bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Biomarkers Defined by Autoantibody Signatures to Aberrant O-Glycopeptide Epitopes
Authors: Wandall Hans H. , Blixt Ola , Tarp Mads A. , Pedersen Johannes W. , Bennett Eric P. , Mandel Ulla , Ragupathi Govind , Livingston Phil O. , Hollingsworth Michael A. , Taylor-Papadimitriou Joyce , Burchell Joy , Clausen Henrik 
Published: February 2010

Abstract
Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evaluated whether autoantibodies generated to aberrant O-glycoforms of MUC1 might serve as sensitive diagnostic biomarkers for cancer. Using an antibody-based glycoprofiling ELISA assay, we documented that aberrant truncated glycoforms were not detected in sera of cancer patients. An O-glycopeptide microarray was developed that detected IgG antibodies to aberrant O-glycopeptide epitopes in patients vaccinated with a keyhole limpet hemocyanin–conjugated truncated MUC1 peptide. We detected cancer-associated IgG autoantibodies in sera from breast, ovarian, and prostate cancer patients against different aberrent O-glycopeptide epitopes derived from MUC1. These autoantibodies represent a previously unaddressed source of sensitive biomarkers for early detection of cancer. The methods we have developed for chemoenzymatic synthesis of O-glycopeptides on microarrays may allow for broader mining of the entire cancer O-glycopeptidome. Cancer Res; 70(4); 1306–13
Surface Charge: A Key Determinant of Protein Localization and Function
Authors: Goldenberg Neil M. , Steinberg Benjamin E. 
Published: February 2010

Abstract
Electrostatic charge at the membrane surface has emerged as a crucial determinant of the localization and activation of many proteins containing polycationic domains in their amino acid sequence. The spatiotemporal regulation of surface charge, as well as the downstream effects of dysregulation of surface charge, may have a significant impact on many of the signaling molecules important to cancer biology such as K-ras. Cancer Res; 70(4); 1277–80
Irreversible Electroporation Therapy in the Liver: Longitudinal Efficacy Studies in a Rat Model of Hepatocellular Carcinoma
Authors: Guo Yang , Zhang Yue , Klein Rachel , Nijm Grace M. , Sahakian Alan V. , Omary Reed A. , Yang Guang-Yu , Larson Andrew C. 
Published: February 2010

Abstract
Irreversible electroporation (IRE) is an innovative local-regional therapy that involves delivery of intense electrical pulses to tissue to induce nanoscale cell membrane defects for tissue ablation. The purpose of this study was to investigate the feasibility of using IRE as a liver-directed ablation technique for the treatment of hepatocellular carcinoma (HCC). In the N1-S1 rodent model, hepatomas were grown in 30 Sprague-Dawley rats that were divided into treatment and control groups. For treatment groups, IRE electrodes were inserted and eight 100-μs 2,500-V pulses were applied to ablate the targeted tumor tissues. For both groups, magnetic resonance imaging scans were performed at baseline and 15-day follow-up intervals to determine tumor sizes (one-dimensional maximum diameter, Dmax; estimated two-dimensional cross-sectional area, Cmax) as a tactic to assess longitudinal outcomes. Additional groups of treated animals were sacrificed at 1-, 3-, and 7-day intervals posttherapy for pathology assessment of treatment response. Magnetic resonance images showed significant tumor size reductions within 15 days posttherapy (32 ± 31% Dmax and 52 ± 39% Cmax decreases compared with 110 ± 35% Dmax and 286 ± 125% Cmax increases for untreated tumors). Pathology correlation studies documented progression from poorly differentiated viable HCC tissues before treatment to extensive tumor necrosis and full regression in 9 of 10 treated rats 7 to 15 days after treatment. Our findings suggest that IRE can be an effective strategy for targeted ablation of liver tumors, prompting its further evaluation for HCC therapy. Cancer Res; 70(4); 1555–63
Gossypol Induces Apoptosis by Activating p53 in Prostate Cancer Cells and Prostate Tumor–Initiating Cells
Authors: Volate Suresh R. , Kawasaki Brian T. , Hurt Elaine M. , Milner John A. , Kim Young S. , White Jeffrey , Farrar William L. 
Published: February 2010

Abstract
Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor–initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC50 between 3 and 5 μmol/L. Additionally, gossypol was effective at inhibiting prostate tumor–initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1–10 μmol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer. Mol Cancer Ther; 9(2); 461–70
Molecular Evolutionary Analysis of Cancer Cell Lines
Authors: Zhang Yan , Italia Michael J. , Auger Kurt R. , Halsey Wendy S. , Van Horn Stephanie F. , Sathe Ganesh M. , Magid-Slav Michal , Brown James R. , Holbrook Joanna D. 
Published: February 2010

AbstractWith genome-wide cancer studies producing large DNA sequence data sets, novel computational approaches toward better understanding the role of mutations in tumor survival and proliferation are greatly needed. Tumors are widely viewed to be influenced by Darwinian processes, yet molecular evolutionary analysis, invaluable in other DNA sequence studies, has seen little application in cancer biology. Here, we describe the phylogenetic analysis of 353 cancer cell lines based on multiple sequence alignments of 3,252 nucleotides and 1,170 amino acids built from the concatenation of variant codons and residues across 494 and 523 genes, respectively. Reconstructed phylogenetic trees cluster cell lines by shared DNA variant patterns rather than cancer tissue type, suggesting that tumors originating from diverse histologies have similar oncogenic pathways. A well-supported clade of 91 cancer cell lines representing multiple tumor types also had significantly different gene expression profiles from the remaining cell lines according to statistical analyses of mRNA microarray data. This suggests that phylogenetic clustering of tumor cell lines based on DNA variants might reflect functional similarities in cellular pathways. Positive selection analysis revealed specific DNA variants that might be potential driver mutations. Our study shows the potential role of molecular evolutionary analyses in tumor classification and the development of novel anticancer strategies. Mol Cancer Ther; 9(2); 279–91
A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts
Authors: Wang Yaolin , Lipari Philip , Wang Xiaoying , Hailey Judith , Liang Lianzhu , Ramos Robert , Liu Ming , Pachter Jonathan A. , Bishop W. Robert , Wang Yan 
Published: February 2010

Abstract
The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410–8
The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance
Authors: Meinel Felix G. , Mandl-Weber Sonja , Baumann Philipp , Leban Johann , Schmidmaier Ralf 
Published: February 2010

AbstractEvidence is increasing that aberrant NF-κB activation is crucial for multiple myeloma pathophysiology and a promising target for new antimyeloma therapies. In this study, we assessed the in vitro antimyeloma activity of the novel NF-κB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo. In mice, V1810 plasma concentrations of 10 μmol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC50 = 5–12 μmol/L) as well as in primary multiple myeloma cells (IC50 = 5–40 μmol/L). Apoptosis induced by V1810 is associated with proteasome-independent inhibition of NF-κB signaling (41% relative reduction), downregulation of Mcl-1, and caspase 3 cleavage. In OPM2, U266, and RPMI-8226 cells, induction of apoptosis is accompanied by cell cycle arrest. Western blots revealed downregulation of Cdk4 as well as cyclin D1 (U266) or cyclin D2 (OPM2, NCI-H929, RPMI-8226), but not cyclin D3. Consistently, retinoblastoma protein was found to be hypophosphorylated. Furthermore, V1810 reverses NF-κB activation induced by the genotoxic drugs melphalan and doxorubicin. V1810 and melphalan synergistically decrease multiple myeloma cell viability. Taken together, the novel, proteasome-independent NF-κB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma cells at a concentration range that can be achieved in vivo. Moreover, V1810 reverses NF-κB activation by alkylating drugs and overcomes NF-κB–mediated resistance to melphalan. Mol Cancer Ther; 9(2); 300–10
Reprogramming Murine Telomerase Rapidly Inhibits the Growth of Mouse Cancer Cells In vitro and In vivo
Authors: Xu Tong , Xu Yucheng , Liao Chun-Peng , Lau Roy , Goldkorn Amir 
Published: February 2010

Abstract
Telomerase plays a critical role in cancer, prompting the pursuit of various telomerase-based therapeutic strategies. One such strategy, telomerase interference, exploits the high telomerase activity in cancer cells and reprograms telomerase to encode “toxic” telomeres. To date, telomerase interference has been tested in human cancer cells xenografted into mice, an approach that does not recapitulate spontaneous malignancy and offers few insights about host toxicities, because human telomerase is targeted in a mouse host. To address these limitations, we designed and validated two new gene constructs specifically targeting mouse telomerase: mutant template mouse telomerase RNA (MT-mTer) and small interfering RNA against wild-type mouse telomerase RNA (α-mTer-siRNA). Using lentiviral delivery in mouse prostate cancer cells, we achieved α-mTer-siRNA–mediated knockdown of wild-type mTer (80% depletion) and concurrent overexpression of MT-mTer (50-fold). We showed that the two constructs effectively synergize to reprogram murine telomerase to add mutant instead of wild-type telomeric repeats, resulting in rapid telomeric uncapping (5-fold increase in DNA damage foci). This, in turn, led to rapid and significant apoptosis (&gt;90% of cells) and growth inhibition in vitro (90% reduction in viable cell mass) and in vivo (75% reduction in tumor allograft wet weight). In summary, we have shown that mouse cancer cells are vulnerable to direct telomerase interference using novel murine telomerase-targeting constructs; this approach can now be used to study the true therapeutic potential of telomerase interference in mouse spontaneous cancer models. Mol Cancer Ther; 9(2); 438–49
A Novel E1B-55kD-Deleted Oncolytic Adenovirus Carrying Mutant KRAS-Regulated hdm2 Transgene Exerts Specific Antitumor Efficacy on Colorectal Cancer Cells
Authors: Liu Chin-Cheng , Liu Jin-Hwang , Wu Suh-Chin , Yen Chueh-Chuan , Chen Wei-Shone , Tsai Ying-Chieh 
Published: February 2010

Abstract
E1B-55kD-deleted adenoviruses have been used as conditionally replicative adenoviruses (CRAds) for therapeutic purposes in tumors with loss-of-function p53 mutation. To target cancer cells that harbor activating mutant KRAS (KRASaMut) but spare p53wild normal cells, we constructed and examined by reporter assays a KRASaMut but not p53-responsive promoter, the Δp53REP2 promoter. The Δp53REP2 promoter, derived from human double minute 2 (hdm2) P2 promoter with its p53 response elements being deleted, was used to regulate the expression of the hdm2 transgene in a novel E1B-55kD-deleted CRAd, the Ad-KRhdm2. The Ad-KRhdm2 selectively replicated in and exerted cytopathic effects on KRASaMut colorectal cancer cell lines (HCT116, LoVo, LS174T, LS123, and SW620), regardless of their p53 gene statuses, by forming plaques and exhibiting cytopathic effect in cultured cells. Ad-KRhdm2, like other E1B-55kD-deleted adenoviruses, also exerted selective cytopathic effects on tumor cells with loss-of-function p53 mutant. The multiplicities of infection of Ad-KRhdm2 required to decrease 50% viability of KRASaMut tumor cells cultured for 7 days were 440 to 3,400 times less than those of MRC5 normal fibroblasts and KRASwild/p53wild RKO tumor cells. Intratumoral injection of Ad-KRhdm2 vectors exhibited specific lytic activities in nude mouse xenografts of KRASaMut cell lines (LoVo, SW620, and LS174T) but not in xenografts of RKO cells. Transduction of KRASaMut/p53wild HCT116, LoVo, and LS174T cells by Ad-KRhdm2 significantly increased Hdm2 expression, decreased p53 level, and abolished the p53-transactivating p21Cip1 promoter activity. Ad-KRhdm2 has shown its therapeutic potential in KRASaMut cancer cells and warrants further clinical trials. Mol Cancer Ther; 9(2); 450–60
Biochemical Characterization of AMG 102: A Neutralizing, Fully Human Monoclonal Antibody to Human and Nonhuman Primate Hepatocyte Growth Factor
Authors: Burgess Teresa L. , Sun Jan , Meyer Susanne , Tsuruda Trace S. , Sun Jilin , Elliott Gary , Chen Qing , Haniu Mitsuru , Barron Will F. , Juan Todd , Zhang Ke , Coxon Angela , Kendall Richard L. 
Published: February 2010

Abstract
AMG 102 is a fully human monoclonal antibody that selectively targets and neutralizes hepatocyte growth factor/scatter factor (HGF/SF). A detailed biochemical and functional characterization of AMG 102 was done to support its clinical development for the treatment of cancers dependent on signaling through the HGF/SF:c-Met pathway. In competitive equilibrium binding experiments, AMG 102 bound to human and cynomolgus monkey HGF with affinities of approximately 19 pmol/L and 41 pmol/L, respectively. However, AMG 102 did not detect mouse or rabbit HGF on immunoblots. Immunoprecipitation experiments showed that AMG 102 preferentially bound to the mature, active form of HGF, and incubation of AMG 102/HGF complexes with kallikrein protease indicated that AMG 102 had no apparent effect on proteolytic processing of the inactive HGF precursor. AMG 102 inhibited human and cynomolgus monkey HGF-induced c-Met autophosphorylation in PC3 cells with IC50 values of 0.12 nmol/L and 0.24 nmol/L, respectively. AMG 102 also inhibited cynomolgus monkey HGF-induced migration of human MDA-MB-435 cells but not rat HGF-induced migration of mouse 4T1 cells. Epitope-mapping studies of recombinant HGF molecules comprising human/mouse chimeras and human-to-mouse amino acid substitutions showed that amino acid residues near the NH2-terminus of the β-chain are critical for AMG 102 binding. Bound AMG 102 protected one trypsin protease cleavage site near the NH2-terminus of the β-chain of human HGF, further substantiating the importance of this region for AMG 102 binding. Currently, AMG 102 is in phase II clinical trials in a variety of solid tumor indications. Mol Cancer Ther; 9(2); 400–9
Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination
Authors: Mordant Pierre , Loriot Yohann , Leteur Céline , Calderaro Julien , Bourhis Jean , Wislez Marie , Soria Jean-Charles , Deutsch Eric 
Published: February 2010

AbstractActivation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. Mol Cancer Ther; 9(2); 358–68
Early Parenteral Nutrition and Successful Postnatal Growth of Premature Infants
Authors: Herrmann Kenneth Ross , Herrmann Kirk Ross 
Published: February 2010

Background:Premature infants have uniformly demonstrated growth failure by 36 weeks postmenstrual age. In an evaluation of care quality, the authors tested the hypothesis that premature infants would grow adequately when they received more than 50 kcal/kg per day of parenteral nutrition.Methods:The study cohort consisted of 84 premature infants born at less than 30 weeks gestation. A computer software program was used to determine parenteral nutrition orders and establish a database. The database provided the nutrition and postnatal growth data. Successful growth was defined as weight greater than the 10th percentile for intrauterine growth.Results:Energy intake exceeded 50 kcal/kg per day after the first day. The cohort weight and head circumference measurements remained above the 10th percentile of intrauterine growth through 36 weeks postmenstrual age. Infants demonstrated successful growth by remaining above the 10th percentile for the following: 4 of 12 (33%) with birth weights 501–750 g, 16 of 26 (62%) with birth weights 751–1,000 g, and 16 of 25 (64%) with birth weights 1,001–1,250 g. These differences were statistically greater than a large reference cohort (P < .0001). Length measurements declined below the 10th percentile of intrauterine growth at 36 weeks postmenstrual age.Conclusions:Postnatal growth failure is not an inevitable consequence of premature birth. The clinical evidence supports previous nutrient recommendations from the American Academy of Pediatrics. Promptly providing premature infants with parenteral nutrition, including calories greater than the basal energy requirement, can produce postnatal growth that remains above the 10th percentile of intrauterine growth.
Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-β signaling at the bipotent erythro-megakaryocytic progenitor stage
Authors: Randrianarison-Huetz Voahangy , Laurent Benoit , Bardet Valérie , Blobe Gerard C. , Huetz François , Duménil Dominique 
Published: February 2010

Abstract
Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis. Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis. We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors. We further identify in this cell population the type III transforming growth factor-β receptor gene, TGFBR3, as a direct target of Gfi-1B. Knockdown of Gfi-1B results in altered transforming growth factor-β (TGF-β) signaling as shown by the increase in Smad2 phosphorylation and its inability to associate to the transcription intermediary factor 1-γ (TIF1-γ). Because the Smad2/TIF1-γ complex is known to specifically regulate erythroid differentiation, we propose that, by repressing TGF-β type III receptor (TβRΙII) expression, Gfi-1B favors the Smad2/TIF1-γ interaction downstream of TGF-β signaling, allowing immature progenitors to differentiate toward the erythroid lineage.
Human mutation D157G in ferroportin leads to hepcidin-independent binding of Jak2 and ferroportin down-regulation
Authors: De Domenico Ivana , Lo Eric , Ward Diane M. , Kaplan Jerry 
Published: February 2010

Abstract
Mutations in the iron exporter ferroportin (Fpn) result in iron overload in macrophages or hepatocytes depending upon the mutation. Patients with Fpn mutation D157G show high serum ferritin and normal to slightly elevated transferrin saturation. Here, we show that Fpn(D157G)–green fluorescent protein (GFP) is down-regulated independent of hepcidin, and that this down-regulation is due to the constitutive binding of Jak2 and Fpn phosphorylation. Expression of Fpn(D157G)-GFP in Danio rerio results in a severe growth defect, which can be rescued by iron supplementation. These results identify a hepcidin-independent regulation of Fpn that can result in alterations in iron homeostasis.