bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth
Authors: Huang Yu-Hung , Peng Weidan , Furuuchi Narumi , Gerhart Jacquelyn , Rhodes Kelly , Mukherjee Neelanjan , Jimbo Masaya , Gonye Gregory E. , Brody Jonathan R. , Getts Robert C. , Sawicki Janet A. 
Published: February 2016

Abstract
Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor–bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo–targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. Cancer Res; 76(6); 1549–59. ©2016 AACR.
Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis
Authors: Wirsdörfer Florian , de Leve Simone , Cappuccini Federica , Eldh Therese , Meyer Alina V. , Gau Eva , Thompson Linda F. , Chen Ning-Yuan , Karmouty-Quintana Harry , Fischer Ute , Kasper Michael , Klein Diana , Ritchey Jerry W. , Blackburn Michael R. , Westendorf Astrid M. , Stuschke Martin , Jendrossek Verena 
Published: February 2016

AbstractRadiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5′-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately 3-fold. Histologic evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P &lt; 0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacologic strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. Cancer Res; 76(10); 3045–56. ©2016 AACR.
An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer
Authors: Olow Aleksandra , Chen Zhongzhong , Niedner R. Hannes , Wolf Denise M. , Yau Christina , Pankov Aleksandr , Lee Evelyn Pei Rong , Brown-Swigart Lamorna , van ‘t Veer Laura J. , Coppé Jean-Philippe 
Published: February 2016

Abstract
Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR.
Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow
Authors: Miftakhova Regina , Hedblom Andreas , Semenas Julius , Robinson Brian , Simoulis Athanasios , Malm Johan , Rizvanov Albert , Heery David M. , Mongan Nigel P. , Maitland Norman J. , Allegrucci Cinzia , Persson Jenny L. 
Published: February 2016

Abstract
Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453–64. ©2016 AACR.
p28-Mediated Activation of p53 in G2–M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy
Authors: Yamada Tohru , Das Gupta Tapas K. , Beattie Craig W. 
Published: February 2016

Abstract
p28 is an anionic cell-penetrating peptide of 28 amino acids that activates wild-type and mutated p53, leading subsequently to selective inhibition of CDK2 and cyclin A expression and G2–M cell-cycle arrest. In this study, we investigated the cytotoxic effects of p28 treatment alone and in combination with DNA-damaging and antimitotic agents on human cancer cells. p28 enhanced the cytotoxic activity of lower concentrations (IC20-50) of DNA-damaging drugs (doxorubicin, dacarbazine, temozolamide) or antimitotic drugs (paclitaxel and docetaxel) in a variety of cancer cells expressing wild-type or mutated p53. Mechanistic investigations revealed that p28 induced a post-translational increase in the expression of wild-type or mutant p53 and p21, resulting in cell-cycle inhibition at the G2–M phase. The enhanced activity of these anticancer agents in combination with p28 was facilitated through the p53/p21/CDK2 pathway. Taken together, these results highlight a new approach to maximize the efficacy of chemotherapeutic agents while reducing dose-related toxicity. Cancer Res; 76(8); 2354–65. ©2016 AACR.
Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals
Authors: Hofmann Jonathan N. , Birmann Brenda M. , Teras Lauren R. , Pfeiffer Ruth M. , Wang Ye , Albanes Demetrius , Baris Dalsu , Colditz Graham A. , De Roos Anneclaire J. , Giles Graham G. , Hosgood H. Dean , Lan Qing , Landgren Ola , Liao Linda M. , Rothman Nathaniel , Weinstein Stephanie J. , Pollak Michael N. , Neuhouser Marian L. , Purdue Mark P. 
Published: February 2016

Abstract
The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47–0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40–0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26–0.65) or obese (OR, 0.41; 95% CI, 0.17–0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73–2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935–41. ©2016 AACR.
Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts
Authors: Nwani Nkechiyere G. , Deguiz Maria L. , Jimenez Benilde , Vinokour Elena , Dubrovskyi Oleksii , Ugolkov Andrey , Mazar Andrew P. , Volpert Olga V. 
Published: February 2016

Abstract
Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor-suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy. Cancer Res; 76(8); 2265–76. ©2016 AACR.
Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab
Authors: Bossi Paolo , Bergamini Cristiana , Siano Marco , Cossu Rocca Maria , Sponghini Andrea P. , Favales Federica , Giannoccaro Marco , Marchesi Edoardo , Cortelazzi Barbara , Perrone Federica , Pilotti Silvana , Locati Laura D. , Licitra Lisa , Canevari Silvana , De Cecco Loris 
Published: February 2016

Abstract
Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.
Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.
Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: &lt;0.0022–1e−07).
Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.
See related commentary by Chau and Hammerman, p. 3710
High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ∼240-Fold Higher Drug Concentration in Urine than Serum
Authors: Liu Zhongbo , Yokoyama Noriko N. , Blair Christopher A. , Li Xuesen , Avizonis Daina , Wu Xue-Ru , Uchio Edward , Youssef Ramy , McClelland Michael , Pollak Michael , Zi Xiaolin 
Published: February 2016

Abstract
While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplastic tissue. We investigated the basis of the unusual sensitivity of this model to metformin, and observed that following oral dosing, urothelium is exposed to drug concentrations via the urine that are approximately 240-fold higher than those in the circulation. In addition, we observed that bladder cancer cell lines (RT4, UMUC-3, and J82) with homozygous deletion of either TSC1 or PTEN are more sensitive to metformin than those (TEU2, TCCSUP, and HT1376) with wild-type TSC1 and PTEN genes. Our findings provide a strong rationale for clinical trials of oral metformin in treatment of superficial bladder cancer. Mol Cancer Ther; 15(3); 430–8. ©2016 AACR.
Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy
Authors: Kim Jeffrey , Ulu Arzu , Wan Debin , Yang Jun , Hammock Bruce D , Weiss Robert H. 
Published: February 2016

Abstract
Kidney cancer is the sixth most common cancer in the United States, and its incidence is increasing. The treatment of this malignancy took a major step forward with the recent introduction of targeted therapeutics, such as kinase inhibitors. Unfortunately, kinase inhibition is associated with the onset of resistance after 1 to 2 years of treatment. Regorafenib, like many multikinase inhibitors, was designed to block the activities of several key kinase pathways involved in oncogenesis (Ras/Raf/MEK/ERK) and tumor angiogenesis (VEGF-receptors), and we have recently shown that it also possesses soluble epoxide hydrolase (sEH) inhibitory activity, which may be contributing to its salutary effects in patients. Because sEH inhibition results in increases in the DHA-derived epoxydocosapentaenoic acids that we have previously described to possess anticancer properties, we asked whether the addition of DHA to a therapeutic regimen in the presence of regorafenib would enhance its beneficial effects in vivo. We now show that the combination of regorafenib and DHA results in a synergistic effect upon tumor invasiveness as well as p-VEGFR attenuation. In addition, this combination showed a reduction in tumor weights, greater than each agent alone, in a mouse xenograft model of human renal cell carcinoma (RCC), yielding the expected oxylipin profiles; these data were supported in several RCC cell lines that showed similar results in vitro. Because DHA is the predominant component of fish oil, our data suggest that this nontoxic dietary supplement could be administered with regorafenib during therapy for advanced RCC and could be the basis of a clinical trial. Mol Cancer Ther; 15(5); 890–8. ©2016 AACR.
Gait Speed Predicts 30-Day Mortality After Transcatheter Aortic Valve Replacement
Authors: Alfredsson Joakim , Stebbins Amanda , Brennan J. Matthew , Matsouaka Roland , Afilalo Jonathan , Peterson Eric D. , Vemulapalli Sreekanth , Rumsfeld John S. , Shahian David , Mack Michael J. , Alexander Karen P. 
Published: February 2016

Background—
Surgical risk scores do not include frailty assessments (eg, gait speed), which are of particular importance for patients with severe aortic stenosis considering transcatheter aortic valve replacement.

Methods and Results—

We assessed the association of 5-m gait speed with outcomes in a cohort of 8039 patients who underwent transcatheter aortic valve replacement (November 2011–June 2014) and were included in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. We evaluated the association between continuous and categorical gait speed and 30-day all-cause mortality before and after adjustment for Society of Thoracic Surgeons–predicted risk of mortality score and key variables. Secondary outcomes included in-hospital mortality, bleeding, acute kidney injury, and stroke. The overall median gait speed was 0.63 m/s (25th–75th percentile, 0.47–0.79 m/s), with the slowest walkers (<0.5 m/s) constituting 28%, slow walkers (0.5–0.83 m/s) making up 48%, and normal walkers (>0.83 m/s) constituting 24% of the population. Thirty-day all-cause mortality rates were 8.4%, 6.6%, and 5.4% for the slowest, slow, and normal walkers, respectively (
P
<0.001). Each 0.2-m/s decrease in gait speed corresponded to an 11% increase in 30-day mortality (adjusted odds ratio, 1.11; 95% confidence interval, 1.01–1.22). The slowest walkers had 35% higher 30-day mortality than normal walkers (adjusted odds ratio, 1.35; 95% confidence interval, 1.01–1.80), significantly longer hospital stays, and a lower probability of being discharged to home.

Conclusions—
Gait speed is independently associated with 30-day mortality after transcatheter aortic valve replacement. Identification of frail patients with the slowest gait speeds facilitates preprocedural evaluation and anticipation of a higher level of postprocedural care.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01737528.
Prevalence and risk factors of postoperative delirium in elderly hip fracture patients
Authors: Guo Yong , Jia Peiyu , Zhang Junfeng , Wang Xuemin , Jiang Hong , Jiang Wei 
Published: February 2016

Objective To explore the risk factors associated with postoperative delirium (PD) in elderly patients following total hip arthroplasty (THA) for hip fracture. Methods This prospective study enrolled elderly patients (≥ 65 years) with hip fractures who underwent THA under general anaesthesia, and who had a complete set of postoperative observations. Detailed medical history and perioperative characteristics were recorded. During the postoperative period, patients were assessed twice daily for PD using the Confusion Assessment Method. Results A total of 572 patients were eligible for inclusion in the study. Of these, 120 patients (21.0%) were diagnosed with PD and 452 patients (79.0%) did not experience PD. Multivariate stepwise logistic regression analyses showed that older age, a history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher C-reactive protein, longer surgery duration and higher volume of red blood cell transfusions were independent risk factors for PD. Conclusions Correcting the modifiable risk factors might help prevent PD. Strategies might include nutritional support, tight blood glucose control, improvement of liver function, preoperative infection control and minimizing surgical injury or blood loss.