bluuebunny/crossref_metadata_2025_split huggingface dataset:
S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer
Authors: Mahon Patrick C. , Baril Patrick , Bhakta Vipul , Chelala Claude , Caulee Krishna , Harada Tomohiko , Lemoine Nicholas R. 
Published: July 2007

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is characterized by a particularly marked resistance to chemotherapy. We previously showed an association between decreased expression of BNIP3 and chemoresistance in PDAC cell lines. To further explore the molecular basis of chemoresistance in PDAC, we analyzed microarray data obtained from normal pancreas and PDAC tumor samples to identify genes exhibiting a negative correlation with the expression profile of BNIP3. This analysis identified several S100 family proteins, of which two, S100A2 and S100A4, showed in vitro the ability to repress exogenous BNIP3 promoter activity. We subsequently showed that RNA interference–mediated S100A4 knockdown resulted in an elevated expression of BNIP3 in PDAC cell lines that possess an unmethylated BNIP3 promoter, suggesting that, in addition to hypermethylation, S100A4 overexpression may represent an alternative mechanism for inhibiting BNIP3 function in PDAC. S100A4 knockdown also resulted in an increased sensitivity of PDAC cell lines to gemcitabine treatment, which was coupled with an increase in apoptosis and cell cycle arrest. To investigate the underlying mechanisms mediating these effects, we studied the effect of silencing the expression of S100A4 on the induction of apoptosis, cell cycle arrest, and the activation of apoptotic mediators. Knockdown of S100A4 clearly induced apoptosis with increased fragmentation of DNA and phosphatidyl serine externalization; activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase; and release of cytochrome c into the cytosol. These findings provide evidence that supports a novel role for S100A4 as a prosurvival factor in pancreatic cancer. [Cancer Res 2007;67(14):6786–95]
Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma
Authors: Singer Samuel , Socci Nicholas D. , Ambrosini Grazia , Sambol Elliot , Decarolis Penelope , Wu Yuhsin , O'Connor Rachael , Maki Robert , Viale Agnes , Sander Chris , Schwartz Gary K. , Antonescu Cristina R. 
Published: July 2007

Abstract
Classification of liposarcoma into three biological types encompassing five subtypes, (a) well-differentiated/dedifferentiated, (b) myxoid/round cell, and (c) pleomorphic, based on morphologic features and cytogenetic aberrations, is widely accepted. However, diagnostic discordance remains even among expert sarcoma pathologists. We sought to develop a more systematic approach to liposarcoma classification based on gene expression analysis and to identify subtype-specific differentially expressed genes that may be involved in liposarcoma genesis/progression and serve as potential therapeutic targets. A classifier based on gene expression profiling was able to distinguish between liposarcoma subtypes, lipoma, and normal fat samples. A 142-gene predictor of tissue class was derived to automatically determine the class of an independent validation set of lipomatous samples and shows the feasibility of liposarcoma classification based entirely on gene expression monitoring. Differentially expressed genes for each liposarcoma subtype compared with normal fat were used to identify histology-specific candidate genes with an in-depth analysis of signaling pathways important to liposarcoma pathogenesis and progression in the well-differentiated/dedifferentiated subset. The activation of cell cycle and checkpoint pathways in well-differentiated/dedifferentiated liposarcoma provides several possible novel therapeutic strategies with MDM2 serving as a particularly promising target. We show that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes. These results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma. [Cancer Res 2007;67(14):6626–36]
Blockade of β-Catenin Signaling by Plant Flavonoid Apigenin Suppresses Prostate Carcinogenesis in TRAMP Mice
Authors: Shukla Sanjeev , MacLennan Gregory T. , Flask Chris A. , Fu Pingfu , Mishra Anil , Resnick Martin I. , Gupta Sanjay 
Published: July 2007

Abstract
Deregulation of β-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 μg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 μmol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of β-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to β-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking β-catenin signaling. [Cancer Res 2007;67(14):6925–35]
Breast Cancer Expressing the Activated HER2/neu Is Sensitive to Gefitinib In vitro and In vivo and Acquires Resistance through a Novel Point Mutation in the HER2/neu
Authors: Piechocki Marie P. , Yoo George H. , Dibbley Susan K. , Lonardo Fulvio 
Published: July 2007

Abstract
The HER2/neu oncogene is an important diagnostic and prognostic factor and therapeutic target in breast and other cancers. We developed and characterized a breast cancer cell line (Bam1a) that overexpresses the activated HER2/neu and ErbB-3 and has a gene expression profile consistent with the ErbB-2 genetic signature. We evaluated the effects of the epidermal growth factor receptor (EGFR)/HER2 inhibitor, gefitinib, on this breast tumor line in vitro and in vivo. We characterized the effects of gefitinib on EGFR, HER2, and ErbB-3 phosphorylation by Western blot and determined the effects on downstream signaling through growth, survival, and stress pathways and the effect on proliferation, cell cycle, and apoptosis. Gefitinib treatment diminished phosphorylation of the ErbB-3 &gt; EGFR &gt; HER2/neu and signal transducers and activators of transcriptions in a dose-dependent fashion. Downstream mitogenic signaling through mitogen-activated protein (MAP)/extracellular signal regulated kinase kinase, p44/42 MAP kinase (MAPK) and stress signaling through c-Jun-NH2-kinase (JNK) 1 and c-Jun was impaired (1 μmol/L, 4–24 h), leading to cytostasis and cell cycle arrest within 24 h by decreased cyclin D1, cyclin B1, and pSer795Rb and increased p27. Proliferation and colony formation were inhibited at 0.5 and 1 μmol/L, respectively, and correlated with altered gene expression profiles. Diminished survival signaling through Akt, induction of bim, loss of connexin43, and decreased production of vascular endothelial growth factor-D preceded caspase-3 and poly(ADP)ribose polymerase (PARP) cleavage and apoptosis (&gt;50% 2 μmol/L, 48 h). Oral administration of gefitinib was able to prevent the outgrowth of Bam1a tumor cells from palpable lesions, shrink established tumors, eliminate HER2 and HER3 phosphorylation, and decrease MAPK and Akt signaling in vivo. A variant of the Bam1a cell line, IR-5, with acquired ability to grow in 5 μmol/L gefitinib was developed and characterized. IR-5 bears a novel point mutation in the HER2/neu that corresponds to a L726I in the ATP-binding pocket and correlates with a log decrease in sensitivity to gefitinib, increased heterodimerization with EGFR and HER3, and impaired down-regulation. Gene expression profiling of IR-5 showed increased expression of EMP-1, NOTCH-1, FLT-1, PDGFB, and several other genes that may contribute to the resistant phenotype and sustain signaling through MAPK and Akt. This model will be useful in understanding the differences between intrinsic drug sensitivity and acquired resistance in the context of therapeutic strategies that target oncogene addicted diseases. [Cancer Res 2007;67(14):6825–43]
Development of Vaccines for High-Risk Ductal Carcinoma In situ of the Breast
Authors: Czerniecki Brian J. , Roses Robert E. , Koski Gary K. 
Published: July 2007

Abstract
Certain ductal carcinoma in situ (DCIS) lesions overexpress the HER-2/neu receptor at this early stage of breast cancer development. Recently, we showed that a HER-2–targeted dendritic cell vaccine could be used to eliminate HER-2–overexpressing cells in patients that harbor these high-risk DCIS lesions. Our findings suggest that vaccinating such patients might diminish the risk of recurrence, protect against the development of invasive breast cancer, and minimize morbidity associated with current treatments. We discuss several implications of this work for developing effective cancer vaccines. [Cancer Res 2007;67(14):6531–4]
Ph+/VE-cadherin+ identifies a stem cell–like population of acute lymphoblastic leukemia sustained by bone marrow niche cells
Authors: Wang Lin , O'Leary Heather , Fortney James , Gibson Laura F. 
Published: July 2007

AbstractAlthough leukemic stem cells (LSCs) show a symbiotic relationship with bone marrow microenvironmental niches, the mechanism by which the marrow microenvironment contributes to self-renewal and proliferation of LSCs remains elusive. In the present study, we identified a unique subpopulation of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) cells coexpressing markers of endothelial cells (including VE-cadherin, PECAM-1, and Flk-1) and committed B-lineage progenitors. After long-term coculture with bone marrow stromal cells, tumor cells formed hematopoietic colonies and cords, expressed early stem- cell markers, and showed endothelial sprouting. Gene expression profiles of LSCs were altered in the presence of stromal cell contact. Stromal cell contact promoted leukemic cell VE-cadherin expression, stabilized β-catenin, and up-regulated Bcr-abl fusion gene expression. Our study indicates that these specific tumor cells are uniquely positioned to respond to microenvironment-derived self-renewing and proliferative cues. Ph+/VE-cadherin+ tumor subpopulation circumvents the requirement of exogenous Wnt signaling for self-renewal through stromal cell support of leukemic cell VE-cadherin expression and up-regulated Bcr-abl tyrosine kinase activity. These data suggest that strategies targeting signals in the marrow microenvironment that amplify the Bcr-abl/VE-cadherin/β-catenin axis may have utility in sensitizing drug-resistant leukemic stem cells.
The Laminin 511/521–binding site on the Lutheran blood group glycoprotein is located at the flexible junction of Ig domains 2 and 3
Authors: Mankelow Tosti J. , Burton Nicholas , Stefansdottir Fanney O. , Spring Frances A. , Parsons Stephen F. , Pedersen Jan S. , Oliveira Cristiano L. P. , Lammie Donna , Wess Timothy , Mohandas Narla , Chasis Joel Anne , Brady R. Leo , Anstee David J. 
Published: July 2007

Abstract
The Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the α5 subunit of Laminin 511/521, an extracellular matrix protein. This interaction may contribute to vaso-occlusive events that are an important cause of morbidity in sickle cell disease. Using x-ray crystallography, small-angle x-ray scattering, and site-directed mutagenesis, we show that the extracellular region of Lutheran forms an extended structure with a distinctive bend between the second and third immunoglobulin-like domains. The linker between domains 2 and 3 appears to be flexible and is a critical determinant in maintaining an overall conformation for Lutheran that is capable of binding to Laminin. Mutagenesis studies indicate that Asp312 of Lutheran and the surrounding cluster of negatively charged residues in this linker region form the Laminin-binding site. Unusually, receptor binding is therefore not a function of the domains expected to be furthermost from the plasma membrane. These studies imply that structural flexibility of Lutheran may be essential for its interaction with Laminin and present a novel opportunity for the development of therapeutics for sickle cell disease.
Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms
Authors: Lenk Guy M , Tromp Gerard , Weinsheimer Shantel , Gatalica Zoran , Berguer Ramon , Kuivaniemi Helena 
Published: July 2007

AbstractBackgroundAbdominal aortic aneurysms are a common disorder with an incompletely understood etiology. We used Illumina and Affymetrix microarray platforms to generate global gene expression profiles for both aneurysmal (AAA) and non-aneurysmal abdominal aorta, and identified genes that were significantly differentially expressed between cases and controls.ResultsAffymetrix and Illumina arrays included 18,057 genes in common; 11,542 (64%) of these genes were considered to be expressed in either aneurysmal or normal abdominal aorta. There were 3,274 differentially expressed genes with a false discovery rate (FDR) ≤ 0.05. Many of these genes were not previously known to be involved in AAA, includingSOSTandRUNX3, which were confirmed using Q-RT-PCR (Pearson correlation coefficient for microarray and Q-RT-PCR data = 0.89; p-values for differences in expression between AAA and controls forSOST: 4.87 × 10-4and forRUNX3: 4.33 × 10-5). Analysis of biological pathways, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), indicated extreme overrepresentation of immune related categories. The enriched categories included the GO category Immune Response (GO:0006955; FDR = 2.1 × 10-14), and the KEGG pathwaysnatural killer cell mediated cytotoxicity(hsa04650; FDR = 5.9 × 10-6) andleukocyte transendothelial migration(hsa04670; FDR = 1.1 × 10-5).ConclusionPrevious studies have provided evidence for the involvement of the immune system in AAA. The current expression analysis extends these findings by demonstrating broad coordinate gene expression in immunological pathways. A large number of genes involved in immune function were differentially expressed in AAA, and the pathway analysis gave these results a biological context. The data provide valuable insight for future studies to dissect the pathogenesis of human AAA. These pathways might also be used as targets for the development of therapeutic agents for AAA.
The distribution of sexually-transmitted Human Papillomaviruses in HIV positive and negative patients in Zambia, Africa
Authors: Ng'andwe Christopher , Lowe John J , Richards Paula J , Hause Lara , Wood Charles , Angeletti Peter C 
Published: July 2007

AbstractBackgroundHuman Papillomaviruses (HPV) are double-stranded DNA viruses, considered to be the primary etiological agents in cervical intraepithelial neoplasias and cancers. Approximately 15–20 of the 40 mucosal HPVs confer a high-risk of progression of lesions to invasive cancer. In this study, we investigated the prevalence of sexually transmitted HPVs in Human Immunodeficiency Virus (HIV) positive and negative patients in Zambia, Africa. The rate of high-risk HPV genotypes worldwide varies within each country. Thus, we sought to investigate the rates of HPV infection in sub-Saharan Africa and the potential role of HIV in affecting the HPV genotype distribution.MethodsThis retrospective cross-sectional study reports findings on the association and effects of HIV on HPV infections in an existing cohort of patients at University Teaching Hospital (UTH) Lusaka, Zambia. The objective of this study was to assess HPV prevalence, genotype distribution and to identify co-factors that influence HPV infection. Polymerase chain reaction (PCR) with two standard consensus primer sets (CpI/II and GP5+/6+) was used to test for the presence of HPV DNA. Primers specific for β-actin were used to monitor DNA quality. Vaginal lavage samples, collected between 1998-1999 from a total of 70 women, were part of a larger cohort that was also analyzed for HIV and human herpesvirus infection. Seventy of the samples yielded usable DNA. HIV status was determined by two rapid assays, Capillus and Determine. The incidence of HIV and HPV infections and HPV genotype distributions were calculated and statistical significance was determined by Chi-Squared test.ResultsWe determined that most common HPV genotypes detected among these Zambian patients were types 16 and 18 (21.6% each), which is approximately three-fold greater than the rates for HPV16, and ten-fold greater than the rates for HPV18 in the United States. The worldwide prevalence of HPV16 is approximately 14% and HPV18 is 5%. The overall ratio of high-risk (HR) to low-risk (LR) HPVs in the patient cohort was 69% and 31% respectively; essentially identical to that for the HR and LR distributions worldwide. However, we discovered that HIV positive patients were two-times as likely to have an HR HPV as HIV negative individuals, while the distribution of LR HPVs was unaffected by HIV status. Interestingly, we observed a nine-fold increase in HPV18 infection frequency in HIV positive versus HIV negative individuals.ConclusionThe rate of oncogenic HPVs (type 16 and 18) in Zambia was much higher than in the U.S., potentially providing an explanation for the high-rates of cervical cancer in Zambia. Surprisingly, we discovered a strong association between positive HIV status and the prevalence of HR HPVs, and specifically HPV18.
RF tumor ablation with internally cooled electrodes and saline infusion: what is the optimal location of the saline infusion?
Authors: Burdío Fernando , Berjano Enrique J , Navarro Ana , Burdío José M , Güemes Antonio , Grande Luis , Sousa Ramón , Subiró Jorge , Gonzalez Ana , Cruz Ignacio , Castiella Tomás , Tejero Eloy , Lozano Ricardo , de Gregorio Miguel A 
Published: July 2007

Abstract

Background
Radiofrequency ablation (RFA) of tumors by means of internally cooled electrodes (ICE) combined with interstitial infusion of saline may improve clinical results. To date, infusion has been conducted through outlets placed on the surface of the cooled electrode. However, the effect of infusion at a distance from the electrode surface is unknown. Our aim was to assess the effect of perfusion distance (PD) on the coagulation geometry and deposited power during RFA using ICE.

Methods
Experiments were performed on excised bovine livers. Perfusion distance (PD) was defined as the shortest distance between the infusion outlet and the surface of the ICE. We considered three values of PD: 0, 2 and 4 mm. Two sets of experiments were considered: 1) 15 ablations of 10 minutes (n ≥ 4 for each PD), in order to evaluate the effect of PD on volume and diameters of coagulation; and 2) 20 additional ablations of 20 minutes. The effect of PD on deposited power and relative frequency of uncontrolled impedance rises (roll-off) was evaluated using the results from the two sets of experiments (n ≥ 7 for each PD). Comparisons between PD were performed by analysis of variance or Kruskal-Wallis test. Additionally, non-linear regression models were performed to elucidate the best PD in terms of coagulation volume and diameter, and the occurrence of uncontrolled impedance rises.

Results
The best-fit least square functions were always obtained with quadratic curves where volume and diameters of coagulation were maximum for a PD of 2 mm. A thirty per cent increase in volume coagulation was observed for this PD value compared to other values (P < 0.05). Likewise, the short coagulation diameter was nearly twenty five per cent larger for a 2 mm PD than for 0 mm. Regarding deposited power, the best-fit least square function was obtained by a quadratic curve with a 2 mm PD peak. This matched well with the higher relative frequency of uncontrolled impedance rises for PD of 0 and 4 mm.

Conclusion
Saline perfusion at around 2 mm from the electrode surface while using an ICE in RFA improves deposition of energy and enlarges coagulation volume.
Successful paclitaxel-based chemotherapy for an alpha-fetoprotein-producing gastric cancer patient with multiple liver metastases
Authors: Takeyama Hiromitsu , Sawai Hirozumi , Wakasugi Takehiro , Takahashi Hiroki , Matsuo Yoichi , Ochi Nobuo , Yasuda Akira , Sato Mikinori , Okada Yuji , Funahashi Hitoshi , Akamo Yoshimi , Manabe Tadao 
Published: July 2007

Abstract

Background
Alpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis.

Case presentation
A 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date.

Conclusion
We consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases.