bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulation of Na+/H+ Exchanger Regulatory Factor 1 Increases Expression and Function of Multidrug Resistance Protein 4
Authors: Hoque Md. Tozammel , Cole Susan P.C. 
Published: June 2008

Abstract
Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the ATP-binding cassette superfamily of membrane transport proteins and confers resistance to nucleoside and nucleotide analogues as well as camptothecin derivatives. MRP4 also mediates the transmembrane transport of several eicosanoids, conjugated estrogens, and cyclic AMP. The subcellular localization of MRP4 depends on the cell type in which it is expressed, but the molecular determinants responsible for trafficking of MRP4 to the plasma membrane are unknown. Here, we describe the interaction of Na+/H+ exchanger regulatory factor 1 (NHERF1) with MRP4 via the last four amino acids (1322ETAL1325) of the transporter. Down-regulation of NHERF1 by small interfering RNA (siRNA) in HeLa cells significantly increased MRP4 levels at the plasma membrane, suggesting that internalization of the transporter was inhibited. Increased plasma membrane MRP4 was accompanied by increased efflux function as reflected by reduced cellular accumulation of the MRP4 substrates 6-mercaptopurine and 9-[2-(phosphonylmethoxy)ethyl]-adenine. Furthermore, enhanced green fluorescent protein-tagged MRP4 was internalized in monensin-treated cells, and this internalization was markedly reduced after NHERF1 down-regulation by siRNA. Together, these data establish NHERF1 as a novel protein-binding partner of MRP4 that plays a significant role in the internalization and drug efflux function of this transporter. [Cancer Res 2008;68(12):4802–9]
Emerging Roles of DMP1 in Lung Cancer
Authors: Inoue Kazushi , Sugiyama Takayuki , Taneja Pankaj , Morgan Rachel L. , Frazier Donna P. 
Published: June 2008

Abstract
The Ras-activated transcription factor DMP1 can stimulate Arf transcription to promote p53-dependent cell arrest. One recent study deepens the pathophysiologic significance of this pathway in cancer, first, by identifying DMP1 losses in human lung cancers that lack ARF/p53 mutations, and second, by demonstrating that Dmp1 deletions in the mouse are sufficient to promote K-ras–induced lung tumorigenesis via mechanisms consistent with a disruption of Arf/p53 suppressor function. These findings prompt further investigations of the prognostic value of DMP1 alterations in human cancers and the oncogenic events that can cooperate with DMP1 inactivation to drive tumorigenesis. [Cancer Res 2008;68(12):4487–90]
A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma
Authors: Gold David V. , Goldenberg David M. , Karacay Habibe , Rossi Edmund A. , Chang Chien-Hsing , Cardillo Thomas M. , McBride William J. , Sharkey Robert M. 
Published: June 2008

Abstract
Preclinical and clinical studies have demonstrated the application of radiolabeled mAb-PAM4 for nuclear imaging and radioimmunotherapy of pancreatic carcinoma. We have now examined the ability of a novel PAM4-based, bispecific monoclonal antibody (mAb) construct, TF10, to pretarget a radiolabeled peptide for improved imaging and therapy. TF10 is a humanized, bispecific mAb, divalent for mAb-PAM4 and monovalent for mAb-679, reactive against the histamine-succinyl-glycine hapten. Biodistribution studies and nuclear imaging of the radiolabeled TF10 and/or TF10-pretargeted hapten-peptide (IMP-288) were conducted in nude mice bearing CaPan1 human pancreatic cancer xenografts. 125I-TF10 cleared rapidly from the blood, with levels decreasing to &lt;1% injected dose per gram (ID/g) by 16 hours. Tumor uptake was 3.47 ± 0.66% ID/g at this time point with no accumulation in any normal tissue. To show the utility of the pretargeting approach, 111In-IMP-288 was administered 16 hours after TF10. At 3 hours postadministration of radiolabeled peptide, imaging showed intense uptake within the tumors and no evidence of accretion in any normal tissue. No targeting was observed in animals given only the 111In-peptide. Tumor uptake of the TF10-pretargeted 111In-IMP-288 was 24.3 ± 1.7% ID/g, whereas for 111In-IMP-288 alone it was only 0.12 ± 0.002% ID/g at 16 hours. Tumor/blood ratios were significantly greater for the pretargeting group (∼1,000:1 at 3 hours) compared with 111In-PAM4-IgG (∼5:1 at 24 hours; P &lt; 0.0003). Radiation dose estimates suggested that TF10/90Y-peptide pretargeting would provide a greater antitumor effect than 90Y-PAM4-IgG. Thus, the results suggest that TF10 pretargeting may provide improved imaging for early detection, diagnosis, and treatment of pancreatic cancer as compared with directly radiolabeled PAM4-IgG. [Cancer Res 2008;68(12):4819–26]
Topical Application of a Bioadhesive Black Raspberry Gel Modulates Gene Expression and Reduces Cyclooxygenase 2 Protein in Human Premalignant Oral Lesions
Authors: Mallery Susan R. , Zwick Jared C. , Pei Ping , Tong Meng , Larsen Peter E. , Shumway Brian S. , Lu Bo , Fields Henry W. , Mumper Russell J. , Stoner Gary D. 
Published: June 2008

Abstract
Reduced expression of proapoptotic and terminal differentiation genes in conjunction with increased levels of the proinflammatory and angiogenesis-inducing enzymes, cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), correlate with malignant transformation of oral intraepithelial neoplasia (IEN). Accordingly, this study investigated the effects of a 10% (w/w) freeze-dried black raspberry gel on oral IEN histopathology, gene expression profiles, intraepithelial COX-2 and iNOS proteins, and microvascular densities. Our laboratories have shown that freeze-dried black raspberries possess antioxidant properties and also induce keratinocyte apoptosis and terminal differentiation. Oral IEN tissues were hemisected to provide samples for pretreatment diagnoses and establish baseline biochemical and molecular variables. Treatment of the remaining lesional tissue (0.5 g gel applied four times daily for 6 weeks) began 1 week after the initial biopsy. RNA was isolated from snap-frozen IEN lesions for microarray analyses, followed by quantitative reverse transcription-PCR validation. Additional epithelial gene-specific quantitative reverse transcription-PCR analyses facilitated the assessment of target tissue treatment effects. Surface epithelial COX-2 and iNOS protein levels and microvascular densities were determined by image analysis quantified immunohistochemistry. Topical berry gel application uniformly suppressed genes associated with RNA processing, growth factor recycling, and inhibition of apoptosis. Although the majority of participants showed posttreatment decreases in epithelial iNOS and COX-2 proteins, only COX-2 reductions were statistically significant. These data show that berry gel application modulated oral IEN gene expression profiles, ultimately reducing epithelial COX-2 protein. In a patient subset, berry gel application also reduced vascular densities in the superficial connective tissues and induced genes associated with keratinocyte terminal differentiation. [Cancer Res 2008;68(12):4945–57]
Insulin-Dependent Leptin Expression in Breast Cancer Cells
Authors: Bartella Viviana , Cascio Sandra , Fiorio Elena , Auriemma Alessandra , Russo Antonio , Surmacz Eva 
Published: June 2008

Abstract
Pathologic conditions associated with hyperinsulinemia, such as obesity, metabolic syndrome, and diabetes, seem to increase the risk of breast cancer. Here, we studied molecular mechanisms by which insulin activates the expression of leptin, an obesity hormone that has been shown to promote breast cancer progression in an autocrine or paracrine way. Using MDA-MB-231 breast cancer cells, we found that (a) insulin stimulated leptin mRNA and protein expression, which was associated with increased activation of the leptin gene promoter; (b) insulin increased nuclear accumulation of transcription factors hypoxia inducible factor (HIF)-1α and Sp1 and their loading on the leptin promoter; (c) small interfering RNA (siRNA)-mediated knockdown of either HIF-1α or Sp1 significantly down-regulated insulin-induced leptin mRNA and protein expression; further inhibition of leptin expression was observed under the combined HIF-1α and Sp1 siRNA treatment; (d) inhibition of extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol-3-OH kinase (PI-3K) pathways significantly, albeit partially, decreased insulin-dependent leptin mRNA and protein expression, which coincided with reduced association of HIF-1α and/or Sp1 with specific leptin promoter regions; and (e) inhibition of ERK1/2 reduced recruitment of both HIF-1α and Sp1 to the leptin promoter, whereas down-regulation of PI-3K influenced only HIF-1α binding. In summary, our data suggest that hyperinsulinemia could induce breast cancer progression through leptin-dependent mechanisms. In MDA-MB-231 cells, this process requires Sp1- and HIF-1α−mediated leptin gene transcription and is partially regulated by the PI-3K and ERK1/2 pathways. [Cancer Res 2008;68(12):4919–27]
Determinants of Incidence and Clearance of High-Risk Human Papillomavirus Infections in Rural Rakai, Uganda
Authors: Safaeian Mahboobeh , Kiddugavu Mohammad , Gravitt Patti E. , Gange Stephen J. , Ssekasanvu Joseph , Murokora Dan , Sklar Marc , Serwadda David , Wawer Maria J. , Shah Keerti V. , Gray Ron 
Published: June 2008

Abstract
Background: We used self-administered vaginal swabs to assess the incidence and clearance of carcinogenic human papillomavirus (HPV) infections in rural Rakai, Uganda.
Methods: Women provided self-administered vaginal swab at annual home-based visits. Type-specific carcinogenic HPV incidence and clearance and risk factors were assessed.
Results: Carcinogenic HPV incidence was 17.3 per 100 person-years among HIV-positive women compared with 7.0 per 100 person-years among HIV-negative women (P &lt; 0.001). HPV-51 had the highest incidence followed by HPV-16 (1.8 per 100 and 1.5 per 100 person-years, respectively). In multivariate model, HIV-positive women were twice as likely to have incident infection compared with HIV-negative women. Younger women were at higher risk for incident infection, as were women with higher lifetime and recent sexual partners, and high perception of AIDS. Married women were less likely to have incident infection. Approximately half of all carcinogenic HPV infections cleared over the study follow-up of 3 years. HPV-31, HPV-35, and HPV-16 had the lowest clearance (16.7%, 27.9%, and 38.3%, respectively). In multivariate model, HIV-positive, women over 30 years with higher HPV viral, burden and more lifetime sex partners were less likely to clear infections.
Conclusions: Self-collected vaginal swabs provide accurate HPV exposure assessment for studying HPV exposure and epidemiology and can be an important tool for research in populations unwilling to undergo pelvic exam. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1300–7)
Pharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human Subjects
Authors: Vareed Shaiju K. , Kakarala Madhuri , Ruffin Mack T. , Crowell James A. , Normolle Daniel P. , Djuric Zora , Brenner Dean E. 
Published: June 2008

AbstractBackground: Curcumin is a polyphenol, found in the spice turmeric, that has promising anticancer properties, but previous studies suggest that absorption of curcumin may be limited.Methods: This study examined the pharmacokinetics of a curcumin preparation in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was administered at doses of 10 g (n = 6) and 12 g (n = 6). Subjects were randomly allocated to dose level for a total of six subjects at each dose level. Serum samples were assayed for free curcumin, for its glucuronide, and for its sulfate conjugate. The data were fit to a one-compartment absorption and elimination model.Results: Using a high-performance liquid chromatography assay with a limit of detection of 50 ng/mL, only one subject had detectable free curcumin at any of the 14 time points assayed, but curcumin glucuronides and sulfates were detected in all subjects. Based on the pharmacokinetic model, the area under the curve for the 10 and 12 g doses was estimated (mean ± SE) to be 35.33 ± 3.78 and 26.57 ± 2.97 μg/mL × h, respectively, whereas Cmax was 2.30 ± 0.26 and 1.73 ± 0.19 μg/mL. The Tmax and t1/2 were estimated to be 3.29 ± 0.43 and 6.77 ± 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate, not mixed conjugates.Conclusion: Curcumin is absorbed after oral dosing in humans and can be detected as glucuronide and sulfate conjugates in plasma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1411–7)
Better Life Expectancy in Women with BRCA2 Compared with BRCA1 Mutations Is Attributable to Lower Frequency and Later Onset of Ovarian Cancer
Authors: Byrd Louise M. , Shenton Andrew , Maher Eamonn R. , Woodward Emma , Belk Rachel , Lim Caron , Lalloo Fiona , Howell Anthony , Jayson Gordon C. , Evans Gareth D. 
Published: June 2008

Abstract
Purpose: No formal assessment of life expectancy in women with BRCA1 and BRCA2 mutations in these genes has been reported previously. We have evaluated life expectancy using actuarial analysis and assessed the effect of breast and ovarian cancers on premature death in &gt;1,000 BRCA1/2 carriers.
Methods: Families with pathogenic mutations in BRCA1 and BRCA2 have been ascertained in a 10-million population region of United Kingdom since 1996. Mutation carriers and their first-degree relatives were used in an analysis of breast and ovarian cancer incidence and mortality as well as to derive and compare an actuarial assessment of life expectancy.
Results: Six hundred twelve BRCA1 and 482 BRCA2 female mutation carriers were identified from 482 families. Life expectancy was significantly reduced for BRCA1 carriers compared with BRCA2 (P = 0.0002). This effect was attributable to an increased death rate from ovarian cancer (P = 0.04). Kaplan-Meier analysis revealed a better long-term survival from early-stage ovarian cancer in BRCA2 carriers but no significant differences in deaths from breast cancer or from women presenting with late-stage ovarian cancer. There was no other major contributing cause to death other than breast/ovarian cancer in BRCA1/2 female carriers.
Conclusion: Interventions to reduce ovarian cancer incidence are likely to have a greater effect on life expectancy in BRCA1 compared with BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1535–42)
Increased Colorectal Epithelial Cell Proliferation and Crypt Fission Associated with Obesity and Roux-en-Y Gastric Bypass
Authors: Sainsbury Anita , Goodlad Robert A. , Perry Sarah L. , Pollard Stephen G. , Robins Gerard G. , Hull Mark A. 
Published: June 2008

Abstract
Background and Aims: The relationship between obesity, weight reduction, and future risk of colorectal cancer is not well understood. Therefore, we compared mucosal biomarkers in normal weight individuals [body mass index (BMI), 18.5-24.9 kg/m2] with those in morbidly obese patients (BMI &gt;40 kg/m2) before and 6 months after Roux-en-Y gastric bypass (RYGB).
Methods: Rectal epithelial cell mitosis, crypt area, and crypt branching were measured following whole crypt microdissection. Apoptosis was measured by immunohistochemistry for neo-cytokeratin 18 on fixed tissue sections. Serum levels of C-reactive protein and cytokines were assayed in combination with quantification of mucosal proinflammatory gene expression by real-time RT-PCR.
Results: Twenty-six morbidly obese patients (mean BMI, 54.4 kg/m2) had significantly increased mitosis, crypt area, and crypt branching (all P &lt; 0.01) compared with 21 age- and sex-matched normal weight individuals (mean BMI, 22.5 kg/m2). Morbidly obese patients underwent a mean excess weight loss of 41.7% at a mean of 26 weeks after RYGB. Surprisingly, this was associated with a further increase in mitosis and decreased apoptosis of epithelial cells. At the same time, lower levels of serum C-reactive protein and interleukin-6 following RYGB were accompanied by a reduction in mucosal IL-6 protein content but elevated mucosal expression of other proinflammatory genes such as cyclooxygenase-1 and cyclooxygenase-2.
Conclusions: Mucosal biomarkers, accepted as indicators of future colorectal cancer risk, are increased in morbidly obese patients compared with normal weight controls. The hyperproliferative state that exists 6 months after RYGB may have important implications for long-term colorectal cancer risk in bariatric surgery patients. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1401–10)
Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma
Authors: Iwakawa Reika , Kohno Takashi , Anami Yoichi , Noguchi Masayuki , Suzuki Kenji , Matsuno Yoshihiro , Mishima Kazuhiko , Nishikawa Ryo , Tashiro Fumio , Yokota Jun 
Published: June 2008

Abstract
Purpose: The p16 gene is frequently inactivated in lung adenocarcinoma. In particular, homozygous deletions (HD) have been frequently detected in cell lines; however, their frequency and specificity is not well-established in primary tumors. The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs in lung adenocarcinoma progression in vivo.
Experimental Design: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis.
Results: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17–29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22–28%) between adenocarcinomas with and without p53 mutations.
Conclusions: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.
Designing Phase 0 Cancer Clinical Trials
Authors: Murgo Anthony J. , Kummar Shivaani , Rubinstein Larry , Gutierrez Martin , Collins Jerry , Kinders Robert , Parchment Ralph E. , Ji Jiuping , Steinberg Seth M. , Yang Sherry X. , Hollingshead Melinda , Chen Alice , Helman Lee , Wiltrout Robert , Tomaszewski Joseph E. , Doroshow James H. 
Published: June 2008

Abstract
Phase 0 trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents before initiating more traditional phase I testing. One of the major objectives of phase 0 trials is to interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed and validated in preclinical models. Thus, close collaboration between laboratory scientists and clinical investigators is essential to the design and conduct of phase 0 trials. Given the relatively small number of patients and tissue samples, showing a significant drug effect in phase 0 trials requires precise and reproducible assay procedures and innovative statistical methodology. Furthermore, phase 0 trials involving limited exposure of a study agent administered at low doses and/or for a short period allow them to be initiated under the Food and Drug Administration exploratory investigational new drug guidance with less preclinical toxicity data than usually required for traditional first-in-human studies. Because of the very limited drug exposure, phase 0 trials offer no chance of therapeutic benefit, which can impede patient enrollment, particularly if invasive tumor biopsies are required. The challenges to accrual are not insurmountable, however, and well-designed and executed phase 0 trials are feasible and have great potential for improving the efficiency and success of subsequent trials, particularly those evaluating molecularly targeted agents.
Association of Megalin Genetic Polymorphisms with Prostate Cancer Risk and Prognosis
Authors: Holt Sarah K. , Karyadi Danielle M. , Kwon Erika M. , Stanford Janet L. , Nelson Peter S. , Ostrander Elaine A. 
Published: June 2008

Abstract
Purpose: Megalin, an endocytic receptor expressed by prostate epithelial cells, can internalize biologically active androgens bound to sex hormone binding globulin. Genetic variation within megalin could potentially influence levels of steroid hormone uptake.
Experimental Design: Forty haplotype-tagging single-nucleotide polymorphisms (htSNP) were analyzed in a population-based, case-control study of 553 Caucasian men who were diagnosed with prostate cancer between the ages of 40 and 64 years from the Seattle-Puget Sound region and 534 control men. Prostate cancer risk was estimated using adjusted unconditional logistic regression for both individual SNPs and haplotypes. Risks of disease recurrence/progression and prostate-specific cancer mortality were estimated using Cox proportional hazards regression.
Results: We found no strong evidence of altered risk of developing prostate cancer for any of the htSNPs when they were assessed individually or in haplotypes. However, three htSNPs were significantly associated with both disease recurrence/progression and mortality. Risk of recurrence/progression alone was also associated with five additional htSNPs, and six other htSNPS showed evidence of modification by primary androgen deprivation therapy. Two additional htSNPs were significantly associated with altered risk of death from prostate cancer.
Conclusions: Preliminary results suggest that common genetic variation within the megalin gene could alter both risk of recurrence/progression and prostate-specific cancer mortality. In addition, androgen deprivation therapy effectiveness may be modified by the activity of this gene. To our knowledge, this is the first study that has examined polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes.
Tissue-Based Research in Kidney Cancer: Current Challenges and Future Directions
Authors: Signoretti Sabina , Bratslavsky Gennady , Waldman Frederick M. , Reuter Victor E. , Haaga John , Merino Maria , Thomas George V. , Pins Michael R. , Libermann Towia , Gillespie John , Tomaszewski Joseph E. , Compton Carolyn C. , Hruszkewycz Andrew , Linehan W. Marston , Atkins Michael B. 
Published: June 2008

Abstract
The past several years have seen unprecedented advances in the application of various therapeutic strategies for the treatment of patients with renal cancer. The availability of active immunotherapy, antiangiogenic therapy, and targeted therapy for this disease has brought front and center issues related to choosing the appropriate treatment for particular patient populations. It is increasingly evident that the most promising treatment selection strategies will incorporate identifying specific features of the tumor itself. To facilitate this move toward personalized medicine, it is critically important to establish some standard principles for renal cancer tissue collection, preparation, and analysis for translational research studies. In this article, we identify and discuss some critical issues related to tissue-based kidney cancer research. We focus on five major areas as follows: (a) surgical and image-guided techniques for tissue collection; (b) quality control of specimen collection, processing, storage, and review; (c) issues related to analysis of paraffin embedded tissues; (d) genomic studies; and (e) assessment of reproducibility of assays across institutions. In addition, some practical implementation strategies are proposed. Although many of the topics discussed are specific for renal cancer, several are also relevant to tissue based biomarker investigations in a broad array of malignancies.