bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revealing Targeted Therapy for Human Cancer by Gene Module Maps
Authors: Wong David J. , Nuyten Dimitry S.A. , Regev Aviv , Lin Meihong , Adler Adam S. , Segal Eran , van de Vijver Marc J. , Chang Howard Y. 
Published: January 2008

Abstract
A major goal of cancer research is to match specific therapies to molecular targets in cancer. Genome-scale expression profiling has identified new subtypes of cancer based on consistent patterns of variation in gene expression, leading to improved prognostic predictions. However, how these new genetic subtypes of cancers should be treated is unknown. Here, we show that a gene module map can guide the prospective identification of targeted therapies for genetic subtypes of cancer. By visualizing genome-scale gene expression in cancer as combinations of activated and deactivated functional modules, gene module maps can reveal specific functional pathways associated with each subtype that might be susceptible to targeted therapies. We show that in human breast cancers, activation of a poor-prognosis “wound signature” is strongly associated with induction of both a mitochondria gene module and a proteasome gene module. We found that 3-bromopyruvic acid, which inhibits glycolysis, selectively killed breast cells expressing the mitochondria and wound signatures. In addition, inhibition of proteasome activity by bortezomib, a drug approved for human use in multiple myeloma, abrogated wound signature expression and selectively killed breast cells expressing the wound signature. Thus, gene module maps may enable rapid translation of complex genomic signatures in human disease to targeted therapeutic strategies. [Cancer Res 2008;68(2):369–78]
Acquired Lymphedema: An Urgent Need for Adequate Animal Models
Authors: Hadamitzky Catarina , Pabst Reinhard 
Published: January 2008

Abstract
In cancer patients, the removal of tumor-draining lymph nodes during tumor resection can lead to acquired lymphedema. This disease, which is characterized by tissue swelling and increased risk of infection due to restricted lymph flow, lacks an effective treatment. Limitations to the design and conduct of randomized trials to date have limited the evaluation of proposed surgical techniques. As a result, animal models have provided an important research base. This review summarizes work in canine, rabbit, and rodent models of acquired lymphedema, focusing on arising limitations and potential applications. [Cancer Res 2008;68(2):343–5]
Cannabinoids for Cancer Treatment: Progress and Promise
Authors: Sarfaraz Sami , Adhami Vaqar M. , Syed Deeba N. , Afaq Farrukh , Mukhtar Hasan 
Published: January 2008

Abstract
Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy. [Cancer Res 2008;68(2):339–42]
Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells
Authors: Memmott Regan M. , Gills Joell J. , Hollingshead Melinda , Powers Margaret C. , Chen Zhiping , Kemp Bruce , Kozikowski Alan , Dennis Phillip A. 
Published: January 2008

AbstractLoss of function of the tumor suppressor LKB1 occurs in 30% to 50% of lung adenocarcinomas. Because LKB1 activates AMP-activated protein kinase (AMPK), which can negatively regulate mTOR, AMPK activation might be desirable for cancer therapy. However, no known compounds activate AMPK independently of LKB1 in vivo, and the usefulness of activating AMPK in LKB1-mutant cancers is unknown. Here, we show that lipid-based Akt inhibitors, phosphatidylinositol ether lipid analogues (PIA), activate AMPK independently of LKB1. PIAs activated AMPK in LKB1-mutant non–small cell lung cancer (NSCLC) cell lines with similar concentration dependence as that required to inhibit Akt. However, AMPK activation was independent of Akt inhibition. AMPK activation was a major mechanism of mTOR inhibition. To assess whether another kinase capable of activating AMPK, CaMKKβ, contributed to PIA-induced AMPK activation, we used an inhibitor of CaMKK, STO-609. STO-609 inhibited PIA-induced AMPK activation in LKB1-mutant NSCLC cells, and delayed AMPK activation in wild-type LKB1 NSCLC cells. In addition, AMPK activation was not observed in NSCLC cells with mutant CaMKKβ, suggesting that CaMKKβ contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKα−/− murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by ∼50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas. [Cancer Res 2008;68(2):580–8]
Regulation of Vascular Endothelial Growth Factor D by Orphan Receptors Hepatocyte Nuclear Factor-4α and Chicken Ovalbumin Upstream Promoter Transcription Factors 1 and 2
Authors: Schäfer Georgia , Wißmann Christoph , Hertel Johannes , Lunyak Victoria , Höcker Michael 
Published: January 2008

Abstract
Vascular endothelial growth factor D has recently been linked to the control of lymphangiogenesis and lymphatic metastasis. The molecular determinants regulating vegf-D gene transcription, however, have not yet been identified. After isolation of 2 kb of 5′-flanking DNA of the human vegf-D gene, we identified a novel, atypical direct repeat (DR) element consisting of a consensus half-site (AGGTCA) at −125/−119 and a degenerated DR half-site (ATGTTA) at −99/−94 as sufficient and necessary for vegf-D transcription. The vegf-D DR element is bound and activated by the orphan receptors hepatocyte nuclear factor 4α (HNF-4α) and chicken ovalbumin upstream promoter transcription factor (COUP-TF)-1/COUP-TF2. Additionally, chromatin immunoprecipitation assays identified transcriptional coactivators cyclic AMP–responsive element binding protein–binding protein and glucocorticoid receptor interacting protein 1 at the vegf-D DR element and functional assays confirmed their stimulatory effect on the vegf-D promoter. Histone deacetylase inhibition by trichostatin A led to accumulation of acetylated histones H3/H4 at the vegf-D promoter, up-regulation of vegf-D mRNA levels, and transactivation of vegf-D promoter reporter gene constructs in cancer cell lines. This study for the first time describes the molecular determinants in cis and trans controlling vegf-D gene transcription and identifies interaction of HNF-4α and COUP-TF1/COUP-TF2 with a proximal, atypical DR element as indispensable for vegf-D transcription. Moreover, our findings suggest that epigenetic control of histone acetylation represents an important determinant of vegf-D gene expression in cancer cells. These results provide novel insights into the molecular machinery controlling vegf-D gene expression and may add to a better understanding of the regulation of lymphangiogenesis in vascular development and cancer. [Cancer Res 2008;68(2):457–66]
Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists
Authors: Bremer Edwin , ten Cate Bram , Samplonius Douwe F. , Mueller Nicole , Wajant Harald , Stel Alja J. , Chamuleau Martine , van de Loosdrecht Arjan A. , Stieglmaier Julia , Fey Georg H. , Helfrich Wijnand 
Published: January 2008

AbstractThe clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity–dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFasL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non–Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells. [Cancer Res 2008;68(2):597–604]
Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis
Authors: Yusuf Nabiha , Nasti Tahseen H. , Long J. Alan , Naseemuddin Mohammed , Lucas Alan P. , Xu Hui , Elmets Craig A. 
Published: January 2008

Abstract
Toll-like receptors (TLR) activate multiple steps in inflammatory reactions in innate immune responses. They also activate signals that are critically involved in the initiation of adaptive immune responses. Many tumorigenic chemicals have been associated with endotoxin hypersensitivity mediated through TLR4. To determine the role of TLR4 in cutaneous skin carcinogenesis, we treated TLR4-deficient C3H/HeJ mice and the TLR4-normal C3H/HeN mice with the carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4-deficient C3H/HeJ mice developed more tumors relative to the TLR4-normal C3H/HeN mice. Both C3H/HeN and C3H/HeJ mice developed a T-cell–mediated immune response to topically applied DMBA. Interestingly, the cell-mediated immune response was mediated by IFN-γ in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-γ following topical application of DMBA, whereas IL-17 was elevated in C3H/HeJ mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA skin tumorigenesis and that this is associated with differences in the T-cell subtype activated. Efforts to divert the cell-mediated immune response from one that is IL-17 mediated to one that is IFN-γ mediated may prove to be beneficial in the prevention of DMBA-induced cutaneous tumors. [Cancer Res 2008;68(2):615–22]
Exercise Effect on Oxidative Stress Is Independent of Change in Estrogen Metabolism
Authors: Schmitz Kathryn H. , Warren Meghan , Rundle Andrew G. , Williams Nancy I. , Gross Myron D. , Kurzer Mindy S. 
Published: January 2008

Abstract
Purpose: The effect of exercise training on lipid peroxidation and endogenous estrogens is not well understood in premenopausal women. Exercise effects on these variables could mediate observed associations of exercise with hormonally related cancers, including breast cancer. The purpose of the study is to determine the effect of 15 weeks of aerobic exercise on lipid peroxidation, endogenous estrogens, and body composition in young, healthy eumenorrheic women.
Methods: Fifteen sedentary premenopausal women (18-25 years) participated. Pre- and post-exercise training urine collection (three 24-h samples) started 48 h after most recent exercise session for analysis of a marker of lipid peroxidation (F2-isoprostane) and endogenous estrogens, including 2-hydroxyestrogens, 4-hydroxyestrogens, 16-α-hydroxyestrone, and ratios of these metabolites (2:16, 2:4). Body composition was measured by dual-energy X-ray absorptiometry, and F2-isoprostanes and estrogens were measured by gas chromatography-mass spectrometry.
Results: Aerobic exercise resulted in a 34% decrease in F2-isoprostane (P = 0.02), a 10% increase in fitness (P = 0.004), a 1.2 kg decrease in body mass (P = 0.007), and a 1.8 kg decrease in fat mass (P = 0.04). No significant changes were noted in estrogens.
Conclusions: The effect of exercise training on oxidative stress may be relevant to risk for hormonally related cancers. (Cancer Epidemiol Biomarkers Prev 2008;17(1):220–3)
Increased Human Buccal Cell Autofluorescence Is a Candidate Biomarker of Tobacco Smoking
Authors: Paszkiewicz Geraldine M. , Timm Earl A. , Mahoney Martin C. , Wallace Paul K. , Sullivan Nasca Maureen A. , Tammela Tracey L. , Hutson Alan , Pauly John L. 
Published: January 2008

Abstract
Human buccal cells display diverse changes that are associated with smoked and smokeless tobacco, and clinicopathologic studies have correlated human buccal cell changes with oral cancer. Reported herein are the results of studies that were undertaken to identify a high-throughput technology that would advance efforts to use human buccal cells. We report that (a) a relatively large (mean ± SD, 2.1 ± 1.4 × 105 cells) population of human buccal cells can be collected in a noninvasive manner with a toothbrush and purified (&gt;98% human buccal cells; n = 138 samples of the oral mucosa; n = 69 donors); (b) despite their large size (diameter, ∼65 μm), the human buccal cells were analyzed successfully with a single laser cytometer (FACScan) and an advanced multispectral cytometer (FACSAria) having three lasers (excitation = 488, 633, and 407 nm wavelengths) and nine distinct emission channels; (c) cytometry revealed that the buccal cells expressed a high level of autofluorescence that was displayed over a broad spectrum (450-780 nm wavelength); (d) autofluorescence of human buccal cells collected from the left and right cheek was consistent, illustrating the reproducibility of the sample collection and assay procedure; (e) human buccal cell autofluorescence differed significantly among 69 adult subjects; and (f) a statistical difference (P = 0.018) between current, former, and never smokers. Summarily, this report is thought to be the first to show the application of flow cytometry for assaying human buccal cells and identifies buccal cell autofluorescence as a candidate biomarker of tobacco smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(1):239–44)
Seroreactivity to Cutaneous Human Papillomaviruses among Patients with Nonmelanoma Skin Cancer or Benign Skin Lesions
Authors: Andersson Kristin , Waterboer Tim , Kirnbauer Reinhard , Slupetzky Katharina , Iftner Thomas , de Villiers Ethel-Michele , Forslund Ola , Pawlita Michael , Dillner Joakim 
Published: January 2008

Abstract
Cutaneous human papillomaviruses (HPV) are common in nonmelanoma skin cancers, benign skin lesions, and healthy skin. Increased seroprevalences for cutaneous HPV among nonmelanoma skin cancer patients have been described. To determine whether antibodies to cutaneous HPV are related to presence of the virus and/or to skin disease, we collected serum and biopsies from both lesions and healthy skin from 434 nonimmunosuppressed patients (72 squamous cell carcinomas, 160 basal cell carcinomas, 81 actinic keratoses, and 121 benign lesions). Biopsies were analyzed for HPV DNA by PCR, cloning, and sequencing. Serum antibodies to the major capsid protein L1 of HPV 1, 5, 6, 8, 9, 10, 15, 16, 20, 24, 32, 36, 38, and 57 as well as to the oncoproteins E6 and E7 of HPV 8 and 38 were detected using a multiplexed fluorescent bead-based assay. Type-specific seroprevalence among patients with the same type of HPV DNA (sensitivity of serology) varied from 0% to at most 28%. Presence of HPV DNA and antibodies to the same HPV type was not significantly correlated. However, seropositivity to any HPV type was significantly more common among patients positive for HPV DNA of any HPV type (odds ratio, 1.90; 95% confidence interval, 1.55-2.34). Seroprevalences were similar among the different patient groups but was, for most HPV types, somewhat higher among squamous cell carcinoma patients than among basal cell carcinoma patients (P &lt; 0.01). In conclusion, additional studies are required to clarify the biological meaning of seropositivity as a marker of cutaneous HPV infection and skin disease. (Cancer Epidemiol Biomarkers Prev 2008;17(1):189–95)
Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells
Authors: Hoque Ashraful , Chen Hongli , Xu Xiao-chun 
Published: January 2008

Abstract
Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G1 phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G1 cell cycle. Future studies should focus on examining statins and other apoptosis-inducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):88–94)
Cord Serum Estrogens, Androgens, Insulin-Like Growth Factor-I, and Insulin-Like Growth Factor Binding Protein-3 in Chinese and U.S. Caucasian Neonates
Authors: Troisi Rebecca , Lagiou Pagona , Trichopoulos Dimitrios , Xu Biao , Chie Lucy , Stanczyk Frank Z. , Potischman Nancy , Adami Hans-Olov , Hoover Robert N. , Hsieh Chung-Cheng 
Published: January 2008

Abstract
Markedly lower breast cancer incidence rates in Asians than Caucasians are not explained by established adult risk factors. Migration studies suggest the importance of early-life exposures, including perhaps the in utero period. Concentrations of steroid hormones and insulin-like growth factors (IGF) were measured in umbilical cord sera from pregnancies in Shanghai, China (n = 121) and Boston, MA (n = 111). Pregnancy characteristics were ascertained by interview and medical records. Means and percent differences in hormone concentrations comparing Chinese with Caucasians and 95% confidence intervals were estimated from linear regression models. Cord concentrations of androstenedione (91.9%), testosterone (257%), estriol (48.6%), and IGF binding protein-3 (21.1%) were significantly higher in the Chinese than U.S. samples, and cord prolactin was lower (−14.9%). Cord estradiol and IGF-I concentrations did not differ by race/ethnicity. With adjustment for gestational length, maternal age, pre-pregnancy weight, and weight gain, androstenedione (60.5%), testosterone (185%), and IGF binding protein-3 (40.4%) remained significantly higher in the Chinese, whereas the higher estriol and lower prolactin concentrations were attenuated. In addition, estradiol levels became lower in the Chinese (−29.8%) but did not reach statistical significance. Results were generally similar when restricted to first full-term pregnancies, with reduced estradiol concentrations in the Chinese reaching statistical significance after adjustment. These data are consistent with the hypothesis that elevated prenatal androgen exposure could mediate reductions in breast cancer risk. The meaning of the change in findings for estrogens after controlling for factors related to the pregnancy is unclear with regard to explaining international breast cancer differences. (Cancer Epidemiol Biomarkers Prev 2008;17(1):224–31)
Sequence Variants of NAT1 and NAT2 and Other Xenometabolic Genes and Risk of Lung and Aerodigestive Tract Cancers in Central Europe
Authors: McKay James D. , Hashibe Mia , Hung Rayjean J. , Wakefield Jon , Gaborieau Valerie , Szeszenia-Dabrowska Neonila , Zaridze David , Lissowska Jolanta , Rudnai Peter , Fabianova Eleonora , Mates Dana , Foretova Lenka , Janout Vladimir , Bencko Vladimir , Chabrier Amelie , Hall Janet , Boffetta Paolo , Canzian Federico , Brennan Paul 
Published: January 2008

Abstract
Tobacco smoke contains an extensive cocktail of highly carcinogenic chemicals. Individuals with a slower elimination rate of the chemicals in tobacco smoke may have increased exposure to their carcinogenic properties compared with those with a faster rate. Polymorphisms that alter the function of the genes involved in the activation or the detoxification of the chemical carcinogens in tobacco smoke can potentially influence an individual's risk of developing a tobacco-related cancer. To test this hypothesis, we have genotyped polymorphisms in 16 genes involved in metabolism of chemical carcinogens in a Central and Eastern European case-control study comprising 2,250 lung cases, 811 upper aerodigestive cancer (UADT) cases, and 2,704 controls. The N-acetyltransferase (NAT) genes were the most implicated in risk, with the NAT1*10 haplotype showing an inverse association in lung cancer, in both heterozygote carriers [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.70-0.93] and homozygote carriers (OR, 0.70; 95% CI, 0.48-1.01), suggesting a genotype dose response (P &lt; 0.001). In UADT cancer, a similar inverse association was noted in NAT1*10 although only in heterozygotes (OR, 0.78; 95%CI, 0.65-0.95). In NAT2, when considering the individuals inferred acetylator phenotypes based on their NAT2 diplotype, “slow” acetylators compared with intermediate or fast acetylators showed no association with risk. None of the other 14 genes provided robust evidence of an association for either lung or UADT cancer. We therefore conclude that, of the genetic variation studied, NAT1 gene was the most likely candidate to influence the risk of developing a tobacco-related cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):141–7)