bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic cell vaccination in human melanoma: relationships between clinical effects and vaccine parameters
Authors: Nakai Noriaki , Hartmann Gunther , Kishimoto Saburo , Katoh Norito 
Published: June 2010

SummaryEleven years have passed since the start of the first trial of dendritic cell (DC) vaccination for melanoma. A review of 54 trials was performed to evaluate the relationship between clinical effects and vaccine parameters. Significant differences were found between use of immature and mature DCs with regard to progressive disease (PD), between stage III and IV for clinical response, between use and non‐use of adjuvants with regard to stable disease (SD) in treatment with tumor/tumor lysate‐pulsed DCs, between positive and negative delayed‐type hypersensitivity (DTH) for PD, and between increased and unchanged interferon (IFN)‐γ‐secreting T cells for clinical response. These results are consistent with the partial efficacy of vaccination with mature DCs in early stage melanoma and the partial correlation of efficacy with positive DTH and increased IFN‐γ‐secreting T cells. DC vaccination alone had a limited clinical effect and a modified regimen is needed to enhance antigen‐specific cytotoxic T cells and decrease immunosuppression.
Combination treatment of db/db mice with exendin‐4 and gastrin preserves β‐cell mass by stimulating β‐cell growth and differentiation
Authors: Tamaki Motoyuki , Fujitani Yoshio , Uchida Toyoyoshi , Hirose Takahisa , Kawamori Ryuzo , Watada Hirotaka 
Published: June 2010

AbstractAim/Introduction:  Preservation of β‐cell mass is crucial for maintaining long‐term glucose homeostasis. Therapies based on incretin and its mimetics are expected to achieve this goal through various biological functions, particularly the restoration of β‐cell mass. Here we tested the effects of gastrin and exendin‐4 in type 2 diabetic animals.Materials and Methods:  The effects of exendin‐4 and gastrin on β‐cell function and mass were examined in 8‐week‐old db/db mice. INS‐1 beta cells and AR42J cells were used to determine the molecular mechanism underlying the effects of the two agents. Immunohistochemistry, western blotting and RT‐PCR assays were used to assess the biological effects of the two agents.Results:  Two weeks of combination administration of exendin‐4 plus gastrin resulted in a significant improvement of glucose tolerance associated with a marked preservation of β‐cell mass in db/db mice. Immunohistochemical analysis showed that such treatment resulted in the appearance of numerous irregularly‐shaped small islets and single insulin‐positive cells. While gastrin had little biological effect on INS‐1 β‐cells consistent with low expression of its intrinsic receptor on these cells, it caused differentiation of AR42J cells into insulin‐producing cells. Co‐stimulation with exendin‐4 significantly enhanced gastrin‐induced endocrine differentiation of AR42J precursor cells. These findings were further supported by enhanced expression of key genes involved in β‐cell differentiation and maturation, such as neurogenin3 (Ngn3) and MafA.Conclusions:  These results suggest that combination treatment of db/db mice with exendin‐4 and gastrin preserves β‐cell mass by stimulating β‐cell growth and differentiation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.00044.x, 2010)
Three dimensional CT angiography versus digital subtraction angiography in the detection of intracranial aneurysms in subarachnoid hemorrhage
Authors: Prestigiacomo Charles J , Sabit Aria , He Wenzhuan , Jethwa Pinakin , Gandhi Chirag , Russin Jonathan 
Published: June 2010

IntroductionRuptured intracranial aneurysms are responsible for over 90% of cases of spontaneous subarachnoid hemorrhage (SAH). Conventional digital subtraction angiography (DSA) remains the gold standard for diagnosing the source of SAH. A prospective study is presented wherein SAH patients underwent three dimensional CT angiography (CTA) prior to DSA in order to assess the specificity and sensitivity of this non-invasive modality to detect aneurysms.Methods179 consecutive patients with spontaneous SAH presented over 36 months, as identified by screening CT and CTA. Patients with negative CTA findings underwent DSA within 24 h of presentation. All patients who were determined to have angiographically negative SAH underwent follow-up DSA 2 weeks later.ResultsOf the 179 patients screened by CTA, 13 (7%) were negative for aneurysms or other vascular lesions (arteriovenous malformation or dural fistula) on CTA and underwent DSA. No new lesions were identified on six vessel angiography, resulting in a 0% false negative rate (sensitivity 100%, predictive value 100%). MRI to rule out thrombosed aneurysms and repeat angiography at the 2 week follow-up were negative.ConclusionsSensitivity and specificity were higher than previously reported, suggesting that CTA may be used as an initial screening tool in lieu of DSA. Further studies are necessary to determine if CTA can supplant DSA in ruling out all forms of vascular disease in idiopathic SAH.
DC-HIL/Glycoprotein Nmb Promotes Growth of Melanoma in Mice by Inhibiting the Activation of Tumor-Reactive T Cells
Authors: Tomihari Mizuki , Chung Jin-Sung , Akiyoshi Hideo , Cruz Ponciano D. , Ariizumi Kiyoshi 
Published: June 2010

AbstractDC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA–transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL–knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8+ T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL–knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy. Cancer Res; 70(14); 5778–87. ©2010 AACR.
Dysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
Authors: Lin Ruo-Kai , Wu Chiu-Yi , Chang Jer-Wei , Juan Li-Jung , Hsu Han-Shui , Chen Chih-Yi , Lu Yun-Yueh , Tang Yen-An , Yang Yi-Chieh , Yang Pan-Chyr , Wang Yi-Ching 
Published: June 2010

Abstract
Overexpression of DNA 5′-cytosine-methyltransferases (DNMT), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, the mechanism of DNMT overexpression remains unclear. Here, we showed that wild-type p53 negatively regulated DNMT1 expression by forming a complex with specificity protein 1 (Sp1) protein and chromatin modifiers on the DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or corepressor. Low level of exogenous Sp1 enhanced the repressive activity of endogenous p53 on the DNMT1 promoter whereas high level of Sp1 upregulated DNMT1 gene expression level in A549 (p53 wild-type) cells. In H1299 (p53 null) cells, exogenous Sp1 induced DNMT1 expression in a dose-dependent manner. We also discovered a new mechanism whereby high level of Sp1, via its COOH-terminal domain, induced interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation (P = 0.014) and high expression of Sp1 protein (P = 0.006). In addition, patients with overexpression of both DNMT1 and Sp1 proteins showed poor prognosis (P = 0.037). Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with gain of transcriptional activation of Sp1 and/or loss of repression of p53. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis. Cancer Res; 70(14); 5807–17. ©2010 AACR.
Altered Dynamics of Intestinal Cell Maturation in Apc1638N/+ Mice
Authors: Wang Donghai , Pezo Rossanna C. , Corner Georgia , Sison Cristina , Lesser Martin L. , Shenoy Shailesh M. , Mariadason John M. , Singer Robert H. , Augenlicht Leonard H. 
Published: June 2010

Abstract
Novel imaging of active transcription sites in interphase nuclei of intestinal epithelial cells in situ showed that key genes associated with Wnt and Notch signaling were dynamically regulated as the cells underwent normal maturation during their migration along the mouse crypt-villus axis (CVA). However, oscillating patterns of activation of these genes were displaced along this axis in the histologically normal intestinal mucosa of Apc1638N/+ mice before tumor development. Gene expression profiling then showed that the normal reprogramming of cells along the CVA was dampened in the Apc1638N/+ mice, with an overrepresentation of c-myc target genes among those loci affected in the mutant mice. Moreover, in the Apc1638N/+ mice, there was a perturbed pattern of expression of lineage-specific markers along the CVA consistent with transcription site repression of the Math1 gene, and genes encoding enzymes of every step of the tricarboxylic acid cycle were downregulated in the crypt of Apc1638N/+ mice compared with WT, but not in the villus. These changes may alter energy metabolism and generate a pseudohypoxic state, suggested by elevated expression of Hif1α and its target genes. Thus, although intestinal tumors develop in Apc1638N/+ mice on focal loss or inactivation of the WT allele, our results show that in the Apc1638N/+ mouse, inheritance of only a single WT Apc allele perturbs the dynamic and complex reprogramming underlying normal cell maturation, which links epithelial function and homeostasis with architectural organization of the intestine. Cancer Res; 70(13); 5348–57. ©2010 AACR.
Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes
Authors: Movahedi Kiavash , Laoui Damya , Gysemans Conny , Baeten Martijn , Stangé Geert , Van den Bossche Jan , Mack Matthias , Pipeleers Daniel , In't Veld Peter , De Baetselier Patrick , Van Ginderachter Jo A. 
Published: June 2010

AbstractTumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6ChiCX3CR1low monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally “re-educating” the TAM compartment. Cancer Res; 70(14); 5728–39. ©2010 AACR.
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Authors: Janakiraman Manickam , Vakiani Efsevia , Zeng Zhaoshi , Pratilas Christine A. , Taylor Barry S. , Chitale Dhananjay , Halilovic Ensar , Wilson Manda , Huberman Kety , Ricarte Filho Julio Cezar , Persaud Yogindra , Levine Douglas A. , Fagin James A. , Jhanwar Suresh C. , Mariadason John M. , Lash Alex , Ladanyi Marc , Saltz Leonard B. , Heguy Adriana , Paty Philip B. , Solit David B. 
Published: June 2010

Abstract
Mutations in RAS proteins occur widely in human cancer. Prompted by the confirmation of KRAS mutation as a predictive biomarker of response to epidermal growth factor receptor (EGFR)–targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a nonbiased manner, the biological, biochemical, and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited mitogen-activated protein/extracellular signal-regulated kinase kinase dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3. Cancer Res; 70(14); 5901–11. ©2010 AACR.
Development of a Lung Cancer Therapeutic Based on the Tumor Suppressor MicroRNA-34
Authors: Wiggins Jason F. , Ruffino Lynnsie , Kelnar Kevin , Omotola Michael , Patrawala Lubna , Brown David , Bader Andreas G. 
Published: June 2010

Abstract
Tumor suppressor microRNAs (miRNA) provide a new opportunity to treat cancer. This approach, “miRNA replacement therapy,” is based on the concept that the reintroduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non–small-cell lung cancer. This formulation is effective when administered locally or systemically. The antioncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy into the clinic. Cancer Res; 70(14); 5923–30. ©2010 AACR.
Breast Carcinoma–Associated Fibroblasts Rarely Contain p53 Mutations or Chromosomal Aberrations
Authors: Hosein Abdel Nasser , Wu Min , Arcand Suzanna L. , Lavallée Sylvie , Hébert Josée , Tonin Patricia N. , Basik Mark 
Published: June 2010

Abstract
It has become increasingly clear that the cells within the tumor microenvironment play a critical role in cancer growth and metastasis. Studies in experimental models suggest that carcinoma-associated fibroblasts (CAF) differ from normal fibroblasts and are capable of promoting cancer progression through a variety of mechanisms. At present, a definitive view is lacking on whether genomic abnormalities are present and whether they might underlie the observed phenotypic differences. This study reports the molecular analysis of the largest series of breast CAFs reported to date, with an array comparative genomic hybridization–based DNA copy number analysis of cultured CAFs derived from 25 freshly resected human breast cancers. We found DNA copy number changes consisting of the whole arm of chromosomes 6p and 9p plus interstitial 4q loss in only one sample. No abnormalities were observed in non–tumor-associated fibroblast counterparts. Karyotyping of the same CAF revealed further chromosomal abnormalities, which included clonal loss of chromosomes, chromosomal duplications, and less frequent chromosomal rearrangements. These abnormalities were not associated with alterations in the global gene expression profile of this particular CAF, relative to its non–tumor-associated fibroblast counterpart. Moreover, this particular patient's CAF also displayed the only p53 mutation in the cohort, the first time such a mutation has been reported in freshly cultured human CAFs. These findings argue that the procancerous effects of CAFs are unlikely to be due to DNA copy number–type genomic abnormalities in the CAFs themselves. As such, breast CAFs should be mainly regarded as genomically stable cellular constituents that exist within complex cancer microenvironments. Cancer Res; 70(14); 5770–7. ©2010 AACR.
Depletion of Tumor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects
Authors: Zhang Wei , Zhu Xiao-Dong , Sun Hui-Chuan , Xiong Yu-Quan , Zhuang Peng-Yuan , Xu Hua-Xiang , Kong Ling-Qun , Wang Lu , Wu Wei-Zhong , Tang Zhao-You 
Published: June 2010

Abstract
Purpose: To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib.
Experimental Design: Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody. The effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drug target macrophages, zoledronic acid (ZA) and clodrolip, was measured in the two models of hepatocellular carcinoma.
Results: Although sorafenib significantly inhibited tumor growth and lung metastasis, it induced a significant increase in peripheral recruitment and intratumoral infiltration of F4/80- and CD11b-positive cells, which was accompanied with elevation of colony-stimulating factor-1, stromal-derived factor 1α, and vascular endothelial growth factor in the tumor and elevation of plasma colony-stimulating factor-1 and mouse vascular endothelial growth factor in peripheral blood, suggesting the role of macrophages in tumor progression under sorafenib treatment. Depletion of macrophages by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with mice treated with sorafenib alone. ZA was more effective than clodrolip.
Conclusions: Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect. Clin Cancer Res; 16(13); 3420–30. ©2010 AACR.
Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer
Authors: Kyula Joan N. , Van Schaeybroeck Sandra , Doherty Joanne , Fenning Catherine S. , Longley Daniel B. , Johnston Patrick G. 
Published: June 2010

Abstract
Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.
Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.
Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-α, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.
Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. Clin Cancer Res; 16(13); 3378–89. ©2010 AACR.