bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Knockout of BRG1 Potentiates Lung Cancer Development
Authors: Glaros Selina , Cirrincione Georgina M. , Palanca Ariel , Metzger Daniel , Reisman David 
Published: May 2008

Abstract
Brahma-related gene 1 (BRG1) is a catalytic subunit of the switch in mating type/sucrose nonfermentation complex and plays an important role in cancer development. Mouse homozygous knockout experiments testing the role of BRG1 in tumorigenesis have been hampered because BRG1 inactivation is embryonic lethal. To bypass this constraint, we developed a lung-specific conditional knockout of BRG1 and examined the effect of BRG1 inactivation in an ethyl carbamate lung carcinogenesis mouse model. We found that the heterozygous loss of BRG1 resulted in increases in both the number and size of tumors when compared with controls. In contrast, when both BRG1 alleles were inactivated, neither the number nor the size of tumors increased compared with controls. In mouse lung tissue where BRG1 was homozygously inactivated, immunostaining for apoptotic markers showed significant increase in Apo-BrdUrd and cleaved caspase-3. These data indicate that a loss of cell viability underlies why biallelic inactivation of BRG1 does not increase tumorigenesis. We also examined mice when exposed to the carcinogen ethyl carbamate and then subjected to BRG1 inactivation. In these cells, loss of BRG1 after carcinogen exposure potentiated tumor development. A subset of tumors retained BRG1 expression, whereas others showed either partial or complete loss of BRG1 expression. Tumors completely devoid of BRG1 expression were significantly larger and expressed higher levels of two markers of proliferation, proliferating cell nuclear antigen and Ki67. Although biallelic inactivation of BRG1 could not initiate tumor development in untransformed cells, our results indicate that transformation and tumor progression are greatly affected by loss of BRG1. [Cancer Res 2008;68(10):3689–96]
A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice
Authors: Kinkade Rebecca , Dasgupta Piyali , Carie Adam , Pernazza Daniele , Carless Melanie , Pillai Smitha , Lawrence Nicholas , Sebti Said M. , Chellappan Srikumar 
Published: May 2008

Abstract
Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251–mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810–8]
Reversible Dysfunction of Wild-Type p53 following Homeodomain-Interacting Protein Kinase-2 Knockdown
Authors: Puca Rosa , Nardinocchi Lavinia , Gal Hilah , Rechavi Gideon , Amariglio Ninette , Domany Eytan , Notterman Daniel A. , Scarsella Marco , Leonetti Carlo , Sacchi Ada , Blandino Giovanni , Givol David , D'Orazi Gabriella 
Published: May 2008

Abstract
About half of cancers sustain mutations in the TP53 gene, whereas the other half maintain a wild-type p53 (wtp53) but may compromise the p53 response because of other alterations. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of p53 oncosuppressor function. Here, we show, by microarray analysis, that wtp53 lost the target gene activation following stable knockdown of HIPK2 (HIPK2i) in colon cancer cell line. Our data show that the stable knockdown of HIPK2 led to wtp53 misfolding, as detected by p53 immunoprecipitation with conformation-specific antibodies, and that p53 protein misfolding impaired p53 DNA binding and transcription of target genes. We present evidence that zinc supplementation to HIPK2i cells increased p53 reactivity to conformation-sensitive PAb1620 (wild-type conformation) antibody and restored p53 sequence-specific DNA binding in vivo and transcription of target genes in response to Adriamycin treatment. Finally, combination of zinc and Adriamycin suppressed tumor growth in vivo and activated misfolded p53 that induced its target genes in nude mice tumor xenografts derived from HIPK2i cells. Bioinformatics analysis of microarray data from colon cancer patients showed significant association of poor survival with low HIPK2 expression only in tumors expressing wtp53. These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53. [Cancer Res 2008;68(10):3707–13]
Repair of 2′-C-Cyano-2′-Deoxy-1-β-d-arabino-Pentofuranosylcytosine–Induced DNA Single-Strand Breaks by Transcription-Coupled Nucleotide Excision Repair
Authors: Wang Yaqing , Liu Xiaojun , Matsuda Akira , Plunkett William 
Published: May 2008

Abstract
The cytosine nucleoside analogue 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) causes DNA single-strand breaks after its incorporation into DNA. This investigation sought to determine if DNA excision repair pathways were activated to repair this damage. Neither the base excision repair nor the mismatch repair pathway seemed to be involved. Cells deficient in the CSB protein, which initiates transcription-coupled nucleotide excision repair (NER) pathway (TC-NER), exhibited increased clonogenic sensitivity to CNDAC, whereas cells deficient in XPC, which initiates global genome NER, were slightly resistant relative to wild-type cells. The cells lacking either helicase XPB, which unwinds 5′ of the lesion, or endonuclease XPF, which incises 5′ to a lesion, exhibited increased clonogenic sensitivity to CNDAC, as did cells lacking the XPF partner protein ERCC1. This sensitization was independent of p53 function. Repletion of XPF restored sensitivity comparable with the wild type. In contrast, cells lacking either XPD, the 3′-helicase, or the 3′-endonuclease XPG were equally as sensitive as wild-type cells. In comparison, cells deficient in XPF were not sensitized to other cytosine nucleoside analogues, troxacitabine and cytarabine. Thus, the single-strand nick caused by CNDAC is recognized and, in part, repaired by the TC-NER pathway. NER proteins that function in the 5′ direction relative to the UV-induced lesion also participate in the repair of the CNDAC-induced nick, in contrast to proteins that process on the 3′ side of the lesion. [Cancer Res 2008;68(10):3881–9]
Memory Th1 Cells Augment Tumor-Specific CTL following Transcutaneous Peptide Immunization
Authors: Hosoi Akihiro , Takeda Yayoi , Furuichi Yoshihiro , Kurachi Makoto , Kimura Kiminori , Maekawa Ryuji , Takatsu Kiyoshi , Kakimi Kazuhiro 
Published: May 2008

AbstractTargeting dendritic cells in vivo by transcutaneous peptide immunization (TCI) represents an efficient immunization strategy to induce tumor-specific CTL because it reflects the physiologic conditions occurring during pathogen infection. Here we show that including a Th1 peptide in TCI can activate preexisting memory Th1 (mTh1) responses and thereby enhance the CTL response. For this purpose, peptide-25, a major Th1 epitope of Ag85B from Mycobacterium tuberculosis, was selected. We adoptively transferred peptide-25–specific mTh1 cells and hgp100-specific naive CTL (pmel-1 TCR transgenic) into C57BL/6 mice. Subsequently, mice were transcutaneously immunized with CTL peptide (hgp100) and Th1 peptide (peptide-25). Five days after TCI, the frequency and function of pmel-1 cells was monitored by intracellular IFN-γ staining, ELISPOT, and in vivo cytotoxicity assays. TCI efficiently expanded hgp100-specific, IFN-γ–producing, strongly cytotoxic CD8+ T cells. Concurrent activation of mTh1 cells by peptide-25 induced a 1.5-fold increase in the number of hgp100-specific CTL with enhanced effector functions. Furthermore, TCI elicited not only prophylactic but also therapeutic antitumor responses that were augmented by peptide-25. These results show that TCI facilitates peptide-specific activation of CD4+ T cells, responsible for the augmenting effect of peptide-25 on the hgp100-specific CTL response. Because a significant proportion of the Japanese population has been vaccinated with Bacillus Calmette-Guerin, they are likely to possess Ag85B- or peptide-25–specific mTh1 cells. Therefore, concomitant activation of Ag85B- or peptide-25–specific mTh1 cells together with tumor-specific CTL by TCI might augment antitumor immune responses in a sizeable fraction of patients. [Cancer Res 2008;68(10):3941–9]
An Anti–Transforming Growth Factor β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments
Authors: Nam Jeong-Seok , Terabe Masaki , Mamura Mizuko , Kang Mi-Jin , Chae Helen , Stuelten Christina , Kohn Ethan , Tang Binwu , Sabzevari Helen , Anver Miriam R. , Lawrence Scott , Danielpour David , Lonning Scott , Berzofsky Jay A. , Wakefield Lalage M. 
Published: May 2008

AbstractOverexpression of transforming growth factor β (TGF-β) is frequently associated with metastasis and poor prognosis, and TGF-β antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti–TGF-β antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell–mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1γ) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-β expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-β antibodies reverse this effect, and the absence of a major effect of TGF-β antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications. [Cancer Res 2008;68(10):3835–43]
Abnormal Cytokinesis after X-Irradiation in Tumor Cells that Override the G2 DNA Damage Checkpoint
Authors: Huang Haomin , Fletcher Lynda , Beeharry Neil , Daniel Rene , Kao Gary , Yen Tim J. , Muschel Ruth J. 
Published: May 2008

Abstract
X-irradiation–induced DNA damage perturbs the G1, S, and G2 phases of the cell cycle. The behavior of cells after they have experienced a DNA damage checkpoint delay is poorly characterized. We therefore examined the fates of irradiated tumor cells that have overcome a prolonged G2 checkpoint delay. Most irradiated cells progressed through mitosis without significant delay, but failed to complete cytokinesis as they remained tethered to each other at the midbody. We observed that the movement of centrioles at the time of cytokinesis was impaired in the irradiated, bridged cells. We attribute the perturbation of centriole dynamics to the presence of chromatin bridges that spanned the daughter cells. The bridged cells exhibited different fates that included death, fusion that formed multinucleated cells, or another round of mitosis with no noticeable cell cycle delays. The presence of γH2AX foci in the bridge as well as in the separated nuclei indicated that cells were proliferating despite the presence of DNA damage. It seems that DNA damage checkpoints were not reactivated in cells that overrode a prolonged G2 delay. Cells deficient in ATM, H2AX, XRCC3, or ligase 4 exhibited a higher frequency of radiation-induced bridges than controls, suggesting that the DNA bridges resulted from inadequate DNA repair. These data show a previously unappreciated cytologic hallmark of DNA damage in dividing cells. Chromatin bridges that interfere with cytokinesis are likely to contribute to the replication failure and clonogenic death of cells exposed to irradiation. [Cancer Res 2008;68(10):3724–32]
DNA Methylation in Benign Breast Epithelium in Relation to Age and Breast Cancer Risk
Authors: Euhus David M. , Bu Dawei , Milchgrub Sara , Xie Xian-Jin , Bian Aihua , Leitch A. Marilyn , Lewis Cheryl M. 
Published: May 2008

AbstractBackground: Many established breast cancer risk factors are related to the timing and duration of exposure to reproductive hormones, which are known to drive breast epithelial cell proliferation. The epigenetic molecular clock hypothesis suggests that CpG island methylation records the cell division history of benign epithelium. In proliferative epithelium, such as breast, this may provide an individualized cell-based measure of cancer risk.Methods: Methylation of cyclin D2, APC, HIN1, RASSF1A, and RAR-β2 was measured by quantitative multiplex methylation-specific PCR in 290 benign and malignant breast epithelial cell samples obtained by palpation-directed fine-needle aspiration biopsy from 164 women. Univariate, multivariate, and unsupervised cluster analysis was used to establish the relationship between TSG methylation and a personal history of breast cancer, predicted breast cancer risk, and specific breast cancer risk factors.Results: RASSF1A methylation was highly correlated with breast cancer risk [odds ratio (OR), 5.28; 95% confidence interval (95% CI), 1.95-14.32; P = 0.001], atypical cytology (OR, 4.11; 95% CI, 1.30-12.98; P = 0.016), and benign breast disease requiring biopsy (OR, 6.12; 95% CI, 1.41-26.51; P = 0.016). RASSF1A methylation increased linearly between ages 32 and 55. Increasing parity was associated with decreased APC methylation.Conclusions: TSG methylation increases in benign breast epithelium with increasing age. Because it is independently related to a personal history of benign or malignant breast disease and to predicted breast cancer risk, it may have value for breast cancer risk stratification and as a surrogate endpoint marker in prevention trials. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1051–9)
Polymorphisms in Steroid Hormone Biosynthesis Genes and Risk of Breast Cancer and Fibrocystic Breast Conditions in Chinese Women
Authors: Sakoda Lori C. , Blackston Christie , Doherty Jennifer A. , Ray Roberta M. , Lin Ming Gang , Stalsberg Helge , Gao Dao Li , Feng Ziding , Thomas David B. , Chen Chu 
Published: May 2008

AbstractCommon variants in genes encoding for key enzymes involved in steroidogenesis may alter sex steroid hormone levels, thereby influencing susceptibility to breast carcinoma and related conditions. In a case-control study of Chinese women, we examined genotypes of the CYP11A1 pentanucleotide [(TAAAA)n] repeat (D15S520), CYP17A1 rs743572, and HSD17B1 rs605059 polymorphisms in relation to the risk of breast cancer and fibrocystic breast conditions, comparing 615 women with breast cancer and 467 women with fibrocystic breast conditions separately with 879 women without clinical breast disease. We also evaluated whether these relationships differed by the presence of proliferation in the extratumoral epithelium or fibrocystic lesions, menopausal status, or body mass index. Only CYP11A1 genotype was related to breast cancer risk, with women homozygous for the 4-repeat allele, relative to those homozygous for the 6-repeat allele, at reduced risk (age-adjusted odds ratio, 0.58; 95% confidence interval, 0.37-0.91). There was some suggestion of a stronger inverse association for breast cancer with evidence of proliferation in the extratumoral epithelium than for breast cancer without extratumoral proliferation. Breast cancer risk associated with CYP11A1 genotype did not differ by menopausal status or body mass index level. No associations between CYP11A1, CYP17A1, and HSD17B1 genotypes and risk of fibrocystic breast conditions were observed. Our findings support the possibility that common allelic variation at the CYP11A1 D15S520 locus alters breast cancer risk in Chinese women. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1066–73)
Measurement of Tobacco Smoke Exposure: Comparison of Toenail Nicotine Biomarkers and Self-Reports
Authors: Al-Delaimy Wael K. , Willett Walter C. 
Published: May 2008

AbstractBackground: Accurate measurement tools of exposure for use in large epidemiologic studies are lacking. Biomarkers of tobacco exposure provide additional advantages to self-reports and there is a need to further develop and validate them. The objective is to compare toenail nicotine levels, a novel biomarker of tobacco exposure, with self-reports of tobacco exposure from a large cohort study.Methods: In this cross-sectional analysis, toenail samples were collected from 2,485 women participating in the Nurses' Health Study in 1982. Detailed self-reports of smoking habits and reported exposure to secondhand smoke (SHS) were collected from these women near the time of toenail collection. The toenail samples were analyzed by a high-performance liquid chromatography method for measuring nicotine.Results: The 5 to 95 percentile range of toenail nicotine was from 0.06 to 4.06 ng/mg toenail and the median level was 0.21 ng/mg. There was a significant difference in toenail nicotine levels according to reported smoking status (the median level for nonsmokers with no SHS was 0.10 ng/mg, the median level for nonsmokers with SHS was 0.14 ng/mg, and the median level for active smokers was 1.77 ng/mg). However there was considerable overlap in nicotine levels according to reported smoking status. Toenail nicotine level was strongly associated with reported smoking level (Spearman r = 0.63), but there was no complete concordance, suggesting that the two methods are measuring different aspects of the same exposure.Conclusion: Our findings show that toenail nicotine levels capture the overall burden of tobacco smoke exposure and provide additional information on exposure not captured by reported history. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1255–61)
Biochemical Markers for Monitoring Response to Therapy: Evidence for Higher Bone Specificity by a Novel Marker Compared with Routine Markers
Authors: Leeming Diana Julie , Hegele Axel , Byrjalsen Inger , Hofmann Rainer , Qvist Per , Karsdal Morten Asser , Schrader Andres Jan , Wagner Reinhold , Olbert Peter 
Published: May 2008

Abstract
The aim of the present study was to compare a novel marker for high bone turnover with two routine markers for screening in prostate cancer patients. The markers were evaluated in two studies: (a) a cross-sectional study of 170 prostate cancer patients with local disease stratified by ±lymph node metastases (N0, N1) compared with controls and (b) a longitudinal study of 40 hormone refractory prostate cancer patients stratified by skeletal involvement and followed during docetaxel (+/−BM) and zoledronate (+BM) treatment. Presence or absence of bone metastases (BM) was assessed by imaging techniques (magnetic resonance imaging or X-ray) and technetium-99m scintigraphy. The serum or urinary levels of alpha C-telopeptide of collagen type I (ααCTX), prostate-specific antigen (PSA), and total alkaline phosphatase (tALP) were assessed. PSA was elevated in both N0 and N1 patients compared with controls, whereas ααCTX was elevated only in N1 patients. tALP exhibited no difference in any of the groups. In the treatment study, PSA decreased with treatment in both the −BM and +BM groups compared with baseline values, showing similar effect of docetaxel or docetaxel/zoledronate treatment on this marker. On the contrary, ααCTX and tALP did not decrease with docetaxel treatment in the −BM group compared with baseline, whereas it decreased significantly with docetaxel/zoledronate treatment in the +BM group, already after 1 month of treatment for ααCTX. Results suggest that ααCTX is superior to PSA and tALP for identifying patients having a high risk of metastatic disease and for monitoring skeletal progression in +BM prostate cancer patients during treatment. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1269–76)
Functional Polymorphisms in Folate Metabolism Genes Influence the Risk of Meningioma and Glioma
Authors: Bethke Lara , Webb Emily , Murray Anne , Schoemaker Minouk , Feychting Maria , Lönn Stefan , Ahlbom Anders , Malmer Beatrice , Henriksson Roger , Auvinen Anssi , Kiuru Anne , Salminen Tiina , Johansen Christoffer , Christensen Helle Collatz , Muir Kenneth , McKinney Patricia , Hepworth Sarah , Dimitropoulou Polyxeni , Lophatananon Artitaya , Swerdlow Anthony , Houlston Richard 
Published: May 2008

Abstract
Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1195–202)