bluuebunny/crossref_metadata_2025 huggingface dataset:
Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor
Authors: Saxena Neeraj K. , Taliaferro-Smith LaTonia , Knight Brandi B. , Merlin Didier , Anania Frank A. , O'Regan Ruth M. , Sharma Dipali
Published: December 2008

Obesity is an independent risk factor for breast cancer, and obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Obesity, as associated with metabolic syndrome, results in an increase in circulating insulin-like growth factor (IGF), which acts as a mitogen. In addition, higher plasma level of adipocytokine leptin is associated with obesity. In the present study, we show that cotreatment with leptin and IGF-I significantly increases proliferation as well as invasion and migration of breast cancer cells. We found a novel bidirectional crosstalk between leptin and IGF-I signaling; IGF-I induced phosphorylation of leptin receptor (Ob-Rb) and leptin induced phosphorylation of IGF-I receptor (IGF-IR), whereas cotreatment induced synergistic phosphorylation and association of Ob-Rb and IGF-IR along with activation of downstream effectors, Akt and extracellular signal–regulated kinase. Leptin increased phosphorylation of IGF signaling molecules insulin-receptor substrate (IRS)-1 and IRS-2. Interestingly, we found that leptin and IGF-I cotreatment synergistically transactivated epidermal growth factor receptor (EGFR), depending on the proteolytic release of EGFR ligands, as the broad-spectrum matrix metalloproteinase inhibitor GM6001 could inhibit this effect. Using clinically relevant EGFR inhibitors, erlotinib and lapatinib, we found that inhibition of EGFR activation effectively inhibited leptin- and IGF-I–induced invasion and migration of breast cancer cells. Taken together, these data suggest a novel bidirectional crosstalk between leptin and IGF-I signaling that transactivates EGFR and promotes the metastatic properties as well as invasion and migration of breast cancer cells. Our findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the procancerous effects of leptin and IGF-I in breast cancers. [Cancer Res 2008;68(23):9712–22]
Anti–Glypican 3 Antibody as a Potential Antitumor Agent for Human Liver Cancer
Authors: Ishiguro Takahiro , Sugimoto Masamichi , Kinoshita Yasuko , Miyazaki Yoko , Nakano Kiyotaka , Tsunoda Hiroyuki , Sugo Izumi , Ohizumi Iwao , Aburatani Hiroyuki , Hamakubo Takao , Kodama Tatsuhiko , Tsuchiya Masayuki , Yamada-Okabe Hisafumi
Published: December 2008

Human glypican 3 (GPC3) is preferentially expressed in the tumor tissues of liver cancer patients. In this study, we obtained a monoclonal antibody (mAb) against the COOH-terminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated GC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. GC33 was efficacious even in an orthotopic model; it markedly reduced the blood α-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. Humanized GC33 (hGC33) was as efficacious as GC33 against the Hep G2 xenograft, but hGC33 lacking carbohydrate moieties caused neither ADCC nor tumor growth inhibition. Depletion of CD56+ cells from human peripheral blood mononuclear cells markedly abrogated the ADCC caused by hGC33. The results show that the antitumor activity of hGC33 is mainly attributable to ADCC, and in human, natural killer cell–mediated ADCC is one possible mechanism of the antitumor effects by GC33. hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors. [Cancer Res 2008;68(23):9832–8]
Genetic Ancestry and Risk of Breast Cancer among U.S. Latinas
Authors: Fejerman Laura , John Esther M. , Huntsman Scott , Beckman Kenny , Choudhry Shweta , Perez-Stable Eliseo , Burchard Esteban González , Ziv Elad
Published: December 2008

U.S. Latinas have a lower incidence of breast cancer compared with non-Latina White women. This difference is partially explained by differences in the prevalence of known risk factors. Genetic factors may also contribute to this difference in incidence. Latinas are an admixed population with most of their genetic ancestry from Europeans and Indigenous Americans. We used genetic markers to estimate the ancestry of Latina breast cancer cases and controls and assessed the association with genetic ancestry, adjusting for reproductive and other risk factors. We typed a set of 106 ancestry informative markers in 440 Latina women with breast cancer and 597 Latina controls from the San Francisco Bay area and estimated genetic ancestry using a maximum likelihood method. Odds ratios (OR) and 95% confidence intervals (95% CI) for ancestry modeled as a continuous variable were estimated using logistic regression with known risk factors included as covariates. Higher European ancestry was associated with increased breast cancer risk. The OR for a 25% increase in European ancestry was 1.79 (95% CI, 1.28–2.79; P < 0.001). When known risk factors and place of birth were adjusted for, the association with European ancestry was attenuated but remained statistically significant (OR, 1.39; 95% CI, 1.06–2.11; P = 0.013). Further work is needed to determine if the association is due to genetic differences between populations or possibly due to environmental factors not measured. [Cancer Res 2008;68(23):9723–8]
The ARF Tumor Suppressor Can Promote the Progression of Some Tumors
Authors: Humbey Olivier , Pimkina Julia , Zilfou Jack T. , Jarnik Michal , Dominguez-Brauer Carmen , Burgess Darren J. , Eischen Christine M. , Murphy Maureen E.
Published: December 2008

p14/p19ARF (ARF) is a tumor suppressor gene that is frequently mutated in human cancer. ARF has multiple tumor suppressor functions, some of which are mediated by signaling to p53. Surprisingly, a significant fraction of human tumors retain persistently high levels of ARF, suggesting that ARF may possess a prosurvival function. We show that ARF protein is markedly up-regulated in cells exposed to nutrient starvation. Cells with silenced ARF show reduced autophagy and reduced viability when placed under conditions of starvation. We show for the first time that ARF silencing can limit the progression of some tumors, such as lymphoma, but not others, such as E1A/Ras-induced tumors. Specifically, myc-driven lymphomas with mutant p53 tend to overexpress ARF; we show that silencing ARF in these tumors greatly impedes their progression. These data are the first to show that ARF can act in a p53-independent manner to promote the progression of some tumors. [Cancer Res 2008;68(23):9608–13]
Folate Targeting Enables Durable and Specific Antitumor Responses from a Therapeutically Null Tubulysin B Analogue
Authors: Leamon Christopher P. , Reddy Joseph A. , Vetzel Marilynn , Dorton Ryan , Westrick Elaine , Parker Nikki , Wang Yu , Vlahov Iontcho
Published: December 2008

The membrane-bound high-affinity folate receptor (FR) is highly expressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney, and brain. Because folate-linked conjugates bind to and become internalized within FR-expressing cells (similar to that of free folic acid), we explored the possibility of using the folate ligand to target a potent, semisynthetic analogue of the microtubule inhibitor tubulysin B to FR-enriched tumors. When tested in vitro, a novel folate conjugate, herein referred to as EC0305, was found to specifically inhibit the growth of a panel of FR-positive cell lines (IC50 range, 1–10 nmol/L) in a dose-dependent manner, whereas cells lacking FR expression were unaffected. The potency of EC0305 was also confirmed against a human KB xenograft-nu/nu mouse cancer model. Here, a brief three times per week, 2-week regimen yielded remarkable antitumor activity (100% tumor-free animals) without causing significant weight loss or major organ tissue degeneration. In contrast, antitumor activity was completely abolished in EC0305-treated animals that were co-dosed with an excess of a nontoxic folate-containing analogue, thereby confirming that the antitumor effect of this agent was mediated by FRs. The advantage provided by folate conjugation was further proved by the untargeted free drug, which was found to be completely inactive at both tolerable and highly toxic dose levels. Collectively, these results show that this potent antiproliferative tubulysin compound can be specifically delivered to FR-positive tumors to provide substantial therapeutic benefit using well-tolerable dosing regimens. [Cancer Res 2008;68(23):9839–44]
Targeting the Stroma by T Cells to Limit Tumor Growth
Authors: Zhang Bin
Published: December 2008

Solid tumors may modulate their environment and keep stromal cells in an immunosuppressive and tumor-promoting state. Recent findings indicate that targeting not only cancer cells but also nonmalignant stromal cells by T cells is required for the eradication of established tumor. Interestingly, a single adoptive transfer of effector T cells that recognize tumor antigen-loaded stromal cells, but not the cancer cells themselves, causes long-term inhibition of tumor growth associated with T cell–mediated killing of stromal CD11b+/Gr1+ myeloid cells. Therefore, targeting tumor stroma by T cells points to an important alternative approach to the effective control of tumor growth, particularly in the absence of direct targeting of cancer cells. [Cancer Res 2008;68(23):9570–3]
Fetal Microchimerism and Cancer
Authors: Sawicki Janet A.
Published: December 2008

The persistence of fetal stem cells with multilineage potential in women who have been pregnant, a phenomenon known as fetal microchimerism, is emerging as a potential contributing factor in certain diseases, including cancer. For example, fetal microchimerism has been implicated in autoimmune disease, wound healing, and cancer. Studies of this phenomenon may provide a novel perspective on cancer in women, including in breast, ovarian, and lung cancers. [Cancer Res 2008;68(23):9567–9]
Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications
Authors: Sarli Vasiliki , Giannis Athanassios
Published: December 2008

Kinesin spindle protein (KSP), a member of the kinesin superfamily of microtubule-based motors, plays a critical role in mitosis as it mediates centrosome separation and bipolar spindle assembly and maintenance. Inhibition of KSP function leads to cell cycle arrest at mitosis with the formation of monoastral microtubule arrays, and ultimately, to cell death. Several KSP inhibitors are currently being studied in clinical trials and provide new opportunities for the development of novel anticancer therapeutics alternative from the available microtubule targeting drugs.
Molecularly Targeted Radiosensitization of Human Prostate Cancer by Modulating Inhibitor of Apoptosis
Authors: Dai Yao , Liu Meilan , Tang Wenhua , DeSano Jeffrey , Burstein Ezra , Davis Mary , Pienta Kenneth , Lawrence Theodore , Xu Liang
Published: December 2008

Purpose: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization.

Experimental Design: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-κB activation was detected by luciferase reporter assay and quantitative real-time PCR.

Results: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-α- and radiation-induced nuclear factor-κB activation in DU-145 cells.

Conclusions: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
Akt-Dependent Proapoptotic Effects of Dietary Restriction on Late-Stage Management of a Phosphatase and Tensin Homologue/Tuberous Sclerosis Complex 2–Deficient Mouse Astrocytoma
Authors: Marsh Jeremy , Mukherjee Purna , Seyfried Thomas N.
Published: December 2008

Purpose: Malignant astrocytomas exhibit constitutive Akt phosphorylation due to reduced phosphatase and tensin homologue (PTEN) tumor suppressor expression or to increased growth factor receptor tyrosine kinase activation. Many astrocytomas are also tuberous sclerosis complex 2 (TSC2) protein deficient and exhibit constitutive mammalian target of rapamycin (mTOR) activity. Astrocytomas harboring PTEN/Akt/TSC2 pathway mutations are dependent on glycolysis to satisfy their bioenergetic requirements. Therapies that disrupt energy homeostasis can potentially manage astrocytoma growth and progression. Although dietary restriction (DR) reduces glycolysis and manages early-stage astrocytoma growth, no prior studies have identified the mechanisms involved or determined if DR can also manage late-stage tumor growth.

Experimental Design: The effects of a late-onset intermittent DR feeding paradigm were examined in adult C57BL/6J mice bearing the syngeneic CT-2A malignant astrocytoma grown orthotopically or subcutaneously.

Results: In contrast to contralateral normal brain, CT-2A was PTEN/TSC2 protein deficient; exhibited constitutive Akt, mTOR, and BAD phosphorylation; and overexpressed insulin-like growth factor-I (IGF-I), IGF-I receptor, hypoxia-inducible transcription factor-1α (HIF-1α), type 1 glucose transporter protein (GLUT1), and pyruvate kinase. DR initiated 10 to 14 days after tumor implantation (late onset) reduced CT-2A growth, delayed malignant progression, and significantly extended survival. DR suppressed phosphorylation of Akt and BAD while reducing expression of IGF-I, HIF-1α, and GLUT1. DR also enhanced procaspase-9/procaspase-3 cleavage but had no effect mTOR phosphorylation.

Conclusions: Our findings indicate that IGF-I/Akt signaling is associated with the antiapoptotic and glycolytic phenotype of the CT-2A astrocytoma and that DR targets this pathway. Moreover, PTEN/TSC2 deficiency may impair adaptation to the DR-induced disruption of energy homeostasis, thus enhancing apoptosis. Our findings highlight the efficacy of late-onset DR in managing astrocytoma growth and suggest that DR may be an effective broad-spectrum inhibitor of Akt signaling in PTEN/TSC2–deficient astrocytomas.
A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Hormone-Refractory Metastatic Prostate Cancer
Authors: Heath Elisabeth I. , Hillman David W. , Vaishampayan Ulka , Sheng Shijie , Sarkar Fazlul , Harper Felicity , Gaskins Melvin , Pitot Henry C. , Tan Winston , Ivy S. Percy , Pili Roberto , Carducci Michael A. , Erlichman Charles , Liu Glenn
Published: December 2008

Purpose: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer.

Experimental Design: Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life.

Results: Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%).

Conclusions: 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.
NGALR Is Overexpressed and Regulated by Hypomethylation in Esophageal Squamous Cell Carcinoma
Authors: Cui Lei , Xu Li-Yan , Shen Zhong-Ying , Tao Qian , Gao Shu-Ying , Lv Zhuo , Du Ze-Peng , Fang Wang-Kai , Li En-Min
Published: December 2008

Purpose: Neutrophil gelatinase-associated lipocalin receptor (NGALR) mRNA level is reduced in isolated chronic myelogenous leukemia blasts but up-regulated in esophageal squamous cell carcinoma (ESCC). The mechanism of NGALR regulation is unknown. Here, we show the expression pattern of NGALR and examine the aberrant methylation of its gene in ESCC and esophageal carcinoma cell lines.

Experimental Design: The expression pattern of NGALR was analyzed by immunohistochemistry in 59 ESCCs and compared with noncancerous tissues. The DNA methylation status was investigated by methylation-specific PCR and by bisulfite genomic sequencing in esophageal carcinoma cell lines and surgically resected samples. Methylated cell lines were treated with a methylation inhibitor to restore NGALR expression.

Results: The expression of NGALR in ESCC was significantly higher in tumor cell membrane and cytoplasm than in normal esophageal epithelium (P < 0.01). Methylated alleles were detected in three NGALR-nonexpressing cell lines but were not detected in three NGALR-expressing cell lines. Treatment of methylated cell lines with 5-aza-2′-deoxycytidine, a methylation inhibitor, restored NGALR expression. In surgically resected samples, 31 of 77 (40.3%) primary esophageal carcinomas and 46 of 77 (59.7%) paired normal tissues contained methylated NGALR alleles (P < 0.05).

Conclusions: Our results suggest that NGALR hypomethylation contributes to its expression in esophageal carcinomas and that this overexpression may play a role in the pathogenesis of esophageal carcinomas.
Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer
Authors: Callahan Michael J. , Nagymanyoki Zoltan , Bonome Tomas , Johnson Michael E. , Litkouhi Babak , Sullivan Elizabeth H. , Hirsch Michelle S. , Matulonis Ursula A. , Liu Joyce , Birrer Michael J. , Berkowitz Ross S. , Mok Samuel C.
Published: December 2008

Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers.

Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes. Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival analyses were done combining CD8 T lymphocyte number and HLA-DMB expression with standard prognostic factors.

Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement in median overall survival in both univariate and multivariate analyses.

Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are associated with improved survival in advanced-stage serous ovarian cancer.
VEGF as a Marker for Outcome Among Advanced Breast Cancer Patients Receiving anti-VEGF Therapy with Bevacizumab and Vinorelbine Chemotherapy
Authors: Burstein Harold J. , Chen Yu-Hui , Parker Leroy M. , Savoie Jennifer , Younger Jerry , Kuter Irene , Ryan Paula D. , Garber Judy E. , Chen Helen , Campos Susana M. , Shulman Lawrence N. , Harris Lyndsay N. , Gelman Rebecca , Winer Eric P.
Published: December 2008

Background: Anti-vascular endothelial growth factor therapy (VEGF) is an important new treatment modality in oncology. We sought to determine the efficacy and safety of the humanized monoclonal anti-VEGF antibody, bevacizumab, and vinorelbine as treatment for refractory breast cancer and to explore the role of plasma VEGF as a predictor of treatment outcome.

Experimental Design: Eligible patients had received one or two prior chemotherapy regimens for metastatic breast cancer or recurred within 12 months of adjuvant therapy and had measurable disease and adequate end-organ function. Patients received bevacizumab 10 mg/kg every 2 weeks, and vinorelbine each week, until tumor progression or prohibitive toxicity. Plasma VEGF was measured at baseline.

Results: Among 56 women treated on protocol, bevacizumab and vinorelbine yielded a 34% response rate (95% confidence interval, 22-48%) and median time to progression of 5.5 months. Activity was observed regardless of tumor hormone receptor status or type or extent of prior chemotherapy. Side effects included uncomplicated neutropenia, hypertension, nasal congestion/epistaxis, and neuropathy, consistent with well-described side effects of the respective agents. Three patients had impaired wound healing following surgical procedures. There were only rare instances of thrombosis or clinically significant proteinuria. Lower levels of baseline VEGF were associated with longer time to progression.

Conclusions: Bevacizumab and vinorelbine are well tolerated and effective as treatment for refractory breast cancer. Plasma VEGF warrants further evaluation as a prognostic marker for treatment outcome in advanced breast cancer patients receiving anti-VEGF therapy.
Prognostic Factors and Survival in 324 Patients with Pancreatic Endocrine Tumor Treated at a Single Institution
Authors: Ekeblad Sara , Skogseid Britt , Dunder Kristina , Öberg Kjell , Eriksson Barbro
Published: December 2008

Purpose: Unequivocal pathologic markers for the prognosis of pancreatic endocrine tumors are often lacking. Suggestions for prognostic guidance include the WHO classification. Recently, a tumor-node-metastasis (TNM) staging system was proposed. We evaluate this system, as well as assess other potential prognostic factors such as tumor Ki67, size, endocrine syndrome, heredity, body mass index (BMI), and plasma chromogranin A, in a large patient material treated at a single institution.

Experimental Design: A total of 324 patients with pancreatic endocrine tumor, consecutively diagnosed and treated at a tertiary referral center, were retrospectively evaluated. Median follow-up was 54 months (range, 1-423 months). Patient and tumor data were extracted from medical records. Univariate and multivariate analyses were done to recognize factors of prognostic value.

Results: The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 ≥2%, chromogranin A ≥3 times the upper normal limit, BMI <20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 ≥2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity.

Conclusions: The recently suggested TNM staging system emerged as a useful clinical tool.
HER-2 Gene Amplification, HER-2 and Epidermal Growth Factor Receptor mRNA and Protein Expression, and Lapatinib Efficacy in Women with Metastatic Breast Cancer
Authors: Press Michael F. , Finn Richard S. , Cameron David , Di Leo Angelo , Geyer Charles E. , Villalobos Ivonne E. , Santiago Angela , Guzman Roberta , Gasparyan Armen , Ma Yanling , Danenberg Kathy , Martin Anne Marie , Williams Lisa , Oliva Cristina , Stein Steven , Gagnon Robert , Arbushites Michael , Koehler Maria T.
Published: December 2008

Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy.

Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory.

Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among “HER-2-negative” breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory.

Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.
Genome-Wide Loss of Heterozygosity and Uniparental Disomy in BRCA1/2-Associated Ovarian Carcinomas
Authors: Walsh Christine S. , Ogawa Seishi , Scoles Daniel R. , Miller Carl W. , Kawamata Norihiko , Narod Steven A. , Koeffler H. Phillip , Karlan Beth Y.
Published: December 2008

Purpose: The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associated and sporadic ovarian cancers would have distinctive genetic profiles despite similarities in histologic appearance.

Experimental Design: A whole-genome copy number analysis of fresh, frozen, papillary serous ovarian cancer DNA was done using the Affymetrix 50K Xba Mapping Array using each patient's normal genomic DNA as the matched control. Loss of heterozygosity and copy number abnormalities were summarized to define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were compared between BRCA-associated and sporadic tumors.

Results: We compared 6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measured by percentage of genome altered, was more pronounced in BRCA-associated tumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We used frequency plots to show the proportion of cases affected by each type abnormality at each genomic region. BRCA-associated tumors showed genome-wide loss of heterozygosity primarily due to the occurrence of UPD rather than deletion. UPD was found in 100% of the BRCA-associated and 50% of the sporadic tumors profiled.

Conclusions: This study reports on a previously underappreciated genetic phenomenon of UPD, which occurs frequently in ovarian cancer DNA. We observed distinct genetic patterns between BRCA-associated and sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways.
Constitutive Activation of Signal Transducer and Activator of Transcription 5 Contributes to Tumor Growth, Epithelial-Mesenchymal Transition, and Resistance to Epidermal Growth Factor Receptor Targeting
Authors: Koppikar Priya , Lui Vivian Wai Yan , Man David , Xi Sichuan , Chai Raymond Liu , Nelson Elizabeth , Tobey Allison B.J. , Grandis Jennifer Rubin
Published: December 2008

Purpose: Signal transducer and activator of transcription 5 (STAT5) is activated in squamous cell carcinoma of the head and neck (SCCHN), where targeting of STAT5 inhibits tumor growth in vitro and in vivo. The role of STAT5 activation in carcinogenesis, tumor progression, and response to therapy remains incompletely understood. In this study, we investigated the effects of STAT5 activation on squamous epithelial carcinogenesis and response to therapy.

Experimental Design: The functional consequences of STAT5 activation in squamous epithelial carcinogenesis were examined using cells derived from normal (Het-1A) and transformed mucosal epithelial cells engineered to express constitutive-active mutants of STAT5.

Results: The growth rate of stable clones derived from both normal and transformed squamous epithelial cells expressing the constitutive-active STAT5 was increased. In SCCHN xenografts, tumor volumes were increased in constitutive-active STAT5 mutant cells compared with vector-transfected controls. Constitutive activation of STAT5 significantly increased cell migration and invasion through Matrigel, as well as the transforming efficiency of SCCHN cells in vitro, as assessed by soft agar assays. The constitutive-active STAT5 clones derived from SCCHN cells showed changes consistent with an epithelial-mesenchymal transition including decreased expression of E-cadherin and increased vimentin in comparison with control transfectants. In these cells, STAT5 activation was associated with resistance to cisplatin-mediated apoptosis and growth inhibition induced by the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib.

Conclusions: These results suggest that constitutive STAT5 signaling enhances tumor growth, invasion, and epithelial-to-mesenchymal transition in squamous epithelial carcinogenesis and may contribute to resistance to epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy.
The Challenge of Herbal Therapies for Prostate Cancer
Authors: Bhatt Rupal S. , Bubley Glenn J.
Published: December 2008

The paper by Singh et al. shows that silibinin inhibits prostate cancer growth in the TRAMP mouse model. Among its other properties, silibinin inhibits the progression of prostate cancer by decreasing angiogenesis and tumor invasion. Identification of the biological effects of herbal remedies such as silibinin is critical for their development as anticancer treatments.
Mite Amylase from Blomia tropicalis (Blo t 4): Differential Allergenicity Linked to Geographical Regions
Authors: Cheong Nge , Ramos John Donnie A. , Tang Chwee Ying , Chng Hiok Hee , Yao Rong , Liang Zongan , Lee Bee Wah , Chua Kaw Yan
Published: December 2008

Background:Blomia tropicalis is an important domestic dust mite in the tropics and subtropics. This study describes cDNA cloning of the group 4 allergen of B. tropicalis, and the evaluation of the sensitization of this allergen in atopic populations from 2 geographic regions. Methods: cDNA cloning was carried out using the Smart RACE cDNA amplification kit. The full-length Blo t 4 cDNA was isolated by cDNA library screening, 5′ and 3′ rapid amplification of cDNA ends and long-distance PCR. Sequence analysis was performed with a combination of the Clustal W, CGC and Blast program packages. The cDNA was expressed in Pichia pastoris yeast. The skin prick test was used to evaluate the sensitization profile of recombinant Blo t 4, crude dust mite allergen extracts and major B. tropicalis recombinant allergen Blo t 5. Results: The cloned Blo t 4 had a molecular weight of 56 kDa and had 68% amino acid homology with group 4 allergens of Dermatophagoides pteronyssinus and 65% with those of Euroglyphus maynei. A sensitization profile to the expressed recombinant Blo t 4 allergen (28%) showed an unusually higher frequency than to the major allergen Blo t 5 (22%) in allergic subjects from Chengdu, PR China. In comparison, the subjects from Singapore showed very low sensitization to Blo t 4 (4%) compared with Blo t 5 (84%). Conclusions: Group 4 allergens of B. tropicalis may be an important dust mite allergen in certain distinct populations.
Is the Effect of Prenatal Paracetamol Exposure on Wheezing in Preschool Children Modified by Asthma in the Mother?
Authors: Garcia-Marcos L. , Sanchez-Solis M. , Perez-Fernandez V. , Pastor-Vivero M.D. , Mondejar-Lopez P. , Valverde-Molina J.
Published: December 2008

Background: There seems to be an association between paracetamol consumption during late pregnancy and the prevalence of wheezing in infancy and childhood. The aim of the present study is to determine whether the aforementioned association is modified by the presence of asthma in the mother. Methods: A total of 1,741 children aged 3–5 years from an epidemiological survey performed in the province of Murcia (Spain) were included in the analysis. Data on paracetamol consumption (never, at least once during pregnancy or at least once per month during pregnancy), wheezing symptoms in the offspring (according to the International Study of Asthma and Allergies in Childhood protocol) and the presence of asthma in the mother, together with other known risk factors for asthma, were obtained by means of a questionnaire. Results: The mean age of the children was 4.08 ± 0.8 years and 51.1% were males. The overall prevalence of current wheezing was 20.2%. The frequency of paracetamol usage was similar among asthmatic and non-asthmatic mothers, and only a small proportion of them took this drug at least once a month (13.8% of asthmatics and 11.0% of non-asthmatics). Compared to the mothers who never took paracetamol, there was a significant association between the mother having taken paracetamol at least once per month during pregnancy and the offspring suffering from wheezing at preschool age, but only among non-asthmatic mothers (odds ratio 1.94, 95% confidence interval 1.34–2.79 vs. odds ratio 1.05, 95% confidence interval 0.21–5.08). This association was maintained after controlling for potential confounders (odds ratio 1.74, 95% confidence interval 1.15–2.61). Conclusions: The frequent usage of paracetamol during pregnancy is associated with the prevalence of wheezing in offspring during preschool years. Asthma in the mother might modify this association.
Pragmatism, Piety, and Environmental Ethics
Authors: Minteer Ben
Published: December 2008

The rise of pragmatism in environmental ethics in the 1990s was driven by several factors, including dissatisfaction with the field's dominant nonanthropocentrism and the desire to increase the political and policy influence of environmental ethics. Yet despite an emphasis on human experience as the foundation of environmental values and action, environmental pragmatists have paid little attention to the religious dimensions of human-nature interactions. In this paper I attempt to address this neglect by exploring the religious thought of John Dewey, arguably the most significant pragmatist philosopher of the classical period. I suggest that Dewey's understanding of religiosity—in particular, his concept of "natural piety"—instructs us to respect nonhuman nature as a source of human imaginative experience and self-unification. Although Dewey's naturalized approach to religious experience retains a broadly instrumentalist view toward nature, it is an instrumentality that supports a humble and appreciative attitude toward the environment and a sense of caution regarding the modification of nature for human purposes. I conclude by arguing that the recovery of Dewey's attitude of natural piety provides an important constraint on more aggressively anthropocentric approaches to human-nature relations, including those promoting sustainability as an alternative to traditional limits-based environmentalism.
Sacrifice and Sustainability
Authors: Chapple Christopher Key
Published: December 2008

Sacrifice in the Jewish, Hellenistic, and Christian traditions involves a giving up, a surrendering of something for the sake of a greater good. Sacrifice in times past took the form of a bloody offering. In Christianity this has been replaced with the Eucharist, which promotes human conscience and adherence to a moral code. Sacrifice in the ancient Vedic traditions of India entailed the offering of an animal or the symbolic offering of a human being that correlated bodily parts to functions of society and the cosmos. Sacrifice in India in rare instances still includes the killing of animals. Ritual throughout India, known as Puja, celebrates the body, the senses, and their connection with the physical world through offerings of fruits, flowers, incense, and other ritual objects.The contemporary challenge presented by the need to develop sustainable lifestyles can draw from both traditions of sacrifice. The Mediterranean model urges people to do with less for the sake of a greater good. The Indic model encourages people to recognize the web of relations among humans, nature, and animals and develop sensitivity to the need for the protection of the earth. Both models of sacrifice can serve as inspiration for the development of reasonable patterns for resource management.
The Greening of China: The Constructive Postmodern Movement in Contemporary China
Authors: McDaniel Jay
Published: December 2008

When China's economy began to grow in the 1980's, many people throughout the world, including many people in China, hoped that China might offer the world a unique model of development. Many Chinese carry this hope even today, and some among them are turning to Whiteheadian or process thought for guidance. Of course Whitehead is a Western philosopher, but they see in his ideas deep similarities with Chinese ways of thinking, enabling Chinese to articulate traditional points of view in a modern setting. With help from Whitehead they are developing what they call a "Constructively Postmodern" approach to China's future. This essay introduces this movement, its core ideas, and some of its key figures, linking them with the theme of religion and sustainability.
Nollywood Films and the Cultural Imperialism Hypothesis
Authors: Akpabio Eno , Mustapha-Lambe Kayode
Published: December 2008

From the viewpoint of the cultural imperialism hypothesis and its complications, the overall aim of this study was to find out if foreign films still had a stranglehold on Nigerian audience members. The findings indicate that a majority of respondents watch and have a favorable attitude towards Nigerian home video films. However, in terms of preference between local and foreign films, a small percentage indicated preference for the former. The study concludes that the high quality of production of American films accounts for the favorable views held by respondents, even though it is apparent that these and other foreign productions no longer have a captive market in Nigeria.
Between Magic and Logic: Globalization and the Challenge of Medical Collaboration in Ngugi's Wizard Of The Crow
Authors: Olaoluwa Senayon
Published: December 2008

Perhaps one of the ways by which the Third World, especially Africa, may negotiate its position in the unfolding global politics is through what has been described as the necessary "fusion of ideas and cultures" (Anyidoho 2006:158), along an intellectual axis for Africa's developmental goals. Therefore, this paper seeks to explore one of the areas of such intellectual contributions through a reading and analysis of the developmental angle of Ngugi wa Thiong'o's latest novel Wizard of the Crow (2006). Although the novel has been aptly described as a novel that reflects "on Africa's dysfunctions… and possibilities" (Reed Business Information 2006) in the age of globalization, this paper seeks to transcend the overwhelming concern about unbridled African despotism caught in the mesh of global politics, which the author critiques in the novel and which many a reviewer has commented upon in order to consider the developmental rays of hope that fire through the narrative simultaneously. By so doing, the paper is concerned with one of the "possibilities" in the positive sense of the word along the line of the reinvention of autochthonous African medical practice, otherwise derogatorily designated as magic and sorcery. The reason is that it is obvious in the novel that there is a possibility of investing the indigenous medical practice with a logical modern appeal to the extent of finding collaboration with Western medical practice in order to earn better reception across global spatial boundaries. In the process of this exploration, I also engage the notion of modernity.
From Drops of Blood: Charisma and Political Legitimacy in the translatio of the 'Uthmānic Codex of al-Andalus
Authors: Zadeh Travis
Published: December 2008

The account of the 'Uthmānic mushaf of Córdoba, which passed from generation to generation across the western shores of Islam, has played a prominent role in the history of al-Andalus and the Maghrib. The prized codex appears throughout historiographical and literary discourses, stretching from the Hispano-Umayyad caliphate to the dynasty of the Banū Marīn in North Africa. Brought into battle against Christians and fellow Muslims, decorated with ornate coverings, and made into the object of countless panegyrics, the 'Uthmānic codex of al-Andalus offers a glimpse into a sustained network of meaning and power. The codex came symbolically to align successive Muslim dynasties to the early history of Islam. Drawing attention to the parallel phenomena of the furta sacra and the translatio of relics in medieval Christian tradition, this article explores the broader political, religious, and literary dimensions which silhouette the veneration toward the 'Uthmānic codex.
Female Corporeality, Magic, and Gender in the Babylonian Talmud
Authors: Murray Michele
Published: December 2008

For the rabbis, female corporeality – and the control of the female body through rules and regulations – was the locus for (decidedly male) rabbinic piety, and a means for the rabbis to workout what constituted ideal maleness. In their constructions of what constituted "male" and "female," the rabbis created a hierarchy in which males – in particular rabbinic males – were at the top of the hierarchy, and females were at the bottom. The focus of this article is the rabbinic taxonomy of human beings as found in the Babylonian Talmud, a multi-layered and edited corpus of Jewish literature dating from the third to the sixth or seventh centuries CE, redacted in its final form in Babylonia. Using what I call a "taxonomical continuum" as a heuristic tool, I explore how the rabbis employed the label of magic in their discourse as a means of expressing gender. I suggest that "male," which for the rabbis was the form of the ideal human being, was at one end of the continuum. The further from the "male" pole a person was placed along the continuum, the less perfect and less ideal – and the more "female" – was that person. I argue that magic was employed as a mechanism for expressing rabbinic perceptions of gender, since the term "magic" has both positive and negative connotations in the Babylonian Talmud. The valence of the term depended on where the individual who performed the supra-natural action in question was found along the rabbinic taxonomic continuum.
Alignment of Hurricane-like Vortices on f and β Planes
Authors: Jones Robert W. , Willoughby Hugh E. , Montgomery Michael T.
Published: December 2008

A nonlinear, two-layer, vortex-tracking semispectral model (i.e., Fourier transformed in azimuth only) is used to study the evolution of dry, but otherwise hurricane-like, initially tilted vortices in quiescent surroundings on f and β planes. The tilt projects onto vorticity asymmetries that are dynamically vortex Rossby waves.

Since the swirling wind in the principal mean vortex used here decays exponentially outside the eyewall, it has an initial potential vorticity (PV) minimum. The resulting reversal of PV gradient meets the necessary condition for inflectional (i.e., barotropic or baroclinic) instability. Thus, the vortex may be inflectionally stable or unstable. On an f plane, the tilt precesses relatively slowly because the critical radius, where the phase speeds of the waves match the mean swirling flow, is far from the center. An alternative Gaussian-like PV monopole that has a monotonic outward decrease of PV is stable to inflectional instability. It has a smaller critical radius and rapid tilt precession. Generally, vortices with fast tilt precession are more stable, as are stronger vortices in higher latitudes.

On a β plane, the interaction between the symmetric vortex and the planetary PV gradient induces β gyres that push the vortex poleward and westward. The interaction between the β gyres and the planetary PV gradient may either create a PV minimum or intensify a minimum inherited from the initial condition. Thus, the nonlinear β effect reduces the ability of the vortex to recover from initial tilt, relative to the same vortex on an f plane. This result contrasts with previous studies of barotropic vortices on f planes, where the linear and nonlinear solutions were nearly identical.