bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smurf2 Regulates the Senescence Response and Suppresses Tumorigenesis in Mice
Authors: Ramkumar Charusheila , Kong Yahui , Cui Hang , Hao Suyang , Jones Stephen N. , Gerstein Rachel M. , Zhang Hong 
Published: May 2012

Abstract
The E3 ubiquitin ligase Smurf2 mediates ubiquitination and degradation of several protein targets involved in tumorigenesis and induces senescence in human cells. However, the functional role of Smurf2 in tumorigenesis has not been fully evaluated. In this study, we generated a mouse model of Smurf2 deficiency to characterize the function of this E3 ligase in tumorigenesis. Smurf2 deficiency attenuated p16 expression and impaired the senescence response of primary mouse embryonic fibroblasts. In support of a functional role in controlling cancer, Smurf2 deficiency increased the susceptibility of mice to spontaneous tumorigenesis, most notably B-cell lymphoma. At a premalignant stage of tumorigenesis, we documented a defective senescence response in the spleens of Smurf2-deficient mice, consistent with a mechanistic link between impaired senescence regulation and increased tumorigenesis. Taken together, our findings offer the genetic evidence of an important tumor suppressor function for Smurf2. Cancer Res; 72(11); 2714–9. ©2012 AACR.
Oncogenic PI3K Mutations Lead to NF-κB–Dependent Cytokine Expression following Growth Factor Deprivation
Authors: Hutti Jessica E. , Pfefferle Adam D. , Russell Sean C. , Sircar Mayukh , Perou Charles M. , Baldwin Albert S. 
Published: May 2012

Abstract
The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis conducted on cells deprived of growth factors identified the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, subtypes frequently exhibiting constitutive PI3K/Akt activity. An NF-κB–dependent subset of genes driven by oncogenic PI3K mutations was also identified that encoded primarily secreted proteins, suggesting a paracrine role for this gene set. Interestingly, while NF-κB activated by oncogenes such as Ras and EGF receptor leads to cell-autonomous effects, abrogating NF-κB in PI3K-transformed cells did not decrease proliferation or induce apoptosis. However, conditioned media from PI3K mutant-expressing cells led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-κB and interleukin-6–dependent manner. Together, our findings describe a PI3K-driven, NF-κB–dependent transcriptional profile that may play a critical role in promoting a microenvironment amenable to tumor progression. These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways. Cancer Res; 72(13); 3260–9. ©2012 AACR.
Temporary Disruption of the Blood–Brain Barrier by Use of Ultrasound and Microbubbles: Safety and Efficacy Evaluation in Rhesus Macaques
Authors: McDannold Nathan , Arvanitis Costas D. , Vykhodtseva Natalia , Livingstone Margaret S. 
Published: May 2012

Abstract
The blood–brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method. Cancer Res; 72(14); 3652–63. ©2012 AACR.
Accumulation of Multipotent Progenitors with a Basal Differentiation Bias during Aging of Human Mammary Epithelia
Authors: Garbe James C. , Pepin Francois , Pelissier Fanny A. , Sputova Klara , Fridriksdottir Agla J. , Guo Diana E. , Villadsen Rene , Park Morag , Petersen Ole W. , Borowsky Alexander D. , Stampfer Martha R. , LaBarge Mark A. 
Published: May 2012

AbstractWomen older than 50 years account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the cellular and molecular mechanisms that underlies these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women ages 16 to 91 years, derived from primary tissues, to investigate the molecular changes that occur in aging breast cells. We found that in finite lifespan cultured and uncultured epithelial cells, aging is associated with a reduction of myoepithelial cells and an increase in luminal cells that express keratin 14 and integrin-α6, a phenotype that is usually expressed exclusively in myoepithelial cells in women younger than 30 years. Changes to the luminal lineage resulted from age-dependent expansion of defective multipotent progenitors that gave rise to incompletely differentiated luminal or myoepithelial cells. The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors, which together increase the potential for malignant transformation. Together, our findings provide a cellular basis to explain the observed vulnerability to breast cancer that increases with age. Cancer Res; 72(14); 3687–701. ©2012 AACR.
CD44s Regulates the TGF-β–Mediated Mesenchymal Phenotype and Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Authors: Mima Kosuke , Okabe Hirohisa , Ishimoto Takatsugu , Hayashi Hiromitsu , Nakagawa Shigeki , Kuroki Hideyuki , Watanabe Masayuki , Beppu Toru , Tamada Mayumi , Nagano Osamu , Saya Hideyuki , Baba Hideo 
Published: May 2012

Abstract
The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β–mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β–mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2–positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β–mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC. Cancer Res; 72(13); 3414–23. ©2012 AACR.
miRNA-708 Control of CD44+ Prostate Cancer–Initiating Cells
Authors: Saini Sharanjot , Majid Shahana , Shahryari Varahram , Arora Sumit , Yamamura Soichiro , Chang Inik , Zaman Mohd Saif , Deng Guoren , Tanaka Yuichiro , Dahiya Rajvir 
Published: May 2012

Abstract
Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44+ cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44+ prostate cancer cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44− population of prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer. Cancer Res; 72(14); 3618–30. ©2012 AACR.
The Continuum Model of Selection in Human Tumors: General Paradigm or Niche Product?
Authors: Leedham Simon , Tomlinson Ian 
Published: May 2012

Abstract
Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and “two hits” at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing “just right” of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic “mini-driver” mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes. Cancer Res; 72(13); 3131–4. ©2012 AACR.
Role of Apollon in Human Melanoma Resistance to Antitumor Agents That Activate the Intrinsic or the Extrinsic Apoptosis Pathways
Authors: Tassi Elena , Zanon Marina , Vegetti Claudia , Molla Alessandra , Bersani Ilaria , Perotti Valentina , Pennati Marzia , Zaffaroni Nadia , Milella Michele , Ferrone Soldano , Carlo-Stella Carmelo , Gianni Alessandro M. , Mortarini Roberta , Anichini Andrea 
Published: May 2012

Abstract
Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression.
Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal–regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents.
Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK- and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors.
Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. Clin Cancer Res; 18(12); 3316–27. ©2012 AACR.
A Molecular Taxonomy for Urothelial Carcinoma
Authors: Sjödahl Gottfrid , Lauss Martin , Lövgren Kristina , Chebil Gunilla , Gudjonsson Sigurdur , Veerla Srinivas , Patschan Oliver , Aine Mattias , Fernö Mårten , Ringnér Markus , Månsson Wiking , Liedberg Fredrik , Lindgren David , Höglund Mattias 
Published: May 2012

Abstract
Purpose: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics.
Experimental Design: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry.
Results: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification.
Conclusions: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 18(12); 3377–86. ©2012 AACR.
CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27− Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian Cancer
Authors: Nielsen Julie S. , Sahota Rob A. , Milne Katy , Kost Sara E. , Nesslinger Nancy J. , Watson Peter H. , Nelson Brad H. 
Published: May 2012

AbstractPurpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8+ T cells and CD20+ B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8+ TIL can mediate direct cytolytic activity against tumors, the role of CD20+ TIL is poorly understood. Here, we investigate the possible contributions of CD20+ TIL to humoral and cellular tumor immunity.Experimental Design: Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8+ and CD20+ TIL were analyzed by immunohistochemistry and flow cytometry. Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA.Results: The vast majority of CD20+ TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20+ TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8+ TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20+ and CD8+ TIL correlated with increased patient survival compared with CD8+ TIL alone.Conclusions: In high-grade serous ovarian tumors, CD20+ TIL have an antigen–experienced but atypical CD27− memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8+ T cells. We propose that the association between CD20+ TIL and patient survival may reflect a supportive role in cytolytic immune responses. Clin Cancer Res; 18(12); 3281–92. ©2012 AACR.
Accuracy of In Vivo Multimodal Optical Imaging for Detection of Oral Neoplasia
Authors: Pierce Mark C. , Schwarz Richard A. , Bhattar Vijayashree S. , Mondrik Sharon , Williams Michelle D. , Lee J. Jack , Richards-Kortum Rebecca , Gillenwater Ann M. 
Published: May 2012

Abstract
If detected early, oral cancer is eminently curable. However, survival rates for oral cancer patients remain low, largely due to late-stage diagnosis and subsequent difficulty of treatment. To improve clinicians' ability to detect early disease and to treat advanced cancers, we developed a multimodal optical imaging system (MMIS) to evaluate tissue in situ, at macroscopic and microscopic scales. The MMIS was used to measure 100 anatomic sites in 30 patients, correctly classifying 98% of pathologically confirmed normal tissue sites, and 95% of sites graded as moderate dysplasia, severe dysplasia, or cancer. When used alone, MMIS classification accuracy was 35% for sites determined by pathology as mild dysplasia. However, MMIS measurements correlated with expression of candidate molecular markers in 87% of sites with mild dysplasia. These findings support the ability of noninvasive multimodal optical imaging to accurately identify neoplastic tissue and premalignant lesions. This in turn may have considerable impact on detection and treatment of patients with oral cancer and other epithelial malignancies. Cancer Prev Res; 5(6); 801–9. ©2012 AACR.
Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia
Authors: Huijgen Roeland , Hutten Barbara A. , Kindt Iris , Vissers Maud N. , Kastelein John J.P. 
Published: May 2012

Background—
Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations.

Methods and Results—

Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148);
P
<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%–87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%–97.1%) and 91.3%, respectively.

Conclusions—
In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.
Impacts of Forecaster Involvement on Convective Storm Initiation and Evolution Nowcasting
Authors: Roberts Rita D. , Anderson Amanda R. S. , Nelson Eric , Brown Barbara G. , Wilson James W. , Pocernich Matthew , Saxen Thomas 
Published: May 2012

Abstract
A forecaster-interactive capability was added to an automated convective storm nowcasting system [Auto-Nowcaster (ANC)] to allow forecasters to enhance the performance of 1-h nowcasts of convective storm initiation and evolution produced every 6 min. This Forecaster-Over-The-Loop (FOTL-ANC) system was tested at the National Weather Service Fort Worth–Dallas, Texas, Weather Forecast Office during daily operations from 2005 to 2010. The forecaster’s role was to enter the locations of surface convergence boundaries into the ANC prior to dissemination of nowcasts to the Center Weather Service Unit. Verification of the FOTL-ANC versus ANC (no human) nowcasts was conducted on the convective scale. Categorical verification scores were computed for 30 subdomains within the forecast domain. Special focus was placed on subdomains that included convergence boundaries for evaluation of forecaster involvement and impact on the FOTL-ANC nowcasts. The probability of detection of convective storms increased by 20%–60% with little to no change observed in the false-alarm ratios. Bias values increased from 0.8–1.0 to 1.0–3.0 with human involvement. The accuracy of storm nowcasts notably improved with forecaster involvement; critical success index (CSI) values increased from 0.15–0.25 (ANC) to 0.2–0.4 (FOTL-ANC). Over short time periods, CSI values as large as 0.6 were also observed. This study demonstrated definitively that forecaster involvement led to positive improvement in the nowcasts in most cases while causing no degradation in other cases; a few exceptions are noted. Results show that forecasters can play an important role in the production of rapidly updated, convective storm nowcasts for end users.