bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary Levels of Tobacco-Specific Nitrosamine Metabolites in Relation to Lung Cancer Development in Two Prospective Cohorts of Cigarette Smokers
Authors: Yuan Jian-Min , Koh Woon-Puay , Murphy Sharon E. , Fan Yunhua , Wang Renwei , Carmella Steven G. , Han Shaomei , Wickham Katie , Gao Yu-Tang , Yu Mimi C. , Hecht Stephen S. 
Published: March 2009

Abstract
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels of urinary total NNAL and risk of lung cancer development was evaluated in two prospective cohorts of Chinese cigarette smokers. We conducted a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls who were individually matched to the index cases by age, gender, neighborhood of residence at cohort enrollment, and date of urine collection. Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risks associated with the second and third tertiles of total NNAL were 1.43 [95% confidence interval (95% CI), 0.86–2.37] and 2.11 (95% CI, 1.25–3.54), respectively (P for trend = 0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI, 3.7–19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine. Findings of the present study directly link NNK exposure to lung cancer development in humans. [Cancer Res 2009;69(7):2990–5]
Potential Stages for Prostate Cancer Prevention with Selenium: Implications for Cancer Survivors
Authors: Facompre Nicole , El-Bayoumy Karam 
Published: March 2009

Abstract
The lack of treatment for “worried well” patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an ample opportunity to intervene with mechanistically based chemopreventive agents at various stages of disease progression. Our rationale for selenium intervention is based on current mechanistic knowledge derived solely from preclinical investigations. Clearly, there is sufficient scientific support for its entry into current clinical trials, the outcome of which will be highly valuable in assessing whether selenium can be recommended for cancer survivors. [Cancer Res 2009;69(7):2699–703]
Clock-Cancer Connection in Non–Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2
Authors: Hoffman Aaron E. , Zheng Tongzhang , Stevens Richard G. , Ba Yue , Zhang Yawei , Leaderer Derek , Yi Chunhui , Holford Theodore R. , Zhu Yong 
Published: March 2009

Abstract
Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non–Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28–4.27), P = 0.006; rs7123390, OR, 2.40 (1.39–4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57–5.63, P = 0.001)]. Each of these associations remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E−9) and hematologic disease (B-H P = 8.01E−8). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development. [Cancer Res 2009;69(8):3605–13]
Cdc7 Kinase Is a Predictor of Survival and a Novel Therapeutic Target in Epithelial Ovarian Carcinoma
Authors: Kulkarni Anjana A. , Kingsbury Sarah R. , Tudzarova Slavica , Hong Hye-Kyung , Loddo Marco , Rashid Mohammed , Rodriguez-Acebes Sara , Prevost Andrew T. , Ledermann Jonathan A. , Stoeber Kai , Williams Gareth H. 
Published: March 2009

Abstract
Purpose: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma.
Experimental Design: A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells.
Results: Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P &lt; 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts disease-free survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P &lt; 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1 to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G1 phase and remain viable.
Conclusions: Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.
Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer
Authors: Eder Joseph Paul , Vande Woude George F. , Boerner Scott A. , LoRusso Patricia M. 
Published: March 2009

Abstract
A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, and thyroid. Notably, activating mutations in c-Met have been positively identified in patients with a particular hereditary form of papillary renal cancer, directly implicating c-Met in human tumorigenesis. Aberrant signaling of the c-Met signaling pathway due to dysregulation of the c-Met receptor or overexpression of its ligand, hepatocyte growth factor (HGF), has been associated with an aggressive phenotype. Extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met and HGF as major targets in cancer drug development. This has led to the development of a variety of c-Met pathway antagonists with potential clinical applications. The three main approaches of pathway-selective anticancer drug development have included antagonism of ligand/receptor interaction, inhibition of the tyrosine kinase catalytic activity, and blockade of the receptor/effector interaction. Several c-Met antagonists are now under clinical investigation. Preliminary clinical results of several of these agents, including both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have been encouraging. Several multitargeted therapies have also been under investigation in the clinic and have demonstrated promise, particularly with regard to tyrosine kinase inhibition.
Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers
Authors: Natrajan Rachael , Lambros Maryou B. , Rodríguez-Pinilla Socorro María , Moreno-Bueno Gema , Tan David S.P. , Marchió Caterina , Vatcheva Radost , Rayter Sydonia , Mahler-Araujo Betania , Fulford Laura G. , Hungermann Daniela , Mackay Alan , Grigoriadis Anita , Fenwick Kerry , Tamber Narinder , Hardisson David , Tutt Andrew , Palacios Jose , Lord Christopher J. , Buerger Horst , Ashworth Alan , Reis-Filho Jorge S. 
Published: March 2009

Abstract
Purpose: To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes.
Experimental Design: Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs.
Results: We show that basal-like and HER-2 tumors are characterized by “sawtooth” and “firestorm” genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification.
Conclusions: Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.
Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines
Authors: Khatri Aparajita , Husaini Yasmin , Ow Kim , Chapman Jane , Russell Pamela J. 
Published: March 2009

AbstractPurpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)–mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival.Experimental Design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology.Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment.Conclusion: Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.
Mathematical Modeling of Herpes Simplex Virus Distribution in Solid Tumors: Implications for Cancer Gene Therapy
Authors: Mok Wilson , Stylianopoulos Triantafyllos , Boucher Yves , Jain Rakesh K. 
Published: March 2009

Abstract
Purpose: Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site.
Experimental Design: The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus.
Results: This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains.
Conclusions: This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes
Authors: Rakha Emad A. , Elsheikh Somaia E. , Aleskandarany Muhammed A. , Habashi Hany O. , Green Andrew R. , Powe Desmond G. , El-Sayed Maysa E. , Benhasouna Ahmed , Brunet Jean-Sébastien , Akslen Lars A. , Evans Andy J. , Blamey Roger , Reis-Filho Jorge S. , Foulkes William D. , Ellis Ian O. 
Published: March 2009

Abstract
Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers.
Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE−).
Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE- tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE- tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival.
Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (in TN tumors) to define BLBC.
High Tumor Metabolic Activity as Measured by Fluorodeoxyglucose Positron Emission Tomography Is Associated with Poor Prognosis in Limited and Extensive Stage Small-Cell Lung Cancer
Authors: Lee Young Joo , Cho Arthur , Cho Byoung Chul , Yun Mijin , Kim Se Kyu , Chang Joon , Moon Jin Wook , Park In Kyu , Choi Hye Jin , Kim Joo-Hang 
Published: March 2009

Abstract
Purpose: We investigated the prognostic effect of incorporating metabolic assessment by 18F-fluoro-2-deoxyglucose uptake on positron emission tomography/computed tomography (18F-FDG-PET/CT) into a conventional staging system in small-cell lung cancer (SCLC).
Experimental Design: Seventy-six consecutive patients with pathologically proven SCLC were enrolled. All patients underwent standard treatment after pretreatment 18F-FDG-PET/CT scanning. The mean values of maximal standardized uptake values (meanSUVmax) of the malignant lesions upon 18F-FDG-PET/CT were calculated. The Cox proportional hazards model was used with performance status, lactate dehydrogenase, stage, and meanSUVmax.
Results: Patients with high meanSUVmax were significantly related with the established poor prognostic factors, such as higher lactate dehydrogenase (P = 0.04) and extensive disease (ED; P = 0.01). Furthermore, in multivariate analysis, patients with high meanSUVmax were associated with poor survival outcomes compared with patients with low meanSUVmax [adjusted hazard ratio, 3.74; 95% confidence interval (95% CI), 1.67-8.37; P = 0.001, for death and adjusted hazard ratio, 2.25; 95% CI, 1.21-4.17; P = 0.01 for recurrence/progression]. In subgroup analysis, limited disease (LD) with high meanSUVmax showed significantly shorter overall survival than LD with low meanSUVmax [high versus low meanSUVmax, 20.1 months (95% CI, 7.9-23.2) versus 35.3 months (95% CI, 27.6-42.9); P = 0.02]. ED with high meanSUVmax had significantly shorter overall survival than ED with low meanSUVmax [high versus low meanSUVmax, 9.5 months (95% CI, 4.9-13.9) versus 17.7 months (95% CI, 12.0-20.1); P = 0.007]. These findings were replicated in progression-free survival analysis.
Conclusions: In SCLC, tumor metabolic activity as assessed by FDG-PET is a significant prognostic factor and identifies subgroups of patients at higher risk of death in both LD and ED SCLC.
Tumor-Localized Ligation of CD3 and CD28 with Systemic Regulatory T-Cell Depletion Induces Potent Innate and Adaptive Antitumor Responses
Authors: Lee Chien-Hsin , Chiang Yi-Hsuan , Chang Shih-En , Chong Chin-Liew , Cheng Bing-Mae , Roffler Steve R. 
Published: March 2009

AbstractPurpose: Tumor-localized activation of immune cells by membrane-tethered anti-CD3 antibodies (CD3L) is under investigation to treat poorly immunogenic tumors. Here we sought to elucidate the mechanism of antitumor immunity elicited by CD3L.Experimental Design: CD3L and CD86 were expressed on poorly immunogenic B16 melanoma cells (B16/3L86 cells) and the effect of various lymphocytes, including CD4+ and CD8+ T cells, natural killer T (NKT) cells, and regulatory T cells, on antitumor activity was investigated.Results: B16/3L86 cells activated naïve T cells; suppressed tumor growth in subcutaneous, peritoneal, and metastasis models; and protected mice from rechallenge with B16 melanoma cells. However, in vivo antitumor activity against primary B16/3L86 tumors unexpectedly depended on NKT cells rather than CD4+ or CD8+ T cells. Treatment of mice with low-dose cyclophosphamide or anti-CD25 antibody to deplete regulatory T cells unmasked latent T-cell antitumor activity; the number of activated CD8+ T cells in tumors increased and B16/3L86 tumors were completely rejected in a CD8+ and CD4+ T-cell–dependent fashion. Furthermore, fibroblasts expressing CD3L and CD86 suppressed the growth of neighboring B16 cancer cells in vivo, and direct intratumoral injection of adenoviral vectors expressing CD3L and CD86 or CD3L and a membrane-tethered anti-CD28 antibody significantly suppressed the growth of subcutaneous tumors.Conclusions: Tumor-located ligation of CD3 and CD28 can activate both innate (NKT cells) and adaptive (CD4+ and CD8+ T cells) responses to create a tumor-destructive environment to control tumor growth, but modulation of regulatory T cells is necessary to unmask local adaptive antitumor responses.
Melan-A–specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4
Authors: Klein Oliver , Ebert Lisa M. , Nicholaou Theo , Browning Judy , Russell Sarah E. , Zuber Marina , Jackson Heather M. , Dimopoulos Nektaria , Tan Bee Shin , Hoos Axel , Luescher Immanuel F. , Davis Ian D. , Chen Weisan , Cebon Jonathan 
Published: March 2009

Abstract
Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known.
Experimental Design: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated.
Results: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A–specific CD8-positive T cells, and a dramatic (&gt;30-fold) increase in Melan-A–specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A–expressing tumor cells.
Conclusions: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.