bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Authors: Kikuchi Ryoko , Tsuda Hitoshi , Kozaki Ken-ichi , Kanai Yae , Kasamatsu Takahiro , Sengoku Kazuo , Hirohashi Setsuo , Inazawa Johji , Imoto Issei 
Published: July 2008

Abstract
Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family, the members of which are implicated in various biological processes, although its receptor remains unknown. We identified a homozygous loss of ANGPTL2 (9q33.3) in the course of screening a panel of ovarian cancer (OC) cell lines for genomic copy-number aberrations using in-house array-based comparative genomic hybridization. ANGPTL2 mRNA expression was observed in normal ovarian tissue and immortalized normal ovarian epithelial cells, but was reduced in some OC lines without its homozygous deletion (18 of 23 lines) and restored after treatment with 5-aza 2′-deoxycytidine. The methylation status of sequences around the ANGPTL2 CpG-island with clear promoter activity inversely correlated with expression. ANGPTL2 methylation was frequently observed in primary OC tissues as well. In an immunohistochemical analysis of primary OCs, ANGPTL2 expression was frequently reduced (51 of 100 cases), and inversely correlated with methylation status. Patients with OC showing reduced ANGPTL2 immunoreactivity had significantly worse survival in the earlier stages (stages I and II), but better survival in advanced stages (stages III and IV). The restoration of ANGPTL2 expression or treatment with conditioned medium containing ANGPTL2 inhibited the growth of OC cells originally lacking the expression of this gene, whereas the knockdown of endogenous ANGPTL2 accelerated the growth of OC cells with the expression of ANGPTL2. These results suggest that, at least partly, epigenetic silencing by hypermethylation of the ANGPTL2 promoter leads to a loss of ANGPTL2 function, which may be a factor in the carcinogenesis of OC in a stage-dependent manner. [Cancer Res 2008;68(13):5067–75]
iASPP Inhibition: Increased Options in Targeting the p53 Family for Cancer Therapy
Authors: Bell Helen S. , Ryan Kevin M. 
Published: July 2008

Abstract
Strategies to induce p53 for cancer therapy offer appeal but many tumors harbor inactivating p53 mutations. One way to address this situation may be to activate the p53-related protein p73, which functions similarly, but unlike p53, is rarely lost or mutated in cancer. Along these lines, a recent study reports that a p53-derived peptide that targets iASPP—a common negative regulator of p53 family members—can effectively trigger tumor cell death by a p73-dependent mechanism. These findings promote further study of iASPP targeting as a therapeutic strategy to activate p73. [Cancer Res 2008;68(13):4959–62]
Functional Genomics Identifies ABCC3 as a Mediator of Taxane Resistance in HER2-Amplified Breast Cancer
Authors: O'Brien Carol , Cavet Guy , Pandita Ajay , Hu Xiaolan , Haydu Lauren , Mohan Sankar , Toy Karen , Rivers Celina Sanchez , Modrusan Zora , Amler Lukas C. , Lackner Mark R. 
Published: July 2008

Abstract
Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents. Enhanced understanding of the genetic alterations characteristic of different subtypes is needed to pave the way for more personalized administration of therapeutic agents. We have taken a functional genomics approach using a well-characterized panel of breast cancer cell lines to identify putative biomarkers of resistance to antimitotic agents such as paclitaxel and monomethyl-auristatin-E (MMAE). In vitro studies revealed a striking difference in sensitivity to these agents between cell lines from different subtypes, with basal-like cell lines being significantly more sensitive to both agents than luminal or HER2-amplified cell lines. Genome-wide association studies using copy number data from Affymetrix single nucleotide polymorphism arrays identified amplification of the chromosome 17q21 region as being highly associated with resistance to both paclitaxel and MMAE. An unbiased approach consisting of RNA interference and high content analysis was used to show that amplification and concomitant overexpression of the gene encoding the ABCC3 drug transporter is responsible for conferring in vitro resistance to paclitaxel and MMAE. We also show that amplification of ABCC3 is present in primary breast tumors and that it occurs predominantly in HER2-amplified and luminal tumors, and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in breast cancer. [Cancer Res 2008;68(13):5380–9]
Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone
Authors: Hoffmann Jens , Vitale Ilio , Buchmann Bernd , Galluzzi Lorenzo , Schwede Wolfgang , Senovilla Laura , Skuballa Werner , Vivet Sonia , Lichtner Rosemarie B. , Vicencio José M. , Panaretakis Theocharis , Siemeister Gerhard , Lage Hermann , Nanty Lisa , Hammer Stefanie , Mittelstaedt Kevin , Winsel Sebastian , Eschenbrenner Julia , Castedo Maria , Demarche Carine , Klar Ulrich , Kroemer Guido 
Published: July 2008

AbstractSagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-XL, or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program. [Cancer Res 2008;68(13):5301–8]
Berberine Modifies Cysteine 179 of IκBα Kinase, Suppresses Nuclear Factor-κB–Regulated Antiapoptotic Gene Products, and Potentiates Apoptosis
Authors: Pandey Manoj K. , Sung Bokyung , Kunnumakkara Ajaikumar B. , Sethi Gautam , Chaturvedi Madan M. , Aggarwal Bharat B. 
Published: July 2008

AbstractBerberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-κB (NF-κB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-κB activation found in certain tumor cells. Suppression of NF-κB activation occurred through the inhibition of phosphorylation and degradation of IκBα by the inhibition of IκB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-κB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-κB–regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-α and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-κB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent. [Cancer Res 2008;68(13):5370–9]
Loss of the Transmembrane but not the Soluble Kit Ligand Isoform Increases Testicular Germ Cell Tumor Susceptibility in Mice
Authors: Heaney Jason D. , Lam Man-Yee J. , Michelson Megan V. , Nadeau Joseph H. 
Published: July 2008

Abstract
Several genetic variants act as modifiers of testicular germ cell tumor (TGCT) susceptibility in the 129/Sv mouse model of human pediatric TGCTs. One such modifier, the Steel locus, encodes the transmembrane-bound and soluble ligand of the kit receptor. Some (Sl and SlJ) but not all (Sld) mutations of the Steel locus increase TGCT incidence in heterozygous mutant mice. Because Sl and SlJ are large deletions that affect multiple transcripts and Sld is an intragenic deletion of the kit ligand (Kitl) from which only the soluble protein is produced, it was uncertain whether Kitl or a neighboring gene is a modifier of TGCT susceptibility. We tested the effect of the small Steel grizzle-belly (Slgb) deletion on TGCT susceptibility to determine whether Kitl is a TGCT modifier gene. An increase in TGCT incidence was observed in Slgb/+ heterozygotes, and fine mapping of the deletion breakpoints revealed that Kitl is the only conventional gene deleted by the mutation, suggesting that Kitl is the TGCT modifier gene at the Steel locus. Additionally, we propose that soluble KITL in Sld/+ heterozygous mutant mice complements a dosage effect of transmembrane-associated kit ligand on TGCT susceptibility and that the kit receptor (Kit) is haplosufficient for primordial germ cell development. [Cancer Res 2008;68(13):5193–7]
Mitogen-Activated Protein Kinase Activation in Lung Adenocarcinoma: A Comparative Study between Ever Smokers and Never Smokers
Authors: Mountzios Giannis , Planchard David , Besse Benjamin , Validire Pierre , Girard Philippe , Devisme Christine , Dimopoulos Meletios-Athanasios , Soria Jean-Charles , Fouret Pierre 
Published: July 2008

AbstractPurpose: There are major differences affecting genes in adenocarcinomas in ever and never smokers. However, data on whether mitogen-activated protein kinase (MAPK) activation state differs according to smoking status are limited.Experimental Design: Expression of activated extracellular signal–regulated kinases, c-Jun NH2-terminal kinases, and P38 enzymes (pP38) were evaluated by means of immunohistochemistry in 188 chemonaïve patients with surgically resected lung adenocarcinoma. Cell viability of the lung adenocarcinoma cell line HCC827 was studied after treatment with cisplatin or the P38 MAPK inhibitor SB 203580.Results: Thirty-seven of 44 never smokers [84%; 95% confidence intervals (95% CI), 70-92%] expressed high pP38 levels compared with 45 of 104 ever smokers (43%; 95% CI, 34-53%; P &lt; 0.0001). The proportion of never smokers expressing high c-Jun NH2-terminal kinase levels (72%; 95% CI, 57-83%) was greater than that of ever smokers (53%; 95% CI, 44-62%; P = 0.03). The proportion of ever smokers expressing high extracellular signal–regulated kinase levels (51%; 95% CI, 42-59%) was similar to that of never smokers (57%; 95% CI, 42-71%; P = 0.47). Never smokers were 10.5 times (95% CI, 3.5-31.5) more likely to express high pP38 levels after adjustment for variables linked to smoking status, including age, sex, and histologic subtype. None of the activated MAPKs predicted for overall survival. Cell viability of HCC827 was significantly reduced after exposure to SB203580 alone or when combined with cisplatin.Conclusions: Life-long nonsmoking is associated with high activated P38 levels in patients with lung adenocarcinoma. Activated P38 can contribute to the viability of adenocarcinoma cells in never smokers, but is not predictive for overall survival.
Decreased Expression of Gastrokine 1 and the Trefoil Factor Interacting Protein TFIZ1/GKN2 in Gastric Cancer: Influence of Tumor Histology and Relationship to Prognosis
Authors: Moss Steven F. , Lee Jin-Woo , Sabo Edmond , Rubin Anna K. , Rommel John , Westley Bruce R. , May Felicity E.B. , Gao John , Meitner Patricia A. , Tavares Rose , Resnick Murray B. 
Published: July 2008

Abstract
Purpose: Transcriptional profiling showed decreased expression of gastrokine 1 (GKN1) and the related trefoil factor interacting protein (TFIZ1/GKN2) in Helicobacter pylori infection. Decreased GKN1 and GKN2 mRNA expression has been reported in gastric adenocarcinoma. We have examined GKN1 and GKN2 protein expression in a large gastric cancer series, correlated expression with tumor subtype, and evaluated their utility as prognostic biomarkers.
Experimental Design: GKN1, GKN2, and the trefoil factors TFF1 and TFF3 were examined in tissue microarrays from 155 distal gastric adenocarcinomas. Immunohistochemical expression was correlated with clinical outcome. GKN1 and GKN2 expression was measured by real-time PCR and Western analysis in samples of gastric cancer and adjacent nonneoplastic mucosa.
Results: GKN1 was lost in 78% of diffuse and 42% of intestinal cancers (P &lt; 0.0001, diffuse versus intestinal). GKN2 expression was lost in 85% of diffuse and 54% of intestinal type cancers (P &lt; 0.002). GKN1 and GKN2 down-regulation were confirmed by Western and real-time PCR analysis. Loss of either protein was associated with significantly worse outcome in intestinal-type tumors by univariate analysis; and GKN2 loss remained a predictor of poor outcome in multivariate analysis (P &lt; 0.033). TFF1 was lost in &gt;70%, and TFF3 was expressed in ∼50% of gastric cancers.
Conclusions: Loss of GKN1 and GKN2 expression occurs frequently in gastric adenocarcinomas, especially in the diffuse subtype. GKN1 and GKN2 loss are associated with shorter overall survival in the intestinal subtype.
Positive Correlations of Oct-4 and Nanog in Oral Cancer Stem-Like Cells and High-Grade Oral Squamous Cell Carcinoma
Authors: Chiou Shih-Hwa , Yu Cheng-Chia , Huang Chi-Yang , Lin Shu-Chun , Liu Chung-Ji , Tsai Tung-Hu , Chou Shiu-Huey , Chien Chian-Shiu , Ku Hung-Hai , Lo Jeng-Fan 
Published: July 2008

Abstract
Purpose: Oral squamous cell carcinoma (OSCC), like many solid tumors, contains a heterogeneous population of cancer cells. Recent data suggest that a rare subpopulation of cancer cells, termed cancer stem cells (CSC), is capable of initiating, maintaining, and expanding the growth of tumor. Identification and characterization of CSC from OSCC facilitates the monitoring, therapy, or prevention of OSCC.
Experimental Design: We enriched oral cancer stem-like cells (OC-SLC) through sphere formation by cultivating OSCC cells from established OSCC cell lines or primary cultures of OSCC patients within defined serum-free medium. Differential expression profile of stemness genes between enriched OC-SLC and parental OSCC was elucidated. Furthermore, immunohistochemical staining of stemness markers on OSCC patient tissues was examined to evaluate the association between stemness genes and prognosis of OSCC.
Results: Enriched OC-SLC highly expressed the stem/progenitor cell markers and ABC transporter gene (Oct-4, Nanog, CD117, Nestin, CD133, and ABCG2) and also displayed induced differentiation abilities and enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Elevated expression of CD133 was shown in the enriched OC-SLC from OSCC patients' tumors. Positive correlations of Oct-4, Nanog, or CD133 expression on tumor stage were shown on 52 OSCC patient tissues. Kaplan-Meier analyses exhibited that Nanog/Oct-4/CD133 triple-positive patients predicted the worst survival prognosis of OSCC patients.
Conclusion: We enriched a subpopulation of cancer stem-like cell from OSCC by sphere formation. The enriched OC-SLC possesses the characteristics of both stem cells and malignant tumors. Additionally, expression of stemness markers (Nanog/Oct-4/CD133) contradicts the survival prognosis of OSCC patients.
Bortezomib-Induced Apoptosis with Limited Clinical Response Is Accompanied by Inhibition of Canonical but not Alternative Nuclear Factor-κB Subunits in Head and Neck Cancer
Authors: Allen Clint , Saigal Kunal , Nottingham Liesl , Arun Pattatheyil , Chen Zhong , Van Waes Carter 
Published: July 2008

Abstract
Purpose: Nuclear factor-κB (NF-κB)/REL transcription factors promote cancer cell survival and progression. The canonical (NF-κB1/RELA or cREL) and alternate (NF-κB2/RELB) pathways require the proteasome for cytoplasmic-nuclear translocation, prompting the investigation of bortezomib for cancer therapy. However, limited clinical activity of bortezomib has been observed in many epithelial malignancies, suggesting this could result from incomplete inhibition of NF-κB/RELs or other prosurvival signal pathways.
Experimental Design: To examine these possibilities, matched biopsies from 24 h posttreatment were obtained from accessible tumors of patients who received low-dose bortezomib (0.6 mg/m2) before reirradiation in a phase I trial for recurrent head and neck squamous cell carcinoma (HNSCC). Effects of bortezomib on apoptosis and proliferation by TUNEL and Ki67 staining were compared with nuclear staining for all five NF-κB subunits, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated signal transducers and activators of transcription 3 (STAT3) in tumor biopsies, and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTP) and DNA binding assay for the five NF-κB subunits in HNSCC cell lines.
Results: HNSCC showed increased nuclear staining for all five NF-κB subunits, phosphorylated ERK1/2, and phosphorylated STAT3. Bortezomib treatment significantly enhanced apoptosis with inhibition of nuclear RELA in three of four tumors, but other NF-κB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was observed within 3 months. In HNSCC cell lines, 10−8 mol/L bortezomib inhibited cell density while inhibiting tumor necrosis factor-α–induced and partially inhibiting basal activation of NF-κB1/RELA, but not NF-κB2/RELB.
Conclusions: Although low-dose bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-κB or other prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC.
Randomized Crossover Pharmacokinetic Study of Solvent-Based Paclitaxel andnab-Paclitaxel
Authors: Gardner Erin R. , Dahut William L. , Scripture Charity D. , Jones Jacquin , Aragon-Ching Jeanny B. , Desai Neil , Hawkins Michael J. , Sparreboom Alex , Figg William D. 
Published: July 2008

AbstractPurpose: Abraxane (ABI-007) is a 130-nm albumin-bound (nab) particle formulation of paclitaxel, devoid of any additional excipients. We hypothesized that this change in formulation alters the systemic disposition of paclitaxel compared with conventional solvent-based formulations (sb-paclitaxel; Taxol), and leads to improved tolerability of the drug.Patients and Methods: Patients with malignant solid tumors were randomized to receive the recommended single-agent dose of nab-paclitaxel (260 mg/m2 as a 30-minute infusion) or sb-paclitaxel (175 mg/m2 as a 3-hour infusion). After cycle 1, patients crossed over to the alternate treatment. Pharmacokinetic studies were carried out for the first cycle of sb-paclitaxel and the first two cycles of nab-paclitaxel.Results: Seventeen patients were treated, with 14 receiving at least one cycle each of nab-paclitaxel and sb-paclitaxel. No change in nab-paclitaxel pharmacokinetics was found between the first and second cycles (P = 0.95), suggesting limited intrasubject variability. Total drug exposure was comparable between the two formulations (P = 0.55) despite the dose difference. However, exposure to unbound paclitaxel was significantly higher after nab-paclitaxel administration, due to the increased free fraction (0.063 ± 0.021 versus 0.024 ± 0.009; P &lt; 0.001).Conclusion: This study shows that paclitaxel disposition is subject to considerable variability depending on the formulation used. Because systemic exposure to unbound paclitaxel is likely a driving force behind tumoral uptake, these findings explain, at least in part, previous observations that the administration of nab-paclitaxel is associated with augmented antitumor efficacy compared with solvent-based paclitaxel.
Effect of Food on the Pharmacokinetic Behavior of the Potent Oral Taxane BMS-275183
Authors: Bröker Linda E. , Valdivieso Manual , Pilat Mary Jo , DeLuca Pamela , Zhou Xiaofei , Parker Susan , Giaccone Giuseppe , LoRusso Patricia M. 
Published: July 2008

Abstract
Purpose: BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-275183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA).
Patients and Methods: The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m2. Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay.
Results: A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D). Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUCinf). No apparent relationship was observed between AUCinf and BSA for either the 200 mg or the 200 mg/m2 regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non–small cell lung cancer patient.
Conclusions: Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.