bluuebunny/crossref_metadata_2025 huggingface dataset:
Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo
Authors: Stan Silvia D. , Hahm Eun-Ryeong , Warin Renaud , Singh Shivendra V.
Published: September 2008

Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone–associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone–associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells. [Cancer Res 2008;68(18):7661–9]
Suppression of Familial Adenomatous Polyposis by CP-31398, a TP53 Modulator, in APCmin/+ Mice
Authors: Rao Chinthalapally V. , Swamy Malisetty V. , Patlolla Jagan M.R. , Kopelovich Levy
Published: September 2008

p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APCmin (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP-31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21WAF1/CIP, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APCmin/+ mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation. [Cancer Res 2008;68(18):7670–5]
Acute Wounds Accelerate Tumorigenesis by a T Cell–Dependent Mechanism
Authors: Stuelten Christina H. , Barbul Adrian , Busch Johanna I. , Sutton Emily , Katz Ryan , Sato Misako , Wakefield Lalage M. , Roberts Anita B. , Niederhuber John E.
Published: September 2008

We investigated the influence of acute wounding on tumor growth in a syngeneic mouse breast cancer model. Metastatic mouse breast cancer cells (4T1) were orthotopically injected into the mammary fat pads of BALB/c mice, and animals were wounded locally by full thickness dermal incisions above the mammary fat pads or remotely above the scapula 9 days later. Local, but not remote, wounding increased tumor size when compared with sham treatment. Injection of wound fluid close to the tumor site increased tumor growth, whereas in vitro wound fluid compared with serum increased the proliferation rate of 4T1 cells. Our results show that wound stroma can unfavorably influence growth of nearby tumors. This effect is T cell–dependent, as local wounding had no effect on tumor growth in nu/nu mice. The effect of wounding on tumor growth can be mimicked by acellular wound fluid, suggesting that T cells secrete or mediate secretion of cytokines or growth factors that then accelerate tumor growth. Here, we define an experimental model of wound-promoted tumor growth that will enable us to identify mechanisms and therapeutic targets to reduce the negative effect of tissue repair on residual tumors. [Cancer Res 2008;68(18):7278–82]
GLI2 Knockdown Using an Antisense Oligonucleotide Induces Apoptosis and Chemosensitizes Cells to Paclitaxel in Androgen-Independent Prostate Cancer
Authors: Narita Shintaro , So Alan , Ettinger Susan , Hayashi Norihiro , Muramaki Mototsugu , Fazli Ladan , Kim Youngsoo , Gleave Martin E.
Published: September 2008

Purpose: GLI transcription factors mediate hedgehog signaling and have been implicated in several human malignancies, including prostate cancer. The objectives of this study were to characterize GLI2 expression levels in human prostate cancer cell lines and tissues to test the effect of antisense oligonucleotide (ASO) targeting GLI2 on androgen-independent (AI) prostate cancer cell lines.

Experimental Design: A tissue microarray was used to characterize differences in GLI2 expression in benign prostate hyperplasia, prostate cancer treated by neoadjuvant hormonal therapy and AI prostate cancer. The effects of GLI2 ASO on PC-3 cell growth and paclitaxel chemosensitivity were assessed in vitro and in vivo. Oligonucleotide spotted microarray analysis was used to determine alteration in GLI2 coregulated genes after ASO treatment.

Results: The expression of GLI2 was significantly higher in prostate cancer than in benign prostate hyperplasia, decreased after androgen ablation in a time-dependent fashion, but became highly expressed again in AI prostate cancer. GLI2 ASO treatment of PC-3 cells reduced GLI2 mRNA and protein levels in a dose-dependent manner. GLI2 knockdown increased PC-3 cell apoptotic rates and significantly decreased cell growth and modulated levels of apoptosis-related genes, such as Bcl2, Bcl-xL, and clusterin. GLI2 knockdown also changed levels of several cell cycle regulators, such as cyclin D1, p27, and PKC-η. Systematic administration of GLI2 ASO in athymic mice significantly delayed PC-3 tumor progression and enhanced paclitaxel chemosensitivity.

Conclusions: These findings suggest that increased levels of GLI2 correlates with AI progression and that GLI2 may be a therapeutic target in castrate-resistant prostate cancer.
Urokinase Plasminogen Activator Receptor Choreographs Multiple Ligand Interactions: Implications for Tumor Progression and Therapy
Authors: Mazar Andrew P.
Published: September 2008

The urokinase plasminogen activator receptor (uPAR) has been implicated in the growth, metastasis, and angiogenesis of several solid and hemotologic malignancies. uPAR is part of a cell surface system that also consists of the serine protease uPA and several specific inhibitors (plasminogen activator inhibitors 1 and 2). This system has classically been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells, and intervening with this proteolysis by targeting uPAR has been proposed to represent a novel approach for inhibiting tumor progression. However, despite abundant evidence suggesting the utility of targeting uPAR for the treatment of cancer, there are currently no uPAR-targeted therapies being evaluated in clinical trials. Recent data have provided new insights into the role of uPAR in tumor progression. In addition to mediating proteolysis, this receptor appears to also mediate cell signaling, proliferation, and survival, and these observations have revealed novel ways to target uPAR. How these data have led to a paradigm shift in how the role of uPAR in tumor progression is perceived as well as past and present attempts to therapeutically target a molecule that is generating renewed interest as a cancer target will be discussed in this article.
Control of Cell Growth and Survival by Enzymes of the Fatty Acid Synthesis Pathway in HCT-116 Colon Cancer Cells
Authors: Zhan Yanai , Ginanni Nicole , Tota Michael R. , Wu Margaret , Bays Nathan W. , Richon Victoria M. , Kohl Nancy E. , Bachman Eric S. , Strack Peter R. , Krauss Stefan
Published: September 2008

Purpose: For many tumor cells, de novo lipogenesis is a requirement for growth and survival. A considerable body of work suggests that inhibition of this pathway may be a powerful approach to antineoplastic therapy. It has recently been shown that inhibition of various steps in the lipogenic pathway individually can induce apoptosis or loss of viability in tumor cells. However, it is not clear whether quantitative differences exist in the ability of lipogenic enzymes to control tumor cell survival. We present a systematic approach that allows for a direct comparison of the control of lipogenic pathway enzymes over tumor cell growth and apoptosis using different cancer cells.

Experimental Design: RNA interference-mediated, graded down-regulation of fatty acid synthase (FAS) pathway enzymes was employed in combination with measurements of lipogenesis, apoptosis, and cell growth.

Results: In applying RNA interference titrations to two lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and FAS, we show that ACC1 and FAS both significantly control cell growth and apoptosis in HCT-116 cells. These results also extend to PC-3 and A2780 cancer cells.

Conclusions: Control of tumor cell survival by different steps in de novo lipogenesis can be quantified. Because ACC1 and FAS both significantly control tumor cell growth and apoptosis, we propose that pharmacologic inhibitors of either enzyme might be useful agents in targeting cancer cells that critically rely on fatty acid synthesis. The experimental approach described here may be extended to other targets or disease-relevant pathways to identify steps suitable for therapeutic intervention.
WNT5A Expression Increases during Melanoma Progression and Correlates with Outcome
Authors: Da Forno Philip D. , Pringle J. Howard , Hutchinson Peter , Osborn Joy , Huang Qiang , Potter Linda , Hancox Rachael A. , Fletcher Alan , Saldanha Gerald S.
Published: September 2008

Purpose: Wnt ligands play a major role in development and are important in cancer. Expression microarray analysis correlates one member of this family, WNT5A, to a subclass of melanomas with increased motility and invasion. There are no large studies of clinical samples primarily addressing the importance of WNT5A in melanoma progression or outcome. Therefore, this study aimed to assess the protein expression of WNT5A during melanoma progression and its effect on outcome.

Experimental Design: Expression of WNT5A was determined in a series of 59 primary melanomas with matched metastases. To provide a benchmark of progression against which to assess WNT5A, expression of p16ink4a was analyzed, as this has been previously well documented in melanoma. The effect of WNT5A protein expression on outcome was assessed in 102 melanomas.

Results: Cytoplasmic WNT5A showed a trend of increasing expression with melanoma progression (P = 0.013), whereas there was diminishing p16ink4a expression (P = 0.006). Nevi showed relatively strong WNT5A expression. Strong cytoplasmic WNT5A was an independent risk factor for reduced metastasis-free and overall survival in multivariate analysis (P = 0.001 and 0.003, respectively).

Conclusion: Cytoplasmic WNT5A increases with melanoma progression and strong expression is associated with poor outcome.
Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas
Authors: Sinicrope Frank A. , Rego Rafaela L. , Okumura Kenji , Foster Nathan R. , O'Connell Michael J. , Sargent Daniel J. , Windschitl Harold E.
Published: September 2008

Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates.

Experimental Design: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil–based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates.

Results: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011).

Conclusions: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil–based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.
Cleaved Forms of the Urokinase Plasminogen Activator Receptor in Plasma Have Diagnostic Potential and Predict Postoperative Survival in Patients with Ovarian Cancer
Authors: Henić Emir , Borgfeldt Christer , Christensen Ib Jarle , Casslén Bertil , Høyer-Hansen Gunilla
Published: September 2008

Purpose: To evaluate the plasma level of different forms of soluble urokinase plasminogen activator receptor (suPAR) as discriminators between malignant, borderline, and benign ovarian tumors and as prognostic markers in patients with ovarian cancer.

Experimental Design: The different suPAR forms were measured in preoperative plasma samples obtained from 335 patients with adnexal lesions using three different time-resolved fluoresence assays (TR-FIA): TR-FIA 1 measuring intact suPAR, suPAR(I-III), TR-FIA 2 measuring the total amount of suPAR(I-III) and the cleaved form, suPAR(II-III), and TR-FIA 3 measuring the liberated uPAR(I). Tumors were classified as benign (n = 211), borderline (possibly malignant; n = 30), and well (n = 19), moderately (n = 15), and poorly (n = 60) differentiated malignant.

Results: All uPAR forms as well as CA125 were statistically significant in univariate analysis discriminating between benign, borderline, and invasive tumors. Restricting the analysis of invasive tumors to early stage (I and II) showed similar results. A combination of CA125 and suPAR(I-III) + suPAR(II-III) discriminated between malignant (all stages) and benign tumors [AUC, 0.94; 95% confidence interval (95% CI), 0.90-0.98] as well as borderline and benign tumors (AUC, 0.78; 95% CI, 0.67-0.89). All suPAR forms were markers for poor prognosis in univariate analyses, and high preoperative plasma level of uPAR(I) is an independent predictor of poor prognosis (hazard ratio, 1.84; 95% CI, 1.15-2.95; P = 0.011) in multivariate analyses including age and CA125.

Conclusions: High concentration of plasma uPAR(I) is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The combination of plasma suPAR(I-III) + suPAR(II-III) and CA125 discriminates between malignant and benign tumors with an AUC of 0.94.
Advances in Targeting IKK and IKK-Related Kinases for Cancer Therapy
Authors: Lee Dung-Fang , Hung Mien-Chie
Published: September 2008

IκB kinases (IKK) and IKK-related kinases play critical roles in regulating the immune response through nuclear factor-κB and IFN regulatory factor–dependent signaling transduction cascades. Recently, these kinases have been implicated in the pathogenesis of many human diseases, including cancer. In fact, dysregulation of IKK activities promotes tumor survival, proliferation, migration, metastasis, and angiogenesis—common characteristics of many types of human cancers. Because of their oncogenic effects in human cancer development, targeting IKK and IKK-related kinases is becoming an increasingly popular avenue for the development of novel therapeutic interventions for cancer. This review will briefly cover the recent discovery of the downstream substrates of IKK and IKK-related kinases, and outline the strategies used for targeting IKK as a therapeutic intervention for cancer.
Tris (Dibenzylideneacetone) Dipalladium, aN-Myristoyltransferase-1 Inhibitor, Is Effective against Melanoma GrowthIn vitroandIn vivo
Authors: Bhandarkar Sulochana S. , Bromberg Jacqueline , Carrillo Carol , Selvakumar Ponniah , Sharma Rajendra K. , Perry Betsy N. , Govindarajan Baskaran , Fried Levi , Sohn Allie , Reddy Kalpana , Arbiser Jack L.
Published: September 2008

Purpose: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA.

Experimental Design: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed.

Results: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma.

Conclusion: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.
Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma
Authors: Riely Gregory J. , Kris Mark G. , Rosenbaum Daniel , Marks Jenifer , Li Allan , Chitale Dhananjay A. , Nafa Khedoudja , Riedel Elyn R. , Hsu Meier , Pao William , Miller Vincent A. , Ladanyi Marc
Published: September 2008

Purpose: KRAS mutations are found in ∼25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib.

Experimental Design: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas.

Results: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G→A) rather than the transversion mutations known to be smoking-related (G→T or G→C; P < 0.0001).

Conclusions: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.
Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival
Authors: van Cruijsen Hester , van der Veldt Astrid A.M. , Vroling Laura , Oosterhoff Dinja , Broxterman Henk J. , Scheper Rik J. , Giaccone Giuseppe , Haanen John B.A.G. , van den Eertwegh Alfons J.M. , Boven Epie , Hoekman Klaas , de Gruijl Tanja D.
Published: September 2008

Purpose: A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients.

Experimental Design: Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data.

Results: Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1+ MDC frequencies were predictive for tumor regression and improved progression-free survival.

Conclusion: The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.
Prognostic Effect of Epithelial Cell Adhesion Molecule Overexpression in Untreated Node-Negative Breast Cancer
Authors: Schmidt Marcus , Hasenclever Dirk , Schaeffer Mitra , Boehm Daniel , Cotarelo Cristina , Steiner Eric , Lebrecht Antje , Siggelkow Wulf , Weikel Wolfgang , Schiffer-Petry Ilka , Gebhard Susanne , Pilch Henryk , Gehrmann Mathias , Lehr Hans-Anton , Koelbl Heinz , Hengstler Jan G. , Schuler Martin
Published: September 2008

Purpose: Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention not only as a prognostic factor in breast cancer but also as a potential target for immunotherapy. We examined Ep-CAM expression in 402 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting.

Experimental Design: Ep-CAM expression was evaluated by immunostaining. Its prognostic effect was estimated relative to overexpression/amplification of HER-2, histologic grade, tumor size, age, and hormone receptor expression.

Results: Ep-CAM status was positive in 106 (26.4%) patients. In multivariate analysis, Ep-CAM status was associated with disease-free survival independent of age, pT stage, histologic grade, estrogen receptor (ER), progesterone receptor (PR), as well as HER2 status (P = 0.028; hazard ratio, 1.60; 95% confidence interval, 1.05-2.44). Recently, so-called triple-negative (HER-2, ER, and PR) breast cancer has received increased attention. We noticed a similar association of Ep-CAM with disease-free survival in the triple-negative group as for the entire cohort.

Conclusion: In this study of untreated breast cancer patients, Ep-CAM overexpression was associated with poor survival in the entire cohort and in the subgroup of triple-negative breast cancer. This suggests that Ep-CAM may be a well-suited target for specific therapies particularly in HER-2–, ER-, and PR-negative tumors.
The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival
Authors: Quaye Lydia , Gayther Simon A. , Ramus Susan J. , Di Cioccio Richard A. , McGuire Valerie , Hogdall Estrid , Hogdall Claus , Blaakr Jan , Easton Douglas F. , Ponder Bruce A.J. , Jacobs Ian , Kjaer Susanne Kruger , Whittemore Alice S. , Pearce Celeste Leigh , Pharoah Paul D.P. , Song Honglin
Published: September 2008

Purpose: The 5-year survival rate for invasive epithelial ovarian cancer is <35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer.

Experimental Design: We evaluated the association between 34 tagging single nucleotide polymorphisms and survival in 1,480 cases of invasive epithelial ovarian cancer cases from three different studies. Cox regression analysis, stratified by study, was used to estimate per rare allele hazard ratios (HR).

Results: The minor allele rs6944385 in BRAF was significantly associated with poor survival [HR, 1.19; 95% confidence intervals (95% CI), 1.02-1.39; P = 0.024]. The association remained after adjusting for prognostic factors (adjusted HR, 1.20; 95 CI, 1.03-1.40; P = 0.018). A haplotype of BRAF was also associated with poor survival (HR, 1.24; 95% CI, 1.02-1.51; P = 0.029) and was more significant after adjustment (HR, 1.44; 95% CI, 1.15-1.81; P = 0.001). We also found evidence of an association between a KRAS haplotype and poor survival in serous subtype (HR, 1.69; 95% CI, 1.21-2.38; P = 0.002), but this was no longer significant after adjustment. Finally, when analyses were restricted to the serous histologic subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007).

Conclusion: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.
Gene Expression Profiling Reveals Similarities between theIn vitroandIn vivoResponses of Immune Effector Cells to IFN-α
Authors: Zimmerer Jason M. , Lesinski Gregory B. , Ruppert Amy S. , Radmacher Michael D. , Noble Carl , Kendra Kari , Walker Michael J. , Carson William E.
Published: September 2008

Purpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the in vivo response to treatment with high-dose IFN-α.

Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α.

Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α in vitro for 18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-α-2b (20 MU/m2 i.v.) revealed significant up-regulation (>2-fold) of 21 genes (P < 0.001). Also, the gene expression profile of in vitro IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy.

Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-α may be a useful predictor of the in vivo response of immune cells to IFN-α immunotherapy.
Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease
Authors: Xu Jianfeng , Isaacs Sarah D. , Sun Jielin , Li Ge , Wiley Kathleen E. , Zhu Yi , Hsu Fang-Chi , Wiklund Fredrik , Turner Aubrey R. , Adams Tamara S. , Liu Wennuan , Trock Bruce J. , Partin Alan W. , Chang Baoli , Walsh Patrick C. , Grönberg Henrik , Isaacs William , Zheng Siqun
Published: September 2008

Purpose: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain.

Experimental Design: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested.

Results: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening.

Conclusions: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.
Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel
Authors: Fetterly Gerald J. , Grasela Thaddeus H. , Sherman Jeffrey W. , Dul Jeanne L. , Grahn Amy , Lecomte Diane , Fiedler-Kelly Jill , Damjanov Nevena , Fishman Mayer , Kane Michael P. , Rubin Eric H. , Tan Antoinette R.
Published: September 2008

Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients.

Experimental Design: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m2). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection.

Results: The MTD of LEP-ETU was identified as 325 mg/m2. DLTs occurring at 375 mg/m2 consisted of febrile neutropenia and neuropathy. The Cmax and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 μg/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m2 q3w. For a dose of 110 mg/m2 given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w.

Conclusions: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m2 LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m2 Taxol q3w. A 275 mg/m2 dose may offer an improved therapeutic index.
The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics)
Authors: Schilsky Richard L. , Gordon Gary , Gilmer Tona M. , Courtneidge Sara A. , Matrisian Lynn M. , Grad Oren , Nelson William G. ,   on behalf of the Translational Research Working Group
Published: September 2008

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of agents—both small molecules and biologics—for the treatment and prevention of cancer. The Agents Developmental Pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of an agent through the translational process to the point where it can begin definitive clinical testing. This article presents the Agents Developmental Pathway and discusses key challenges associated with the processes described.
Translational Research Working Group Developmental Pathway for Immune Response Modifiers
Authors: Cheever Martin A. , Schlom Jeffrey , Weiner Louis M. , Lyerly H. Kim , Disis Mary L. , Greenwood Addison , Grad Oren , Nelson William G. ,   for the Translational Research Working Group
Published: September 2008

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the investment of National Cancer Institute in translational research and envision its future. The Translational Research Working Group conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of immune response modifiers such as vaccines and cytokines. A hallmark of the Immune Response Modifier Developmental Pathway is the coordinated development of multiple components. The Immune Response Modifier Pathway was conceived not as a comprehensive description of the corresponding real-world processes but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper discusses key challenges associated with the immune response modifier agent development process in light of the pathway.
Physiologie de la croissance
Authors: Rosenbloom Arlan L.
Published: September 2008

La croissance humaine est un processus dynamique et complexe qui commence par la fécondation de l’ovule et se termine par la soudure des épiphyses aux métaphyses des os longs, qui marque la fin de l’adolescence. La croissance se déroule par phases dont les caractéristiques sont distinctes en termes d’influences dominantes de facteurs et profils génétiques, environnementaux ou nutritionnels. La croissance prénatale est la phase la plus spectaculaire, atteignant une vitesse qui ne sera plus jamais égalée. Elle dépend principalement de la corpulence et du statut nutritionnel de la mère, l’héritage génétique parental ayant peu d’influence. Le facteur de croissance de type insulinique (insulin-like growth factor; IGF) et l’insuline sont essentiels, tandis que les hormones thyroïdiennes et l’hormone de croissance (GH) ne le sont pas. La petite enfance est une période où la vitesse de croissance se modifie rapidement, passant de 20 centimètres par an pendant les premiers mois à 10–12 cm par an vers l’âge d’un an. Cette phase est fortement tributaire de l’héritage génétique, avec de fréquents ajustements à un percentile approprié. Elle dépend également d’une sécrétion et d’une action normales des hormones thyroïdiennes et de la GH (stimulation de la synthèse d’IGF-I par le foie et promotion de la différenciation des chondrocytes et de la sécrétion locale d’IGF-I). La croissance est en moyenne de 10–13 cm par an au cours de la deuxième année et de 7,5–10 cm par an au cours de la troisième, puis se stabilise par la suite à 5–6 cm par an, avec persistance de la dépendance à une action et une sécrétion normales d’hormones thyroïdiennes et de GH. La diminution de l’inhibition de l’axe hypothalamo-gonadotrophine avec une lente augmentation de la production des hormones sexuelles marque le début de l’adolescence, qui est associée à une poussée de croissance résultant de l’augmentation de la production d’insuline, de GH et d’IGF-I, outre le fort accroissement des hormones sexuelles. Les tendances séculaires observées au cours des 150 dernières années traduisent les influences de l’environnement sur la croissance. De très nombreux produits de gènes agissant sur la plaque de croissance ont été décrits. De plus, la mise en évidence de facteurs de différenciation de l’hypophyse et de contrôle génétique, ainsi que l’identification de gènes contrôlant plusieurs étapes d’actions hormonales clés accroissent les connaissances sur l’interaction complexe de facteurs génétiques, de l’environnement et du milieu hormonal dans le processus de croissance.
Les nouvelles normes de croissance de l’OMS
Authors: Ziegler Ekhard E. , Nelson Steven E.
Published: September 2008

Les nouvelles normes de croissance de l’Organisation mondiale de la Santé (OMS) ont été créées dans l’intention d’obtenir des normes de croissance globalement applicables décrivant la croissance des enfants telle qu’elle se déroule dans des conditions nutritionnelles optimales et en l’absence de contraintes externes. En d’autres termes, elles représentent la croissance telle qu’elle devrait être. Les données destinées à la création des nouvelles normes ont été recueillies chez des enfants de six pays vivant dans des circonstances favorables. De plus, les données de certains sujets se situant à des valeurs extrêmes de poids et de taille ont été exclues. De façon non surprenante, les nouvelles normes de croissance diffèrent de plusieurs façons des autres courbes de croissance de référence. Ces différences étant nombreuses, seules quelques remarques générales sont possibles. (1) Au cours des dix premiers mois de la vie, les poids et tailles indiqués par les normes de l’OMS sont plus élevés à tous les percentiles que ceux indiqués par toute autre courbe de référence. (2) Au cours du deuxième semestre de la vie et jusqu’à l’âge de deux ans, le poids mentionné par les normes de l’OMS (mais non la taille) est plus bas que celui indiqué par les autres courbes. (3) Entre 2 et 5 ans, le poids de référence de l’OMS tend à se situer à l’extrémité inférieure du spectre, particulièrement aux plus bas percentiles, tandis que la courbe Euro-Growth occupe l’extrémité supérieure pour le poids à tous les percentiles. (4) Une évaluation fonctionnelle a montré que, comparativement à d’autres courbes de référence, les normes de l’OMS identifiaient moins d’enfants de 1 à 5 ans comme étant en sous-poids et un plus grand nombre d’enfants de 2 à 5 ans comme étant en surpoids.
Petite et grande taille
Authors: Bramswig Jurgen H.
Published: September 2008

Une petite taille ou une grande taille doit être considérée d’abord comme une variation normale de la taille. Elle appartient au continuum de la courbe de distribution gaussienne normale, qui définit les limites inférieure et supérieure de la normale comme étant les 3ème et 97ème percentiles. Dans ce contexte, il est très important de différencier des variations normales de la taille et de la croissance de situations pathologiques. Les variations staturales normales sont une petite ou une grande taille familiale ou idiopathique. Les variations normales de la croissance sont diagnostiquées comme accélération ou retard constitutionnel de la croissance et de la puberté et s’observent à tous les percentiles. Les patients dans une situation staturale pathologique présentent habituellement des troubles syndromiques, squelettiques ou chromosomiques, par exemple un syndrome de Russell-Silver ou de Marfan, une achondroplasie ou un syndrome d’Ullrich-Turner ou de Klinefelter. De nombreux cas de petite taille pathologique sont associés à un retard de croissance intra-utérin. La taille finale (moyenne) n’atteint pas nécessairement la taille cible, mais atteint une valeur inférieure ou supérieure au 3ème ou au 97ème percentile dans la population. La taille des patients atteints de troubles de la croissance peut être petite, normale ou grande. La vitesse de croissance est ralentie ou accélérée chez ces patients en raison de maladies viscérales ou psychosomatiques chroniques très diverses. À l’heure actuelle, un traitement par hormone de croissance (GH) est disponible pour les patients présentant un déficit en GH, un syndrome d’Ullrich-Turner, une insuffisance rénale chronique, un retard de croissance intra-utérin et un syndrome de Prader-Willi. L’indication de la GH dans le traitement de la petite taille idiopathique est actuellement acceptée uniquement aux États-Unis. Des données indiquent que les patients présentant un déficit documenté en GH et traités par cette hormone atteignent une taille adulte voisine de leur taille cible. Une amélioration statistiquement significative de la taille adulte a été documentée dans toutes les autres indications. Le suivi à long terme de ces patients devrait démontrer une amélioration tant cliniquement que statistiquement significative de leur taille à l’âge adulte. En fonction des résultats, il pourrait être nécessaire de reconsidérer certaines des indications du traitement par GH.
Croissance et maladies chroniques
Authors: Patel Leena
Published: September 2008

De nombreuses affections altèrent la croissance. La mucoviscidose, la maladie de Crohn et l’arthrite juvénile idiopathique sont des maladies chroniques relativement fréquentes dans l’enfance et associées à une altération substantielle de la croissance. Un retard de croissance peut être le premier signe d’une pathologie, mais le profil de la croissance est également une mesure utile de la sévérité d’une maladie et de sa réponse au traitement. Outre son intérêt diagnostique, la petite taille résultante peut non seulement être inacceptable pour le patient, mais aussi nuire à son état physique s’il est atteint d’une maladie telle la mucoviscidose. Une altération de la croissance chez un enfant atteint d’une maladie chronique est associée à des perturbations de l’axe hormone de croissance (GH)–facteur insulinique de croissance (IGF) et résulte principalement d’une sous-nutrition, d’une inflammation chronique et d’une corticothérapie prolongée. Une sous-nutrition aboutit à des adaptations majeures du système endocrine visant à conserver l’énergie, détourner des substrats de la croissance et de la reproduction et fournir des sources alternatives d’énergie pour l’homéostasie critique de l’organisme. Un processus inflammatoire chronique aggrave une sous-nutrition, mais des cytokines pro-inflammatoires telles que l’interleukine-6, le facteur de nécrose tumorale α (TNF-α) et l’interleukine-1β altèrent également la croissance indépendamment de la nutrition en perturbant l’intégrité de l’axe GH–IGF et en exerçant des effets locaux directs sur la chondrogenèse dans la plaque de croissance. Ces mécanismes régulateurs de la croissance subissent des perturbations supplémentaires sous l’effet de la corticothérapie administrée dans le traitement de certaines affections chroniques en raison de ses propriétés anti-inflammatoires et immunosuppressives. Il est probable que les processus entravant la croissance ralentissent la sénescence de la plaque de croissance, ce qui permet une croissance de rattrapage lors de la récupération d’une maladie chronique et le sevrage d’une corticothérapie. Les essais cliniques de la GH recombinante humaine (rhGH) chez des patients présentant un retard de croissance ont suggéré une amélioration de la croissance linéaire ainsi que des effets bénéfiques sur la composition de l’organisme et l’évolution clinique. Ces essais ont été de relativement courte durée, et il est donc nécessaire d’évaluer les bénéfices à long terme ainsi que la tolérance de la rhGH, particulièrement en association à une corticothérapie.
Changes in Erythrocyte Glutathione and Plasma Membrane Calcium Pump in Preterm Newborns Treated Antenatally with MgSO4
Authors: Zylinska Ludmila , Gulczynska Ewa , Kozaczuk Anna
Published: September 2008

Background: Magnesium is required for the proper activity of many metabolic pathways in every cell type. Mg deficiency gives rise to preterm birth and low body weight that are associated with pathological circumstances, including disturbed ions homeostasis and insufficient antioxidant protection. Antenatal MgSO4 treatment has been reported to exhibit a protective effect on the developing fetus; however, the molecular mechanism of this protection remains not fully understood. Objectives: Since Mg ions very rapid cross the placenta, our study tested the hypothesis whether prenatal exposure to MgSO4 may modify the expression and activity of erythrocyte plasma membrane calcium pump (PMCA), and total erythrocyte glutathione (GSH) concentration in preterm newborns. Methods: Immunocharacteristics of erythrocyte PMCA in control and MgSO4-treated newborns were done using general and isoform-specific antibodies. The hydrolytic activity of PMCA was determined with and without calmodulin. Total GSH erythrocyte levels were analyzed by a quantitative assay using Ellman reagent. All assays were done after delivery and 24 h later. Results: Significant differences were present in PMCA amount, isoform composition, basal activity and sensitivity for stimulation by calmodulin in both groups of neonates. The total GSH content altered during examined time, but only in the control group. Conclusions: Prenatal treatment with MgSO4 may exert a significant influence on calcium homeostasis and nonenzymatic antioxidant reserve in the erythrocytes of preterm newborns.