bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sodium Channel Subunit SCNN1B Suppresses Gastric Cancer Growth and Metastasis via GRP78 Degradation
Authors: Qian Yun , Wong Chi Chun , Xu Jiaying , Chen Huarong , Zhang Yanquan , Kang Wei , Wang Hua , Zhang Li , Li Weilin , Chu Eagle S.H. , Go Minnie Y.Y. , Chiu Philip W.Y. , Ng Enders K.W. , Chan Francis K.L. , Sung Joseph J.Y. , Si Jianmin , Yu Jun 
Published: February 2017

Abstract
There remains a paucity of functional biomarkers in gastric cancer. Here, we report the identification of the sodium channel subunit SCNN1B as a candidate biomarker in gastric cancer. SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in gastric cancer cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in gastric cancer patients, especially those with late-stage disease. Functional studies demonstrated that SCNN1B overexpression was sufficient to suppress multiple features of cancer cell pathophysiology in vitro and in vivo. Mechanistic investigations revealed that SCNN1B interacted with the endoplasmic reticulum chaperone, GRP78, and induced its degradation via polyubiquitination, triggering the unfolded protein response (UPR) via activation of PERK, ATF4, XBP1s, and C/EBP homologous protein and leading in turn to caspase-dependent apoptosis. Accordingly, SCNN1B sensitized gastric cancer cells to the UPR-inducing drug tunicamycin. GRP78 overexpression abolished the inhibitory effect of SCNN1B on cell growth and migration, whereas GRP78 silencing aggravated growth inhibition by SCNN1B. In summary, our results identify SCNN1B as a tumor-suppressive function that triggers UPR in gastric cancer cells, with implications for its potential clinical applications as a survival biomarker in gastric cancer patients. Cancer Res; 77(8); 1968–82. ©2017 AACR.
Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion
Authors: Ohishi Tomokazu , Yoshida Haruka , Katori Masamichi , Migita Toshiro , Muramatsu Yukiko , Miyake Mao , Ishikawa Yuichi , Saiura Akio , Iemura Shun-ichiro , Natsume Tohru , Seimiya Hiroyuki 
Published: February 2017

Abstract
Tankyrase, a PARP that promotes telomere elongation and Wnt/β-catenin signaling, has various binding partners, suggesting that it has as-yet unidentified functions. Here, we report that the tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton and cancer cell invasion, which is closely associated with cancer progression. TNKS1BP1 colocalized with actin filaments and negatively regulated cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion, and lamellipodia ruffling were increased with activation of the ROCK/LIMK/cofilin pathway. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity–dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the tankyrase-TNKS1BP1 axis constitutes a posttranslational modulator of cell invasion whose aberration promotes cancer malignancy. Cancer Res; 77(9); 2328–38. ©2017 AACR.
CD40 Signaling Drives Potent Cellular Immune Responses in Heterologous Cancer Vaccinations
Authors: Nimanong Supot , Ostroumov Dmitrij , Wingerath Jessica , Knocke Sarah , Woller Norman , Gürlevik Engin , Falk Christine S. , Manns Michael P. , Kühnel Florian , Wirth Thomas C. 
Published: February 2017

Abstract
Antagonistic antibodies targeting coinhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited because of the insufficient induction of adaptive immune responses. Here, we describe a novel vaccination method consisting of a primary dendritic cell (DC) immunization followed by a composite vaccination, including an agonistic CD40 antibody, soluble antigen, and a TLR3 agonist, referred to as CoAT. In mice, DC/CoAT prime-boost vaccinations targeting either MHC class I or II neoantigens or tumor-associated antigens rendered up to 60% of the total T-cell population specific for a single tumor epitope. DC/CoAT induced durable and complete remissions of large subcutaneous tumors without detectable side effects. Thus, booster vaccinations with agonistic costimulatory antibodies represent an ideal means to amplify DC vaccinations and induce robust T-cell immune responses while providing maximum flexibility regarding the choice of antigen. Cancer Res; 77(8); 1918–26. ©2017 AACR.
Tumor-Associated Neutrophils and Macrophages Promote Gender Disparity in Hepatocellular Carcinoma in Zebrafish
Authors: Yan Chuan , Yang Qiqi , Gong Zhiyuan 
Published: February 2017

Abstract
Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than women, but the mechanistic basis of this gender disparity is obscure. Chronic inflammation is a major etiologic factor in HCC, so we investigated the role of cortisol in gender discrepancy in a zebrafish model of HCC. Inducible expression of oncogenic KrasV12 in hepatocytes of transgenic zebrafish resulted in accelerated liver tumor progression in males. These tumors were more heavily infiltrated with tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) versus females, and they both showed protumor gene expression and promoted tumor progression. Interestingly, the adrenal hormone cortisol was predominantly produced in males to induce Tgfb1 expression, which functioned as an attractant for TAN and TAM. Inhibition of cortisol signaling in males, or increase of cortisol level in females, decreased or increased the numbers of TAN and TAM, respectively, accompanied by corresponding changes in protumor molecular expression. Higher levels of cortisol, TGFB1, and TAN/TAM infiltration in males were also confirmed in human pre-HCC and HCC samples, features that positively correlated in human patients. These results identify increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human. Cancer Res; 77(6); 1395–407. ©2017 AACR.
Amplification of EGFR Wild-Type Alleles in Non–Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors
Authors: Nukaga Shigenari , Yasuda Hiroyuki , Tsuchihara Katsuya , Hamamoto Junko , Masuzawa Keita , Kawada Ichiro , Naoki Katsuhiko , Matsumoto Shingo , Mimaki Sachiyo , Ikemura Shinnosuke , Goto Koichi , Betsuyaku Tomoko , Soejima Kenzo 
Published: February 2017

Abstract
EGFR-mutated lung cancers account for a significant subgroup of non–small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src–AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. Cancer Res; 77(8); 2078–89. ©2017 AACR.
Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis
Authors: Valerio Daria G. , Xu Haiming , Chen Chun-Wei , Hoshii Takayuki , Eisold Meghan E. , Delaney Christopher , Cusan Monica , Deshpande Aniruddha J. , Huang Chun-Hao , Lujambio Amaia , Zheng YuJun George , Zuber Johannes , Pandita Tej K. , Lowe Scott W. , Armstrong Scott A. 
Published: February 2017

Abstract
Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator–based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9–driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci in Mof-deficient MLL-AF9 tumor cells. In parallel, Mof loss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and human MLL-AF9 leukemia cell lines. Furthermore, Mof inactivation suppressed leukemia development in an NUP98-HOXA9–driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustain MLL-AF9 leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treat MLL-rearranged leukemias. Cancer Res; 77(7); 1753–62. ©2017 AACR.
Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation
Authors: Cui Ye , Steagall Wendy K. , Lamattina Anthony M. , Pacheco-Rodriguez Gustavo , Stylianou Mario , Kidambi Pranav , Stump Benjamin , Golzarri Fernanda , Rosas Ivan O. , Priolo Carmen , Henske Elizabeth P. , Moss Joel , El-Chemaly Souheil 
Published: February 2017

Abstract
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.
Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair
Authors: Lu Yanxin , Kwintkiewicz Jakub , Liu Yang , Tech Katherine , Frady Lauren N. , Su Yu-Ting , Bautista Wendy , Moon Seog In , MacDonald Jeffrey , Ewend Matthew G. , Gilbert Mark R. , Yang Chunzhang , Wu Jing 
Published: February 2017

Abstract
Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas. Cancer Res; 77(7); 1709–18. ©2017 AACR.
Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells
Authors: Tong Jingshan , Wang Peng , Tan Shuai , Chen Dongshi , Nikolovska-Coleska Zaneta , Zou Fangdong , Yu Jian , Zhang Lin 
Published: February 2017

AbstractThe Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3β phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1–targeting agents that can overcome drug resistance. Cancer Res; 77(9); 2512–21. ©2017 AACR.
Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways
Authors: Milani Gloria , Lana Tobia , Bresolin Silvia , Aveic Sanja , Pastò Anna , Frasson Chiara , te Kronnie Geertruy 
Published: February 2017

Abstract
Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemia in vitro model systems were used to investigate microvesicles as vehicles of protein-coding messages. Several leukemic cells (K562, LAMA-87, TOM-1, REH, and SHI-1), each carrying a specific chromosomal translocation, were analyzed. In the leukemic cells, these chromosomal translocations are transcribed into oncogenic fusion transcripts and the transfer of these transcripts was monitored from leukemic cells to microvesicles for each of the cell lines. Microarray gene expression profiling was performed to compare transcriptomes of K562-derived microvesicles and parental K562 cells. The data show that oncogenic BCR-ABL1 transcripts and mRNAs related to basic functions of leukemic cells were included in microvesicles. Further analysis of microvesicles cargo revealed a remarkable enrichment of transcripts related to cell membrane activity, cell surface receptors, and extracellular communication when compared with parental K562 cells. Finally, coculturing of healthy mesenchymal stem cells (MSC) with K562-derived microvesicles displayed the transfer of the oncogenic message, and confirmed the increase of target cell proliferation as a function of microvesicle dosage.
Implications: This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein–coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683–95. ©2017 AACR.
Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina
Authors: Barańska Malwina , Sikora Adam , Buszko Katarzyna , Siemińska Emilia , Marszałł Michał Piotr , Siller-Matula Jolanta , Jilma Bernd , Alexopoulos Dimitrios , Fabiszak Tomasz , Kubica Jacek , Niezgoda Piotr , Sikora Joanna 
Published: February 2017

SummaryOral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.
Effects of Upgrade Versus De Novo Cardiac Resynchronization Therapy on Clinical Response and Long-Term Survival
Authors: Vamos Mate , Erath Julia W. , Bari Zsolt , Vagany Denes , Linzbach Sven P. , Burmistrava Tatsiana , Israel Carsten W. , Duray Gabor Z. , Hohnloser Stefan H. 
Published: February 2017

Background—
Benefits of cardiac resynchronization therapy (CRT) on morbidity and mortality in selected patients are well known. Although the number of upgrade procedures from single- or dual-chamber devices to CRT is increasing, there are only sparse data on the outcomes of upgrade procedures compared with de novo CRT. This study aimed to evaluate clinical response and survival in patients receiving de novo versus upgrade CRT defibrillator therapy.

Methods and Results—

Prospectively collected outcome data were compared in patients undergoing de novo or upgrade CRT defibrillator implantation at 3 implant centers in Germany and Hungary. Clinical response was defined as an improvement by at least one New York Heart Association (NYHA) functional class. CRT implantation was performed in 552 consecutive patients of whom 375 underwent a de novo and 177 an upgrade procedure. Upgrade patients were more often implanted for secondary prevention, suffered more often from atrial fibrillation, chronic kidney disease, diabetes mellitus, and dyslipidemia, and had more often a non-LBBB (left bundle branch block) wide QRS complex, and lower left ventricular ejection fraction. Upgrade procedures were associated with a lower response rate compared to the de novo group (57% versus 69%,
P
univariate=0.008,
P
multivariate=0.021). During the follow-up of 37±28 months, survival was worse after upgrade compared with de novo CRT defibrillator implantations (hazard ratio, 1.65; 95% confidence interval, 1.22–2.24;
P
=0.001) even after careful adjustment for important baseline variables (adjusted hazard ratio, 1.68; 95% confidence interval, 1.20–2.34;
P
=0.002) and after propensity-score matching (propensity-adjusted hazard ratio, 1.79; 95% confidence interval, 1.08–2.95;
P
=0.023).

Conclusions—
Both clinical response and long-term survival were less favorable in patients undergoing CRT upgrade compared to de novo implantations.
Targets and End Points in Cardiac Autonomic Denervation Procedures
Authors: Rivarola Esteban W. , Hachul Denise , Wu Tan , Pisani Cristiano , Hardy Carina , Raimundi Fabrizio , Melo Sissy , Darrieux Francisco , Scanavacca Mauricio 
Published: February 2017

Background—
Autonomic denervation is an alternative approach for patients with symptomatic bradycardia. No consensus exists on the critical targets and end points of the procedure. The aim of this study was to identify immediate end points and critical atrial regions responsible for vagal denervation.

Methods and Results—

We enrolled 14 patients (50% men; age: 34.0±13.8 years) with cardioinhibitory syncope, advanced atrioventricular block or sinus arrest, and no structural heart disease. Anatomic mapping of ganglionated plexuses was performed, followed by radiofrequency ablation. Heart rate, sinus node recovery time, Wenckebach cycle length, and atrial-His (AH) interval were measured before and after every radiofrequency pulse. Wilcoxon signed-rank test was used for comparison. Significant shortening of the R-R interval (
P
=0.0009), Wenckebach cycle length (
P
=0.0009), and AH intervals (
P
=0.0014) was observed after ablation. The heart rate elevation was 23.8±12.5%, and the Wenckebach cycle length and AH interval shortening was 18.1±11% and 24.6±19%, respectively. Atropine bolus injection (0.04 mg/kg) did not increase heart rate further. Targeting a single spot of the left side (64% of the patients) or right side (36%) of the interatrial septum was observed to be responsible for ≥80% of the final R-R and AH interval shortening during ablation.

Conclusions—
Targeting specific sites of the interatrial septum is followed by an increase in heart rate and atrioventricular nodal conduction properties and might be critical for vagal attenuation. The R-R interval, Wenckebach cycle length, and AH interval shortening, associated with a negative response to atropine, could be considered immediate end points of the procedure.