic HrasG12V-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein whereas RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2C305F mutant, correlates with increased p53 expression in MDM2C305F cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by downregulation of RPL23. Thus, although the RPL11–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic c-MYC–induced tumorigenesis, the RPL23–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic RAS-induced tumorigenesis. Cancer Res; 76(17); 5030–9. ©2016 AACR.
HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation
Authors: Sugata Kenji , Yasunaga Jun-ichirou , Kinosada Haruka , Mitobe Yuichi , Furuta Rie , Mahgoub Mohamed , Onishi Chiho , Nakashima Kazutaka , Ohshima Koichi , Matsuoka Masao 
Published: July 2016

Abstract
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and other inflammatory diseases in infected individuals. However, a complete understanding of how HTLV-1 transforms T cells is lacking. Expression of the chemokine receptor CCR4 on ATL cells and HTLV-1–infected cells suggested the hypothesis that CCR4 may mediate features of ATL and inflammatory diseases caused by HTLV-1. In this study, we show that the constitutively expressed HTLV-1 bZIP factor (HBZ) encoded by HTLV-1 is responsible for inducing CCR4 and its ability to promote T-cell proliferation and migration. Ectopic expression of HBZ was sufficient to stimulate expression of CCR4 in human and mouse T cells. Conversely, HBZ silencing in ATL cell lines was sufficient to inhibit CCR4 expression. Mechanistic investigations showed that HBZ induced GATA3 expression in CD4+ T cells, thereby activating transcription from the CCR4 promoter. In an established air pouch model of ATL, we observed that CD4+ T cells of HBZ transgenic mice (HBZ-Tg mice) migrated preferentially to the pouch, as compared with those in nontransgenic mice. Migration of CD4+ T cells in HBZ-Tg mice was inhibited by treatment with a CCR4 antagonist. Proliferating (Ki67+) CD4+ T cells were found to express high levels of CCR4 and CD103. Further, CD4+ T-cell proliferation in HBZ-Tg mice was enhanced by coordinate treatment with the CCR4 ligands CCL17 and 22 and with the CD103 ligand E-cadherin. Consistent with this finding, we found that ATL cells in clinical skin lesions were frequently positive for CCR4, CD103, and Ki67. Taken together, our results show how HBZ activates CCR4 expression on T cells to augment their migration and proliferation, two phenomena linked to HTLV-1 pathogenesis. Cancer Res; 76(17); 5068–79. ©2016 AACR.
BATON-CRC: A Phase II Randomized Trial Comparing Tivozanib Plus mFOLFOX6 with Bevacizumab Plus mFOLFOX6 in Stage IV Metastatic Colorectal Cancer
Authors: Benson Al B. , Kiss Igor , Bridgewater John , Eskens Ferry A.L.M. , Sasse Carolyn , Vossen Sandra , Chen Jihong , Van Sant Chip , Ball Howard A. , Keating Anne , Krivoshik Andrew 
Published: July 2016

Abstract
Purpose: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab.
Experimental Design: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses.
Results: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693–1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies.
Conclusions: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058–67. ©2016 AACR.
Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells
Authors: Horikawa Naoki , Abiko Kaoru , Matsumura Noriomi , Hamanishi Junzo , Baba Tsukasa , Yamaguchi Ken , Yoshioka Yumiko , Koshiyama Masafumi , Konishi Ikuo 
Published: July 2016

Abstract
Purpose: High VEGF expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSC), in ovarian cancer.
Experimental Design: High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and IHC for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. In addition, the therapeutic effects of anti-Gr-1 antibodies were examined.
Results: Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocyte-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment.
Conclusions: VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587–99. ©2016 AACR.
Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer
Authors: Wang Jian , Yang Shouhui , He Peijun , Schetter Aaron J. , Gaedcke Jochen , Ghadimi B. Michael , Ried Thomas , Yfantis Harris G. , Lee Dong H. , Gaida Matthias M. , Hanna Nader , Alexander H. Richard , Hussain S. Perwez 
Published: July 2016

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection.
Experimental Design: Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (≤7 months, N = 11) and long surviving (≥2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan–Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses.
Results: Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3′UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC.
Conclusions: Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992–6001. ©2016 AACR.
FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs
Authors: Ison Gwynn , Beaver Julia A. , McGuinn W. David , Palmby Todd R. , Dinin Jeannette , Charlab Rosane , Marathe Anshu , Jin Runyan , Liu Qi , Chen Xiao Hong , Ysern Xavier , Stephens Olen , Bai Ge , Wang Yaning , Dorff Sarah E. , Cheng Joyce , Tang Shenghui , Sridhara Rajeshwari , Pierce William , McKee Amy E. , Ibrahim Amna , Kim Geoffrey , Pazdur Richard 
Published: July 2016

Abstract
On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m2 orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. Clin Cancer Res; 22(18); 4545–49. ©2016 AACR.
Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer
Authors: De Robertis Mariangela , Loiacono Luisa , Fusilli Caterina , Poeta Maria Luana , Mazza Tommaso , Sanchez Massimo , Marchionni Luigi , Signori Emanuela , Lamorte Giuseppe , Vescovi Angelo Luigi , Garcia-Foncillas Jesus , Fazio Vito Michele 
Published: July 2016

AbstractPurpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC.Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response.Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I–III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status.Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. Clin Cancer Res; 23(1); 159–70. ©2016 AACR.
Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C
Authors: Wei Jun-Cheng , Yang Jie , Liu Dan , Wu Ming-Fu , Qiao Long , Wang Jun-Nai , Ma Quan-Fu , Zeng Zhen , Ye Shuang-Mei , Guo En-Song , Jiang Xue-Feng , You Lan-Ying , Chen Ying , Zhou Li , Huang Xiao-Yuan , Zhu Tao , Meng Li , Zhou Jian-Feng , Feng Zuo-Hua , Ma Ding , Gao Qing-Lei 
Published: July 2016

Abstract
Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.
Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs.
Results: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells.
Conclusions: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214–24. ©2016 AACR.