bluuebunny/crossref_metadata_2025_split huggingface dataset:
Globo-H Ceramide Shed from Cancer Cells Triggers Translin-Associated Factor X-Dependent Angiogenesis
Authors: Cheng Jing-Yan , Wang Sheng-Hung , Lin Juway , Tsai Yi-Chien , Yu John , Wu Jen-Chine , Hung Jung-Tung , Lin Jin-Jin , Wu Yih-Yiing , Yeh Kun-Tu , Yu Alice L. 
Published: October 2014

Abstract
Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca2+ mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer+ breast cancer specimens contained higher vessel density than GHCer− breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca2+ mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis. Cancer Res; 74(23); 6856–66. ©2014 AACR.
Early Pregnancy Sex Steroids and Maternal Breast Cancer: A Nested Case–Control Study
Authors: Fortner Renée T. , Schock Helena , Kaaks Rudolf , Lehtinen Matti , Pukkala Eero , Lakso Hans-Åke , Tanner Minna , Kallio Raija , Joensuu Heikki , Grankvist Kjell , Zeleniuch-Jacquotte Anne , Toniolo Paolo , Lundin Eva , Surcel Helja-Marja 
Published: October 2014

Abstract
Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (&lt;140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case–control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age &lt;40 [4th vs. 1st quartile OR 1.60 (1.07–2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51–1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age &lt;40 at diagnosis. We observed no association between steroid hormones and ER+/PR+ disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER−/PR− breast cancer in women diagnosed age &lt;40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor–negative cancers is needed to further characterize this association. Cancer Res; 74(23); 6958–67. ©2014 AACR.
DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
Authors: Klajic Jovana , Busato Florence , Edvardsen Hege , Touleimat Nizar , Fleischer Thomas , Bukholm Ida , Børresen-Dale Anne-Lise , Lønning Per Eystein , Tost Jörg , Kristensen Vessela N. 
Published: October 2014

Abstract
Purpose: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.
Experimental Design: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.
Results: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.
Conclusion: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. Clin Cancer Res; 20(24); 6357–66. ©2014 AACR.
Ramucirumab: Successfully Targeting Angiogenesis in Gastric Cancer
Authors: Javle Milind , Smyth Elizabeth C. , Chau Ian 
Published: October 2014

Abstract
Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer-related mortality. Early detection, aggressive surgical resection, and postoperative adjuvant therapy have led to survival improvement for early-stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for antiangiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pretreated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA-approved therapy for advanced gastric cancer after prior chemotherapy. Clin Cancer Res; 20(23); 5875–81. ©2014 AACR.
A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma
Authors: Sborov Douglas W. , Nuovo Gerard J. , Stiff Andrew , Mace Thomas , Lesinski Gregory B. , Benson Don M. , Efebera Yvonne A. , Rosko Ashley E. , Pichiorri Flavia , Grever Michael R. , Hofmeister Craig C. 
Published: October 2014

Abstract
Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.
Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.
Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.
Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.
Team Work Matters: Dual Inhibition Puts Non-Hodgkin Lymphoma Under Siege
Authors: Bianchi Giada , Ghobrial Irene M. 
Published: October 2014

Abstract
Inhibitors of PI3K/mTOR and histone deacetylases (HDAC) are effective in non-Hodgkin lymphoma (NHL). However, clinical resistance eventually ensues and combinatory therapies are sought to prevent it. Preclinical evaluation of dual PI3K/mTOR and HDAC inhibition is synergistic against NHL, paving the way for bench-to-bedside translation. Clin Cancer Res; 20(23); 5863–5. ©2014 AACR.
Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport
Authors: Bola Becky M. , Chadwick Amy L. , Michopoulos Filippos , Blount Kathryn G. , Telfer Brian A. , Williams Kaye J. , Smith Paul D. , Critchlow Susan E. , Stratford Ian J. 
Published: October 2014

Abstract
Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. Thus, we combined AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts and showed that the combination provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors. Mol Cancer Ther; 13(12); 2805–16. ©2014 AACR.
Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
Authors: Pecot Chad V. , Wu Sherry Y. , Bellister Seth , Filant Justyna , Rupaimoole Rajesha , Hisamatsu Takeshi , Bhattacharya Rajat , Maharaj Anshumaan , Azam Salma , Rodriguez-Aguayo Cristian , Nagaraja Archana S. , Morelli Maria Pia , Gharpure Kshipra M. , Waugh Trent A. , Gonzalez-Villasana Vianey , Zand Behrouz , Dalton Heather J. , Kopetz Scott , Lopez-Berestein Gabriel , Ellis Lee M. , Sood Anil K. 
Published: October 2014

Abstract
Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS-mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced &gt;90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional “undruggable” targets. Mol Cancer Ther; 13(12); 2876–85. ©2014 AACR.
Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer
Authors: Puig Marta , Lugo Roberto , Gabasa Marta , Giménez Alícia , Velásquez Adriana , Galgoczy Roland , Ramírez Josep , Gómez-Caro Abel , Busnadiego Óscar , Rodríguez-Pascual Fernando , Gascón Pere , Reguart Noemí , Alcaraz Jordi 
Published: October 2014

Abstract
The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non–small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by β1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC–TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC–TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC–TAFs (&gt;50%) compared with ADC–TAFs (10%–20%). In contrast, SCC–TAFs were largely serum desensitized, whereas ADC–TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC–TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC–TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC–TAFs.
Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells. Mol Cancer Res; 13(1); 161–73. ©2014 AACR.
A DRD1 Polymorphism Predisposes to Lung Cancer among Those Exposed to Secondhand Smoke during Childhood
Authors: Robles Ana I. , Yang Ping , Jen Jin , McClary Andrew C. , Calhoun Kara , Bowman Elise D. , Vähäkangas Kirsi , Greathouse K. Leigh , Wang Yi , Olivo-Marston Susan , Wenzlaff Angela S. , Deng Bo , Schwartz Ann G. , Ryan Bríd M. 
Published: October 2014

Abstract
Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P &lt; 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P &lt; 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P &lt; 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.
Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation
Authors: Zhu Junlan , Zhang Jingjie , Huang Haishan , Li Jingxia , Yu Yonghui , Jin Honglei , Li Yang , Deng Xu , Gao Jimin , Zhao Qinshi , Huang Chuanshu 
Published: October 2014

Abstract
Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. Cancer Prev Res; 7(12); 1270–81. ©2014 AACR.
Hypotension During Hospitalization for Acute Heart Failure Is Independently Associated With 30-Day Mortality
Authors: Patel Priyesh A. , Heizer Gretchen , O’Connor Christopher M. , Schulte Phillip J. , Dickstein Kenneth , Ezekowitz Justin A. , Armstrong Paul W. , Hasselblad Vic , Mills Roger M. , McMurray John J.V. , Starling Randall C. , Tang W.H. Wilson , Califf Robert M. , Hernandez Adrian F. 
Published: October 2014

Background—
Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood.

Methods and Results—

Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76–2.23;
P
<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17–2.60;
P
<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13–1.52;
P
=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06–1.40;
P
=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57–2.61;
P
<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34–1.86;
P
<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22–1.61;
P
<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction
P
=0.874 for death,
P
=0.908 for death/heart failure hospitalization,
P
=0.238 death/all-cause hospitalization).

Conclusions—
Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00475852.