bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the Antigenic Diversity of Placenta-Binding
Plasmodium falciparum
Variants and the Antibody Repertoire among Pregnant Women
Authors: Hommel Mirja , Elliott Salenna R. , Soma Viju , Kelly Greg , Fowkes Freya J. I. , Chesson Joanne M. , Duffy Michael F. , Bockhorst Joseph , Avril Marion , Mueller Ivo , Raiko Andrew , Stanisic Danielle I. , Rogerson Stephen J. , Smith Joseph D. , Beeson James G. 
Published: February 2010

ABSTRACT

Pregnant women are infected by specific variants of
Plasmodium falciparum
that adhere and accumulate in the placenta. Using serological and molecular approaches, we assessed the global antigenic diversity of surface antigens expressed by placenta-binding isolates to better understand immunity to malaria in pregnancy and evolution of polymorphisms and to inform vaccine development. We found that placenta-binding isolates originating from all major regions where malaria occurs were commonly recognized by antibodies in different populations of pregnant women. There was substantial antigenic overlap and sharing of epitopes between isolates, including isolates from distant geographic locations, suggesting that there are limitations to antigenic diversity; however, differences between populations and isolates were also seen. Many women had cross-reactive antibodies and/or a broad repertoire of antibodies to different isolates. Studying VAR2CSA as the major antigen expressed by placenta-binding isolates, we identified antibody epitopes encoded by variable sequence blocks in the DBL3 domain. Analysis of global
var2csa
DBL3 sequences demonstrated that there was extensive sharing of variable blocks between Africa, Asia, Papua New Guinea, and Latin America, which likely contributes to the high level of antigenic overlap between different isolates. However, there was also evidence of geographic clustering of sequences and differences in VAR2CSA sequences between populations. The results indicate that there is limited antigenic diversity in placenta-binding isolates and may explain why immunity to malaria in pregnancy can be achieved after exposure during one pregnancy. Inclusion of a limited number of variants in a candidate vaccine may be sufficient for broad population coverage, but geographic considerations may also have to be included in vaccine design.
Convergence of the Sequence of Successive Approximations to a Fixed Point
Authors: Suzuki Tomonari 
Published: February 2010

AbstractIf "Equation missing" is a complete metric space and "Equation missing" is a contraction on "Equation missing", then the conclusion of the Banach-Caccioppoli contraction principle is that the sequence of successive approximations "Equation missing" of "Equation missing" starting from any point "Equation missing" converges to a unique fixed point. In this paper, using the concept of "Equation missing"-distance, we obtain simple, sufficient, and necessary conditions of the above conclusion.
Evaluation of the Proteasome Inhibitor MLN9708 in Preclinical Models of Human Cancer
Authors: Kupperman Erik , Lee Edmund C. , Cao Yueying , Bannerman Bret , Fitzgerald Michael , Berger Allison , Yu Jie , Yang Yu , Hales Paul , Bruzzese Frank , Liu Jane , Blank Jonathan , Garcia Khristofer , Tsu Christopher , Dick Larry , Fleming Paul , Yu Li , Manfredi Mark , Rolfe Mark , Bolen Joe 
Published: February 2010

Abstract
The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, severalgroups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. Cancer Res; 70(5); 1970–80
Talin1 Promotes Tumor Invasion and Metastasis via Focal Adhesion Signaling and Anoikis Resistance
Authors: Sakamoto Shinichi , McCann Richard O. , Dhir Rajiv , Kyprianou Natasha 
Published: February 2010

Abstract
Talin1 is a focal adhesion complex protein that regulates integrin interactions with ECM. This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell adhesion, migration, and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1-regulated cell survival signals via phosphorylation of focal adhesion complex proteins, such as focal adhesion kinase and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the transgenic adenocarcinoma mouse prostate mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared with primary prostate tumors (P &lt; 0.0001). These findings suggest (a) a therapeutic significance of disrupting talin1 signaling/focal adhesion interactions in targeting metastatic prostate cancer and (b) a potential value for talin1 as a marker of tumor progression to metastasis. Cancer Res; 70(5); 1885–95
A Bax-Mediated Mechanism for Obatoclax-Induced Apoptosis of Cholangiocarcinoma Cells
Authors: Smoot Rory L. , Blechacz Boris R.A. , Werneburg Nathan W. , Bronk Steve F. , Sinicrope Frank A. , Sirica Alphonse E. , Gores Gregory J. 
Published: February 2010

Abstract
Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells “primed” for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was to examine the single-agent activity of obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by obatoclax treatment. Despite single-agent activity by obatoclax, the mitochondria from these cells did not release cytochrome c after incubation with this BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for obatoclax but did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death. Cancer Res; 70(5); 1960–9
The COXEN Principle: Translating Signatures of In vitro Chemosensitivity into Tools for Clinical Outcome Prediction and Drug Discovery in Cancer
Authors: Smith Steven C. , Baras Alexander S. , Lee Jae K. , Theodorescu Dan 
Published: February 2010

Abstract
Substantial effort has been devoted to in vitro testing of candidate chemotherapeutic agents. In particular, the United States National Cancer Institute Developmental Therapeutics Program (NCI-DTP) Human Tumor Cell Line Screen has screened hundreds of thousands of compounds and extracts, for which data on more than 40,000 compounds tested on a panel of 60 cancer cell lines (NCI-60) are publically available. In tandem, gene expression profiling has brought about a sea change in our understanding of cancer biology, allowing discovery of biomarkers or signatures able to characterize, classify, and prognosticate clinical behavior of human tumors. Recent studies have used tumor profiling matched to clinical trial outcome data to derive gene expression models predicting therapeutic outcomes, though such efforts are costly, time-consuming, tumor type-specific, and not amenable to rare diseases. Furthermore, addition of new or established drugs to multidrug combinations in which such models are already available requires the entire model to be re-derived. Can the aforementioned in vitro testing platform, coupled to the universal language of genomics, be used to develop, a priori, gene expression models predictive of clinical outcomes? Recent advances, including the CO-eXpression ExtrapolatioN (COXEN) algorithm, suggest that development of these models may be possible and raise important implications for future trial design and drug discovery. Cancer Res; 70(5); 1753–8
Protein Kinase D1 Inhibits Cell Proliferation through Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Secretion in Prostate Cancer
Authors: Biswas M. Helal Uddin , Du Cheng , Zhang Chuanyou , Straubhaar Juerg , Languino Lucia R. , Balaji K.C. 
Published: February 2010

Abstract
We and others previously showed that protein kinase D1 (PKD1) is downregulated in several cancers including prostate; interacts with E-cadherin, a major cell adhesion epithelial protein; and causes increased cell aggregation and decreased motility of prostate cancer cells. In this study, we show that PKD1 complexes with β3-integrin, resulting in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase–ERK pathway, which causes increased production of matrix metalloproteinase (MMP)-2 and MMP-9, that is associated with shedding of soluble 80 kDa E-cadherin extracellular domain. Interestingly, decreased cell proliferation following PKD1 transfection was rescued by MMP-2 and MMP-9 inhibitors and augmented by recombinant MMP-2 (rMMP-2) and rMMP-9 proteins, suggesting an antiproliferative role for MMPs in prostate cancer. Translational studies by in silico analysis of publicly available DNA microarray data sets show a significant direct correlation between PKD1 and MMP-2 expression in human prostate tissues. The study shows a novel mechanism for antiproliferative effects of PKD1, a protein of emerging translational interest in several human cancers, through increased production of MMP-2 and MMP-9 in cancer cells. Cancer Res; 70(5); 2095–104
ZIP4 Regulates Pancreatic Cancer Cell Growth by Activating IL-6/STAT3 Pathway through Zinc Finger Transcription Factor CREB
Authors: Zhang Yuqing , Bharadwaj Uddalak , Logsdon Craig D. , Chen Changyi , Yao Qizhi , Li Min 
Published: February 2010

Abstract
Purpose: Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth.
Experimental Design: The expression of cyclin D1, interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) in pancreatic cancer xenografts and cells were examined by real-time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of cAMP response element–binding protein (CREB) is examined by a promoter activity assay.
Results: Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)–injected orthotopic xenografts and was downregulated in the ZIP4-silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of STAT3, an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity and caused increased phosphorylation of CREB.
Conclusions: Our study suggest that ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth and suggest new therapeutic targets, including ZIP4, IL-6, and STAT3, in pancreatic cancer treatment. Clin Cancer Res; 16(5); 1423–30
Diverse Patterns of T-Cell Response against Multiple Newly Identified Human Y Chromosome–Encoded Minor Histocompatibility Epitopes
Authors: Ofran Yishai , Kim Haesook T. , Brusic Vladimir , Blake Loren , Mandrell Michael , Wu Catherine J. , Sarantopoulos Stefanie , Bellucci Roberto , Keskin Derin B. , Soiffer Robert J. , Antin Joseph H. , Ritz Jerome 
Published: February 2010

AbstractPurpose: Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA.Experimental Design: We developed an algorithm based on genetic disparities between Y chromosome–encoded and X chromosome–encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome–derived, HLA A*0201–restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A*0201 positive.Results: Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A*0201–restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A*0201, each patient responded to a unique set of peptides.Conclusions: Novel HLA A*0201–restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia. Clin Cancer Res; 16(5); 1642–51
Association of Polymorphisms inAKT1andEGFRwith Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib
Authors: Giovannetti Elisa , Zucali Paolo A. , Peters Godefridus J. , Cortesi Filippo , D'Incecco Armida , Smit Egbert F. , Falcone Alfredo , Burgers Jacobus A. , Santoro Armando , Danesi Romano , Giaccone Giuseppe , Tibaldi Carmelo 
Published: February 2010

AbstractEGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non–small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR −191C/A (P &lt; 0.001), −216 G/T (P &lt; 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade &gt;1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR −191C/A, −216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization. Mol Cancer Ther; 9(3); 581–93
Reduced Argininosuccinate Synthetase Is a Predictive Biomarker for the Development of Pulmonary Metastasis in Patients with Osteosarcoma
Authors: Kobayashi Eisuke , Masuda Mari , Nakayama Robert , Ichikawa Hitoshi , Satow Reiko , Shitashige Miki , Honda Kazufumi , Yamaguchi Umio , Shoji Ayako , Tochigi Naobumi , Morioka Hideo , Toyama Yoshiaki , Hirohashi Setsuo , Kawai Akira , Yamada Tesshi 
Published: February 2010

Abstract
Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 × 10−5). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P &lt; 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G0-G1 arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. Mol Cancer Ther; 9(3); 535–44
Epidermal Growth Factor–Induced Heparanase Nucleolar Localization Augments DNA Topoisomerase I Activity in Brain Metastatic Breast Cancer
Authors: Zhang Lixin , Sullivan Peggy , Suyama Julie , Marchetti Dario 
Published: February 2010

Abstract
Identification of molecular mechanisms responsible for brain metastatic breast cancer (BMBC) is imperative to develop novel therapies. However, current understanding of the molecular circuitry that governs BMBC dissemination remains fragmentary. Heparanase (HPSE) is the only functional mammalian endoglycosidase whose activity correlates with cancer metastasis, angiogenesis, and the reduced postoperative survival of cancer patients, making it an active target for anticancer therapeutics. We hypothesized that human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) activation promotes HPSE function in human BMBC. To address this, we examined HPSE content, activity, and intracellular trafficking in a HER2/EGFR-expressing BMBC model system and show that HPSE is present, functional, and correlates with HER2 status. Further, we showed that EGF induced nucleolar translocation of HPSE in these cells in a dose- and time-dependent manner upon activation of HER2/EGFR. Knockdowns of HER2/EGFR by small interference RNA abolished EGF-induced HPSE nucleolar translocalization. It was also noted that nucleolar HPSE modulates DNA topoisomerase I (Topo I), an enzyme that is highly present in nucleoli, essential for DNA replication and transcription in a variety of tumors, and inhibited by heparan sulfate. Evidence is provided that HPSE can regulate Topo I activity, which subsequently affects BMBC cell proliferation. Finally, we showed that the nucleolar presence of HPSE with Topo I colocalization is detected only in HER2-overexpressing BMBC patient specimens. Altogether, these findings support the notion that HPSE is a critical downstream target of HER2 mechanisms driving BMBC and is potentially relevant for BMBC therapeutic interventions. Mol Cancer Res; 8(2); 278–90