bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer
Authors: Tosolini Marie , Kirilovsky Amos , Mlecnik Bernhard , Fredriksen Tessa , Mauger Stéphanie , Bindea Gabriela , Berger Anne , Bruneval Patrick , Fridman Wolf-Herman , Pagès Franck , Galon Jérôme 
Published: February 2011

AbstractThe tumor microenvironment includes a complex network of immune T-cell subpopulations. In this study, we systematically analyzed the balance between cytotoxic T cells and different subsets of helper T cells in human colorectal cancers and we correlated their impact on disease-free survival. A panel of immune related genes were analyzed in 125 frozen colorectal tumor specimens. Infiltrating cytotoxic T cells, Treg, Th1, and Th17 cells were also quantified in the center and the invasive margin of the tumors. By hierarchical clustering of a correlation matrix we identified functional clusters of genes associated with Th17 (RORC, IL17A), Th2 (IL4, IL5, IL13), Th1 (Tbet, IRF1, IL12Rb2, STAT4), and cytotoxicity (GNLY, GZMB, PRF1). Patients with high expression of the Th17 cluster had a poor prognosis, whereas patients with high expression of the Th1 cluster had prolonged disease-free survival. In contrast, none of the Th2 clusters were predictive of prognosis. Combined analysis of cytotoxic/Th1 and Th17 clusters improved the ability to discriminate relapse. In situ analysis of the density of IL17+ cells and CD8+ cells in tumor tissues confirmed the results. Our findings argue that functional Th1 and Th17 clusters yield opposite effects on patient survival in colorectal cancer, and they provide complementary information that may improve prognosis. Cancer Res; 71(4); 1263–71. ©2011 AACR.
Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity
Authors: Inoue Satoshi , Ding Hui , Portilla-Arias Jose , Hu Jinwei , Konda Bindu , Fujita Manabu , Espinoza Andres , Suhane Sonal , Riley Marisa , Gates Marcus , Patil Rameshwar , Penichet Manuel L. , Ljubimov Alexander V. , Black Keith L. , Holler Eggehard , Ljubimova Julia Y. 
Published: February 2011

Abstract
Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report the characterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, and nonimmunogenic PMLA [poly(β-l-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemic treatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth of HER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neu receptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopy demonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemic treatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth and tumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab or AON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLA nanoplatform for combination cancer therapy. Cancer Res; 71(4); 1454–64. ©2011 AACR.
Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β
Authors: Al-Mulla Fahd , Bitar Milad S. , Al-Maghrebi May , Behbehani Abdulla I. , Al-Ali Waleed , Rath Oliver , Doyle Brendan , Tan Kit Yee , Pitt Andrew , Kolch Walter 
Published: February 2011

Abstract
Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor κB signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3β protein levels and its active form. Depletion of RKIP augments oxidative stress–mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3β by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3β inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and β-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3β expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression. Cancer Res; 71(4); 1334–43. ©2011 AACR.
Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis
Authors: Franco Omar E. , Jiang Ming , Strand Douglas W. , Peacock James , Fernandez Suzanne , Jackson Roger S. , Revelo Monica P. , Bhowmick Neil A. , Hayward Simon W. 
Published: February 2011

Abstract
Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272–81. ©2011 AACR.
Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming
Authors: Powell Anne E. , Anderson Eric C. , Davies Paige S. , Silk Alain D. , Pelz Carl , Impey Soren , Wong Melissa H. 
Published: February 2011

AbstractThe most deadly phase in cancer progression is attributed to the inappropriate acquisition of molecular machinery leading to metastatic transformation and spread of disease to distant organs. Although it is appreciated that metastasis involves epithelial–mesenchymal interplay, the underlying mechanism defining this process is poorly understood. Specifically, how cancer cells evade immune surveillance and gain the ability to navigate the circulatory system remains a focus. One possible mechanism underlying metastatic conversion is fusion between blood-derived immune cells and cancer cells. While this notion is a century old, in vivo evidence that cell fusion occurs within tumors and imparts genetic or physiologic changes remains controversial. We have previously demonstrated in vivo cell fusion between blood cells and intestinal epithelial cells in an injury setting. Here, we hypothesize that immune cells, such as macrophages, fuse with tumor cells imparting metastatic capabilities by transferring their cellular identity. We used parabiosis to introduce fluorescent-labeled bone marrow-derived cells to mice with intestinal tumors, finding that fusion between circulating blood-derived cells and tumor epithelium occurs during the natural course of tumorigenesis. Moreover, we identify the macrophage as a key cellular partner for this process. Interestingly, cell fusion hybrids retain a transcriptome identity characteristic of both parental derivatives, while also expressing a unique subset of transcripts. Our data supports the novel possibility that tumorigenic cell fusion may impart physical behavior attributed to migratory macrophages, including navigation of circulation and immune evasion. As such, cell fusion may represent a promising novel mechanism underlying the metastatic conversion of cancer cells. Cancer Res; 71(4); 1497–505. ©2011 AACR.
MTGR1 Is Required for Tumorigenesis in the Murine AOM/DSS Colitis-Associated Carcinoma Model
Authors: Barrett Caitlyn W. , Fingleton Barbara , Williams Amanda , Ning Wei , Fischer Melissa A. , Washington Mary K. , Chaturvedi Rupesh , Wilson Keith T. , Hiebert Scott W. , Williams Christopher S. 
Published: February 2011

Abstract
Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1−/− mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1−/− mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1−/− tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1−/− tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3+ and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1−/− mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis. Cancer Res; 71(4); 1302–12. ©2011 AACR.
Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data
Authors: Jung Yeonjoo , Lee Sanghyuk , Choi Hyung-Seok , Kim Soon-Nam , Lee Eunyoung , Shin Youngah , Seo Jihae , Kim Bumjin , Jung Yeonhwa , Kim Wan Kyu , Chun Ho-Kyung , Lee Woo Yong , Kim Jaesang 
Published: February 2011

Abstract
Purpose: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras.
Experimental Design: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes.
Results: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling.
Conclusions: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC. Clin Cancer Res; 17(4); 700–9. ©2011 AACR.
Markers of Pancreatic Cancer: Working Toward Early Detection
Authors: Goggins Michael 
Published: February 2011

Abstract
Because early detection of pancreatic cancer is the best way to cure this disease, investigators continue to try to identify accurate markers of early pancreatic cancer. Because early-stage pancreatic cancer is generally asymptomatic, the only reliable way to detect it is by targeting individuals at increased risk for pancreatic screening. Clin Cancer Res; 17(4); 635–7. ©2011 AACR.
Low-Dose Valproic Acid Enhances Radiosensitivity of Prostate Cancer through Acetylated p53-Dependent Modulation of Mitochondrial Membrane Potential and Apoptosis
Authors: Chen Xufeng , Wong Jeffrey Y.C. , Wong Patty , Radany Eric H. 
Published: February 2011

Abstract
Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers, including prostate cancer. However, the mechanisms of action are not well understood. In this study, we show in prostate cancer cells that valproic acid (VPA) at low concentrations has minimal cytotoxic effects yet can significantly increase radiation-induced apoptosis. VPA seems to stabilize a specific acetyl modification (lysine 120) of the p53 tumor suppressor protein, resulting in an increase in its proapoptotic function at the mitochondrial membrane. These effects of VPA are independent of any action of the p53 protein as a transcription factor in the nucleus, since these effects were also observed in native and engineered prostate cancer cells containing mutant forms of p53 protein having no transcription factor activity. Transcription levels of p53-related or Bcl-2 family member proapoptotic proteins were not affected by VPA exposure. The results of this study suggest that, in addition to nuclear-based pathways previously reported, HDIs may also result in radiosensitization at lower concentrations via a specific p53 acetylation and its mitochondrial-based pathway(s). Mol Cancer Res; 9(4); 448–61. ©2011 AACR.
Additional Ablation of Complex Fractionated Atrial Electrograms After Pulmonary Vein Isolation in Patients With Atrial Fibrillation
Authors: Li Wei-ju , Bai Yong-yi , Zhang Hong-yin , Tang Ri-bo , Miao Cheng-long , Sang Cai-hua , Yin Xian-dong , Dong Jian-zeng , Ma Chang-sheng 
Published: February 2011

Background—
The efficacy of additional complex fractionated atrial electrogram (CFAE) ablation after pulmonary vein antrum isolation (PVAI) in patients with atrial fibrillation (AF) remains controversial. This meta-analysis was performed to assess the additional efficacy of CFAEs ablation after a single procedure without antiarrhythmic drugs.

Methods and Results—

Trials were identified in MEDLINE, Cochrane Library, Embase, Google Scholar, reviews, and reference lists of relevant papers. Controlled cohort studies comparing the long-term efficacy of combined CFAEs plus PVAI ablation with PVAI alone were included. The primary end point was the maintenance of sinus rhythm without antiarrhythmic drugs. Seven controlled trials (9 comparisons) with a total of 622 participants (332 patients underwent PVAI plus CFAE ablation and 330 patients underwent PVAI alone) were included in the meta-analysis. In an overall pooled estimate, compared with PVI alone, long-term rates of sinus rhythm maintenance (relative risk, 1.17, 95% confidence interval, 1.03 to 1.33,
P
=0.019) were increased by additional CFAE ablation. Subgroup analysis demonstrated that additional CFAEs ablation increased rates of sinus rhythm maintenance in nonparoxysmal AF (relative risk, 1.35; 95% confidence interval, 1.04 to 1.75;
P
=0.022), whereas had no effect on patients with paroxysmal AF (relative risk, 1.04; 95% confidence interval, 0.92 to 1.18;
P
=0.528).

Conclusions—
Adjuvant CFAE ablation in addition to standard PVAI increases the rate of long-term sinus rhythm maintenance in nonparoxysmal AF patients after a single procedure without antiarrhythmic drugs but does not provide additional benefit to sinus rhythm maintenance in paroxysmal AF patients.
Dense Genotyping of Candidate Gene Loci Identifies Variants Associated With High-Density Lipoprotein Cholesterol
Authors: Edmondson Andrew C. , Braund Peter S. , Stylianou Ioannis M. , Khera Amit V. , Nelson Christopher P. , Wolfe Megan L. , DerOhannessian Stephanie L. , Keating Brendan J. , Qu Liming , He Jing , Tobin Martin D. , Tomaszewski Maciej , Baumert Jens , Klopp Norman , Döring Angela , Thorand Barbara , Li Mingyao , Reilly Muredach P. , Koenig Wolfgang , Samani Nilesh J. , Rader Daniel J. 
Published: February 2011

Background—
Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.

Methods and Results—

Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including
ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664
) and provide evidence that suggests an association in several previously unreported candidate gene loci (including
ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4
). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.

Conclusions—
Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.
Left Ventricular Assist Device Therapy in Patients With Restrictive and Hypertrophic Cardiomyopathy
Authors: Topilsky Yan , Pereira Naveen L. , Shah Dipesh K. , Boilson Barry , Schirger John A. , Kushwaha Sudhir S. , Joyce Lyle D. , Park Soon J. 
Published: February 2011

Background—
Left ventricular assist device (LVAD) is being increasingly used in patients with end-stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end-stage heart failure caused by restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients.

Methods and Results—

Eighty-three patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics and surgical and long-term impact of LVAD therapy in 8 patients with RCM or HCM and compared their outcomes with the 75 patients with dilated and ischemic cardiomyopathy. Compared with patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end-diastolic dimensions (52.5±6 mm versus 68.6±8 mm;
P
<0.0001) and increased thickness of septal (16 [12, 19] mm versus 10[8.5, 11] mm,
P
=0.0003) and higher left ventricular ejection fraction (21 [20, 36]% versus 17 [15, 22]%;
P
=0.0009). We found no difference in early mortality (12.5% versus 9.3%,
P
=0.57) or length of hospital stay (11 [8, 45] days versus 18.5 [12.2, 27.7] days;
P
=0.51) between the 2 groups. The right atrial pressure was higher (18 [15, 20] mm Hg versus 12 [9, 15] mm Hg,
P
=0.03), and pump flow was lower (4.3 [3.8, 4.5] L versus 5.2 [4.7, 5.5] L,
P
=0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% versus 44.5%,
P
=0.006). There was no difference in the total number of blood units transfused. Median (min, max) follow-up duration after LVAD implantation was 166 [1, 1044] days. The 1-year actuarial survival rate was not different between the 2 groups (87.5% [95% confidence interval, 52.9% to 97.8%] versus 73.2 [95% confidence interval, 60% to 85%];
P
=0.77).

Conclusions—
Our preliminary data show that patients with end-stage heart failure caused by RCM or HCM may benefit from continuous axial flow LVAD therapy. This small study suggests that mortality is comparable with those patients who have dilated or ischemic cardiomyopathy, but right heart failure, prolonged inotropic use, and central venous catheter infections are more common in patients with RCM and HCM who were treated with LVAD. Because of the small numbers the differences should be interpreted cautiously, and prospective clinical trials would be required to recommend this therapy for these patients as bridge to transplantation or destination treatment.