bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer
Authors: Prenen Hans , Tejpar Sabine , Cutsem Eric Van 
Published: May 2010

Abstract
The introduction of new cytotoxic agents and new targeted therapies has significantly broadened the therapeutic options for and the outcomes of patients with metastatic colorectal cancer (CRC). The introduction of the anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, has clearly contributed to this development. The concept of KRAS as a marker for resistance to anti-EGFR antibodies has been validated. However, new challenges have emerged: the complete understanding of the crucial and central role of KRAS in processes of tumor growth and the development of new treatment strategies for KRAS mutant tumors. KRAS seems to be so crucial that a further classification and description in KRAS wild-type and mutant may be warranted. Testing for KRAS mutations marks, therefore, a paradigm shift in the management of metastatic CRC. This testing also highlights the unmet need for new treatment options in KRAS mutant metastatic CRC. In this review we will focus on possible new treatment options for these patients. Clin Cancer Res; 16(11); 2921–6. ©2010 AACR.
Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome
Authors: Jönsson Göran , Busch Christian , Knappskog Stian , Geisler Jürgen , Miletic Hrvoje , Ringnér Markus , Lillehaug Johan R. , Borg Åke , Lønning Per Eystein 
Published: May 2010

Abstract
Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.
Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.
Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P &lt; 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P &lt; 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).
Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Clin Cancer Res; 16(13); 3356–67. ©2010 AACR.
Phase II Study on the Addition of ASA404 (Vadimezan; 5,6-Dimethylxanthenone-4-Acetic Acid) to Docetaxel in CRMPC
Authors: Pili Roberto , Rosenthal Mark A. , Mainwaring Paul N. , Van Hazel Guy , Srinivas Sandy , Dreicer Robert , Goel Sanjay , Leach Joseph , Wong Shirley , Clingan Peter 
Published: May 2010

Abstract
Purpose: This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC).
Experimental Design: Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either ≤10 cycles of docetaxel 75 mg/m2 alone (D; n = 39) or docetaxel plus ASA404 1,200 mg/m2 (A-D; n = 35). Study endpoints included prostate-specific antigen response, tumor response, median time to tumor progression, median survival, and toxicity.
Results: The overall pattern of adverse events was similar in the two groups; however, there was a higher incidence of cardiac adverse events and neutropenia in the A-D group. Coadministration of ASA404 with docetaxel did not affect total systemic exposure of either drug. A higher prostate-specific antigen response rate was reported with A-D versus D (59.4% versus 36.8%), together with a larger median percentage reduction in prostate-specific antigen (84.0% versus 61.9%) and a shorter median time to prostate-specific antigen nadir (105 versus 119 d). Tumor response rate was 23.1% with A-D and 9.1% with D. Time to tumor progression and median survival were similar in the groups (time to tumor progression, 8.7 mo for A-D and 8.4 mo for D; survival, 17.0 mo for A-D and 17.2 mo for D). Hazard ratios for time to tumor progression and survival were 0.81 and 0.80, respectively, favoring A-D; 2-year survival was 33.3% with A-D and 22.8% with D.
Conclusion: The study met some endpoints (prostate-specific antigen response, tumor response) but not others (i.e., time to tumor progression). The results indicate that the combination of ASA404 with docetaxel has acceptable toxicity, lacks adverse pharmacokinetic interaction, and, overall, has activity in CRMPC. Clin Cancer Res; 16(10); 2906–14. ©2010 AACR.
Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals
Authors: Mitsui Jun , Nishikawa Hiroyoshi , Muraoka Daisuke , Wang Linan , Noguchi Takuro , Sato Eiichi , Kondo Satoshi , Allison James P. , Sakaguchi Shimon , Old Lloyd J. , Kato Takuma , Shiku Hiroshi 
Published: May 2010

AbstractPurpose: Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.Experimental Design: The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti–glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).Results: Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb–treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb–treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.Conclusions: This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. Clin Cancer Res; 16(10); 2781–91. ©2010 AACR.
Susceptibility Loci Associated with Prostate Cancer Progression and Mortality
Authors: Gallagher David J. , Vijai Joseph , Cronin Angel M. , Bhatia Jasmine , Vickers Andrew J. , Gaudet Mia M. , Fine Samson , Reuter Victor , Scher Howard I. , Halldén Christer , Dutra-Clarke Ana , Klein Robert J. , Scardino Peter T. , Eastham James A. , Lilja Hans , Kirchhoff Tomas , Offit Kenneth 
Published: May 2010

Abstract
Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer–specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs.
Results: On univariate analysis, two SNPs were associated (P &lt; 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer–specific mortality. Applying a Bonferroni correction (P &lt; 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer–specific mortality in KLK3 (P &lt; 0.0005 by both univariate and multivariable analysis).
Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer–specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819–32. ©2010 AACR.
Epigenetic Markers in Rectal Cancer
Authors: Xu Lei , Czito Brian G. , Willett Christopher G. 
Published: May 2010

Abstract
DNA methylation changes in rectal cancer may serve as a new screening marker and a tool for monitoring recurrence. Importantly, these changes may also function as a predictive marker to allow appropriate exclusion of (neo)adjuvant therapies in patients at low risk for disease recurrence, sparing them from potential treatment-related morbidities. Clin Cancer Res; 16(10); 2699–701. ©2010 AACR.
Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial
Authors: Carthon Bradley C. , Wolchok Jedd D. , Yuan Jianda , Kamat Ashish , Ng Tang Derek S. , Sun Jingjing , Ku Geoffrey , Troncoso Patricia , Logothetis Christopher J. , Allison James P. , Sharma Padmanee 
Published: May 2010

Abstract
Purpose: Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti–CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.
Experimental Design: Six patients were treated with 3 mg/kg/dose of anti–CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.
Results: Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti–CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.
Conclusions: Our trial shows that anti–CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting. Clin Cancer Res; 16(10); 2861–71. ©2010 AACR.
Microenvironmental Regulation of Chemokine (C-X-C-Motif) Receptor 4 in Ovarian Carcinoma
Authors: Barbolina Maria V. , Kim Mijung , Liu Yueying , Shepard Jaclyn , Belmadani Abdelhak , Miller Richard J. , Shea Lonnie D. , Stack M. Sharon 
Published: May 2010

Abstract
The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that antimetastatic therapies may improve patient survival. EOC metastasis involves intraperitoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by—or in response to—tumor cells. As cells penetrating the submesothelial surface encounter an interstitial collagen-rich extracellular matrix, we have used three-dimensional type I collagen gels to model early events resulting from intraperitoneal anchoring. In this study, we show a novel pathway of CXCR4 upregulation through β1 integrin – and NFκB-dependent signaling pathways in response to three-dimensional type I collagen. We also show the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of the CXCR4-SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis. Mol Cancer Res; 8(5); 653–64. ©2010 AACR.
Mechanisms of Motility in Metastasizing Cells
Authors: Yilmaz Mahmut , Christofori Gerhard 
Published: May 2010

Abstract
Cell migration and invasion are critical parameters in the metastatic dissemination of cancer cells and the formation of metastasis, the major cause of death in cancer patients. Migratory cancer cells undergo dramatic molecular and cellular changes by remodeling their cell-cell and cell-matrix adhesion and their actin cytoskeleton, molecular processes that involve the activity of various signaling networks. Although in the past years, we have substantially expanded our knowledge on the cellular and molecular processes underlying cell migration and invasion in experimental systems, we still lack a clear understanding of how cancer cells disseminate in metastatic cancer patients. Different types of cancer cell migration seem to exist, including single-cell mesenchymal or amoeboid migration and collective cell migration. In most epithelial cancers, loss of the cell-cell adhesion molecule E-cadherin and gain of mesenchymal markers and promigratory signals underlie the conversion of epithelial, differentiated cells to mesenchymal, migratory, and invasive cells, a process referred to as the epithelial-to-mesenchymal transition. Although solitary migrating epithelial cancer cells have mostly undergone epithelial-to-mesenchymal transition (mesenchymal migration), and sometimes even lose their cell-matrix adhesion (amoeboid migration), collective migration of cancer cells in cell sheets, clusters, or streams is also frequently observed. The molecular mechanisms defining the different modes of cancer cell migration remain in most parts to be delineated. Mol Cancer Res; 8(5); 629–42. ©2010 AACR.
Incremental Prognostic Value of Coronary CT Angiography in Patients With Suspected Coronary Artery Disease
Authors: Russo Vincenzo , Zavalloni Andrea , Bacchi Reggiani Maria Letizia , Buttazzi Katia , Gostoli Valentina , Bartolini Simone , Fattori Rossella 
Published: May 2010

Background—
Multidetector CT coronary angiography (MDCTCA) is capable of detecting coronary artery disease (CAD) with a high diagnostic accuracy. In particular, this technique is credited with having a negative predictive value close to 100%. However, data about the prognostic value of MDCTCA are currently lacking. We sought to determine the prognostic value of MDCTCA in patients with suspected but undocumented CAD and, in particular, the incremental prognostic value as compared with clinical risk and calcium scoring.

Methods and Results—

A total of 441 patients (age, 59.7±11.6 years) with suspected CAD underwent MDCTCA to evaluate the presence and severity of the disease. Patients were followed up as to the occurrence of hard cardiac events (cardiac death, nonfatal myocardial infarction, and unstable angina requiring hospitalization). Coronary lesions were detected in 297 (67.3%) patients. During a mean follow-up of 31.9±14.8 months, 44 hard cardiac events occurred in 40 patients. CT calcium scoring showed a statistically significant incremental prognostic value as compared to a baseline clinical risk model (
P
=0.018), whereas MDCTCA provided an additional incremental prognostic value as compared with a baseline clinical risk model plus calcium scoring if considering both nonobstructive versus obstructive CAD (
P
=0.016) or, better, plaque composition (calcified versus noncalcified and/or mixed plaques,
P
=0.0001). During follow-up, an excellent prognosis was noted in patients with normal coronary arteries, with an annualized incidence rate of 0.88% if compared with those with mild CAD (3.89%) and with patients with significant coronary disease (8.09%). The presence of noncalcified or mixed plaques, regardless of lesion severity, was found to be the strongest predictor of events (
P
<0.0001) as a potential marker of plaque vulnerability.

Conclusions—
MDCTCA provides independent and incremental prognostic information as compared to baseline clinical risk factors and calcium scoring in patients with suspected CAD.
Unreliable Assessment of Necrotic Core by Virtual Histology Intravascular Ultrasound in Porcine Coronary Artery Disease
Authors: Thim Troels , Hagensen Mette Kallestrup , Wallace-Bradley David , Granada Juan F. , Kaluza Greg L. , Drouet Ludovic , Paaske William P. , Bøtker Hans Erik , Falk Erling 
Published: May 2010

Background—
Intravascular ultrasound–derived virtual histology (VH IVUS) is used increasingly in clinical research to assess composition and vulnerability of coronary atherosclerotic lesions. However, the ability of VH IVUS to quantify individual plaque components, in particular the size of the destabilizing necrotic core, has never been validated. We tested for correlation between VH IVUS necrotic core size and necrotic core size by histology in porcine coronary arteries with human-like coronary disease.

Methods and Results—
In adult atherosclerosis-prone minipigs, 18 advanced coronary lesions were assessed by VH IVUS in vivo followed by postmortem microscopic examination (histology). We found no correlation between the size of the necrotic core determined by VH IVUS and histology. VH IVUS displayed necrotic cores in lesions lacking cores by histology.

Conclusions—
We found no correlation between necrotic core size determined by VH IVUS and real histology, questioning the ability of VH IVUS to detect rupture-prone plaques, so-called thin-cap fibroatheromas.
MOTIPS: Automated Motif Analysis for Predicting Targets of Modular Protein Domains
Authors: Lam Hugo YK , Kim Philip M , Mok Janine , Tonikian Raffi , Sidhu Sachdev S , Turk Benjamin E , Snyder Michael , Gerstein Mark B 
Published: May 2010

Abstract

Background
Many protein interactions, especially those involved in signaling, involve short linear motifs consisting of 5-10 amino acid residues that interact with modular protein domains such as the SH3 binding domains and the kinase catalytic domains. One straightforward way of identifying these interactions is by scanning for matches to the motif against all the sequences in a target proteome. However, predicting domain targets by motif sequence alone without considering other genomic and structural information has been shown to be lacking in accuracy.

Results
We developed an efficient search algorithm to scan the target proteome for potential domain targets and to increase the accuracy of each hit by integrating a variety of pre-computed features, such as conservation, surface propensity, and disorder. The integration is performed using naïve Bayes and a training set of validated experiments.

Conclusions
By integrating a variety of biologically relevant features to predict domain targets, we demonstrated a notably improved prediction of modular protein domain targets. Combined with emerging high-resolution data of domain specificities, we believe that our approach can assist in the reconstruction of many signaling pathways.
A predicted physicochemically distinct sub-proteome associated with the intracellular organelle of the anammox bacterium Kuenenia stuttgartiensis
Authors: Medema Marnix H , Zhou Miaomiao , van Hijum Sacha AFT , Gloerich Jolein , Wessels Hans JCT , Siezen Roland J , Strous Marc 
Published: May 2010

Abstract

Background
Anaerobic ammonium-oxidizing (anammox) bacteria perform a key step in global nitrogen cycling. These bacteria make use of an organelle to oxidize ammonia anaerobically to nitrogen (N2) and so contribute ~50% of the nitrogen in the atmosphere. It is currently unknown which proteins constitute the organellar proteome and how anammox bacteria are able to specifically target organellar and cell-envelope proteins to their correct final destinations. Experimental approaches are complicated by the absence of pure cultures and genetic accessibility. However, the genome of the anammox bacterium Candidatus "Kuenenia stuttgartiensis" has recently been sequenced. Here, we make use of these genome data to predict the organellar sub-proteome and address the molecular basis of protein sorting in anammox bacteria.

Results
Two training sets representing organellar (30 proteins) and cell envelope (59 proteins) proteins were constructed based on previous experimental evidence and comparative genomics. Random forest (RF) classifiers trained on these two sets could differentiate between organellar and cell envelope proteins with ~89% accuracy using 400 features consisting of frequencies of two adjacent amino acid combinations. A physicochemically distinct organellar sub-proteome containing 562 proteins was predicted with the best RF classifier. This set included almost all catabolic and respiratory factors encoded in the genome. Apparently, the cytoplasmic membrane performs no catabolic functions. We predict that the Tat-translocation system is located exclusively in the organellar membrane, whereas the Sec-translocation system is located on both the organellar and cytoplasmic membranes. Canonical signal peptides were predicted and validated experimentally, but a specific (N- or C-terminal) signal that could be used for protein targeting to the organelle remained elusive.

Conclusions
A physicochemically distinct organellar sub-proteome was predicted from the genome of the anammox bacterium K. stuttgartiensis. This result provides strong in silico support for the existing experimental evidence for the existence of an organelle in this bacterium, and is an important step forward in unravelling a geochemically relevant case of cytoplasmic differentiation in bacteria. The predicted dual location of the Sec-translocation system and the apparent absence of a specific N- or C-terminal signal in the organellar proteins suggests that additional chaperones may be necessary that act on an as-yet unknown property of the targeted proteins.