bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating angiopoietin‐1 to angiopoietin‐2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents
Authors: Terpos Evangelos , Anargyrou Konstantinos , Katodritou Eirini , Kastritis Efstathios , Papatheodorou Athanasios , Christoulas Dimitrios , Pouli Anastasia , Michalis Eurydiki , Delimpasi Sosana , Gkotzamanidou Maria , Nikitas Nikitas , Koumoustiotis Vasilios , Margaritis Dimitrios , Tsionos Konstantinos , Stefanoudaki Ekaterini , Meletis John , Zervas Konstantinos , Dimopoulos Meletios A. ,   on behalf of the Greek Myeloma Study Group, Greece
Published: April 2011

AbstractThe circulating levels of several angiogenic cytokines [angiopoietin‐1 (Ang‐1), angiopoietin‐2 (Ang‐2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang‐1/Ang‐2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin‐1/angiopoietin‐2 ratio correlated with advanced disease features including international staging system (ISS)‐3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin‐2) we found that angiopoietin‐2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang‐1/Ang‐2 ratio correlated with survival. Patients with circulating Ang‐1/Ang‐2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first‐line therapy with novel agent‐based regimens (65% of our patients). Furthermore, a subset of ISS‐3 patients with serum Ang‐1/Ang‐2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang‐1/Ang‐2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50–2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.
Differential carcinogenicity of cigarette smoke in mice exposed either transplacentally, early in life or in adulthood
Authors: Balansky Roumen , Ganchev Gancho , Iltcheva Marietta , Nikolov Manasi , Steele Vernon E. , De Flora Silvio 
Published: April 2011

AbstractCigarette smoke (CS) plays a dominant role in the epidemiology of human cancer. However, it is difficult to reproduce its carcinogenicity in laboratory animals. Recently, we showed that CS becomes a potent carcinogen in mice when exposure starts soon after birth. In our study, we comparatively evaluated the carcinogenic response to mainstream CS in mice at different ages. Neonatal mice were exposed daily for 4 months to CS, starting within 12 hr after birth, and sacrificed at 8 months. Adult mice were exposed for the same time period (3–7 months) and sacrificed at 11 months. Other mice were exposed transplacentally or both transplacentally and early in life. A total of 351 neonatal mice and 80 adult Swiss H mice were used. With varying intensity depending on age, CS induced pulmonary emphysema, bronchial and alveolar epithelial hyperplasia, blood vessel proliferation and hemangiomas and microadenomas in lung as well as parenchymal degeneration of liver. Histopathological alterations of kidney were only observed in mice exposed to CS early in life. Lung adenomas and malignant tumors of various histopathological nature were detected in neonatally exposed mice but not in adults. Transplacental CS induced the formation of lung adenomas in the offspring 8 months after birth. Previous exposure during pregnancy attenuated CS‐related alveolar epithelial hyperplasia induced after birth. In conclusion, the carcinogenic response to CS varies depending on the developmental stage. The early postnatal life and the prenatal life are particularly at risk for the later development of CS‐related tumors.
Nuclear HER3 is associated with favorable overall survival in uveal melanoma
Authors: Trocmé Eric , Mougiakakos Dimitrios , Johansson C. Christian , All‐Eriksson Charlotta , Economou Mario A. , Larsson Olle , Seregard Stefan , Kiessling Rolf , Lin Yingbo 
Published: April 2011

AbstractHER3 is a member of the epidermal growth factor receptor (EGFR) family and is expressed in several types of cancer. Both the cytoplasmic and nuclear appearances of the receptor have been reported. Here, we investigate the expression and subcellular distribution of HER3 in uveal melanoma (UM) cells and tissues and its potential impact on clinical outcome of patients. Paraffin‐embedded samples from 128 consecutive UM patients, enucleated without alternative treatment on UM diagnosis, were evaluated for HER3 using immunohistochemistry. Immunoreactivity was scored for frequency, intensity of positive cells, and subcellular distribution. The results were correlated with the established clinicopathological parameters using univariate and multivariate statistical analyses. HER3 expression was shown in 70% of the cases (89/128). This contrasts with the other EGFR family receptors (EGFR, HER2 and HER4) that are infrequently expressed in UM. Surprisingly, HER3 was found to be localized solely in the cell nuclei in 56 cases. The remaining 33 HER3 positive cases showed diffuse distribution (cytoplasmic ± nuclear). Nuclear HER3 was independently correlated with a more favorable overall survival (p = 0.043 and hazard ratio = 0.618) compared to cases with diffuse and/or no HER3. Nuclear localization of HER3 was also confirmed in fresh UM material and in UM cell lines. In conclusion, HER3 is frequently localized solely in the cell nuclei in UM and as such it predicts a more favorable overall survival.
In vivo pH in metabolic‐defective Ras‐transformed fibroblast tumors: Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH
Authors: Chiche Johanna , Fur Yann Le , Vilmen Christophe , Frassineti Frédéric , Daniel Laurent , Halestrap Andrew P. , Cozzone Patrick J. , Pouysségur Jacques , Lutz Norbert W. 
Published: April 2011

AbstractWe present an investigation of tumor pH regulation, designed to support a new anticancer therapy concept that we had previously proposed. Our study uses a tumor model of ras‐transformed hamster fibroblasts, CCL39, xenografted in the thighs of nude mice. We demonstrate, for the first time, that genetic modifications of specific mechanisms of proton production and/or proton transport result in distinct, reproducible changes in intracellular and extracellular tumor pH that can be detected and quantified noninvasively in vivo, simultaneously with determinations of tumor energetic status and necrosis in the same experiment. The CCL39 variants used were deficient in the sodium/proton exchanger, NHE‐1, and/or in the monocarboxylate transporter, MCT4; further, variants were deficient in glycolysis or respiration. MCT4 expression markedly increased the gradient between intracellular and extracellular pH from 0.14 to 0.43 when compared to CCL39 wild‐type tumors not expressing MCT4. The other genetic modifications studied produced smaller but significant increases in intracellular and decreases in extracellular pH. In general, increased pH gradients were paralleled by increased tumor growth performance and diminished necrotic regions, and 50% of the CCL39 variant expressing neither MCT4 nor NHE‐1, but possessing full genetic capacity for glycolysis and oxidative phosphorylation, underwent regression before reaching a 1‐cm diameter. Except for CCL39 wild‐type tumors, no significant HIF‐1α expression was detected. Our in vivo results support a multipronged approach to tumor treatment based on minimizing intracellular pH by targeting several proton production and proton transport processes, among which the very efficient MCT4 proton/lactate co‐transport deserves particular attention.
Indocyanine green enhanced near‐infrared laser treatment of murine mammary carcinoma
Authors: Shafirstein Gal , Bäumler Wolfgang , Hennings Leah J. , Siegel Eric R. , Friedman Ran , Moreno Mauricio A. , Webber Jessica , Jackson Cassie , Griffin Robert J. 
Published: April 2011

AbstractIt is well accepted that near‐infrared (NIR) lasers are appropriate to ablate benign lesions and induce irreversible thermal injury in deeply seated blood vessels. At this wavelength, the laser light penetrates deep (3–5 mm) into the skin. However, many researchers have reported noticeable pain, extending from mild to severe, during and immediately after NIR laser treatment. Intravenous administration of an exogenous chromophore [indocyanine green (ICG), dye] can effectively convert NIR laser light into heat. In this approach, the presence of ICG has shown to enhance thermal injury of blood vessels in the treatment of healthy tissues. However, the effectiveness of thermal injury on the regression of cutaneous carcinomas during ICG/NIR laser therapy has not been assessed. The purpose of our study was to evaluate the potential benefit of using ICG/NIR laser therapy to regress superficial carcinoma with thermal injury. Two groups of A/J mice with subcutaneous mammary adenocarcinoma tumors (7–9 mm) were irradiated with a 808‐nm NIR laser preceded by tail vein injection of ICG dye or sterile saline. Histological evaluation of the subcutaneous tissue revealed minor thermal damage and necrosis in the laser/saline group and substantial damage (up to 100% necrosis) in the laser/ICG group. The laser/ICG‐treated group showed a steady reduction in tumor volume compared to the laser/saline group: 48% by day 5 (p = 0.045) and 69–70% by days 8, 9 and 10 (p values 0.0005 or less). The vascular‐targeted ICG–NIR laser therapy appears to have potential for treating superficial tumors.
CDKI‐71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol
Authors: Liu Xiangrui , Shi Shenhua , Lam Frankie , Pepper Chris , Fischer Peter M. , Wang Shudong 
Published: April 2011

AbstractCancer cells appear to depend heavily on antiapoptotic proteins for survival and so targeted inhibition of these proteins has therapeutic potential. One innovative strategy is to inhibit the cyclin‐dependent kinases (CDKs) responsible for the regulation of RNA polymerase II (RNAPII). In our study, we investigated the detailed cellular mechanism of a novel small‐molecule CDK inhibitor (CDKI‐71) in cancer cell lines, primary leukemia cells, normal B ‐ & T‐ cells, and embryonic lung fibroblasts and compared the cellular and molecular responses to the clinical CDK inhibitor, flavopiridol. Like flavopiridol, CDKI‐71 displayed potent cytotoxicity and caspase‐dependent apoptosis induction that were closely associated with the inhibition of RNAPII phosphorylation at serine‐2. This was caused by effective targeting of cyclinT–CDK9 and resulted in the downstream inhibition of Mcl‐1. No correlation between apoptosis and inhibition of cell‐cycle CDKs 1 and 2 was observed. CDKI‐71 showed a 10‐fold increase in potency in tumor cell lines when compared to MRC‐5 human fibroblast cells. Significantly, CDKI‐71 also demonstrated potent anti‐chronic lymphocytic leukemia activity with minimal toxicity in normal B‐ and T‐cells. In contrast, flavopiridol showed little selectivity between cancer and normal cells. Here, we provide the first cell‐based evidence that flavopiridol induces DNA double‐strand breaks: a fact which may explain why flavopiridol has such a narrow therapeutic window in preclinical and clinical settings. Taken together, our data provide a rationale for the development of selective CDK inhibitors as therapeutic agents and CDKI‐71 represents a promising lead in this context.
Experience with high‐risk human papillomavirus testing on vaginal brush‐based self‐samples of non‐attendees of the cervical screening program
Authors: Gök Murat , van Kemenade Folkert J. , Heideman Daniëlle A.M. , Berkhof Johannes , Rozendaal Lawrence , Spruyt Johan W.M. , Beliën Jeroen A.M. , Babovic Milena , Snijders Peter J.F. , Meijer Chris J.L.M. 
Published: April 2011

AbstractWe evaluated the effect of offering brush‐based vaginal self‐sampling for high‐risk human papillomavirus (hrHPV) testing to non‐attendees of the cervical screening program on response rate, compliance to follow‐up and cervical intraepithelial neoplasia grade 2 or 3 (CIN2+/CIN3+) yield. In addition, concordance of hrHPV test results between physician‐taken cervical scrapes and vaginal self‐samples was determined. A total of 26,409 nonattending women were randomly assigned to receive a vaginal brush device for hrHPV testing by Hybrid Capture‐2® method (i.e., self‐sampling group, n = 26,145) or a reinvitation for regular cytology‐based screening (i.e., recall control group, n = 264). hrHPV‐positive self‐sampling responders were invited for a physician‐taken scrape for cytology and blinded hrHPV testing. If cytology was abnormal, women were referred for colposcopy. Response rate in the self‐sampling group was significantly increased compared to the recall control group (30.8% versus 6.5%; p < 0.001). The concordance rate between hrHPV detection in self‐samples and corresponding physician‐taken cervical scrape samples was 68.8%. Amongst women with CIN3+ and CIN2+, the concordance rates in hrHPV positivity between both samples were 95.5% and 93.8%, respectively. Adherence at baseline to cytology triage of hrHPV‐positive self‐sampling women (89.1%) and colposcopy referral of those with abnormal cytology (95.8%) was high. The CIN2+/CIN3+/carcinoma yields were 1.5%, 1.0% and 0.1%, respectively, in self‐sampling responders. In conclusion, offering hrHPV testing on self‐sampled vaginal material with a brush device to non‐attendees significantly increases the attendance to the regular screening program, yields hrHPV test results that are in very good concordance with those of physician‐taken scrapes in women with CIN2+/CIN3+, and is effective in detecting CIN2+/CIN3+.
Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer
Authors: Park Yongjung , Kim Yoonjung , Lee Eun Young , Lee Jong‐Han , Kim Hyon‐Suk 
Published: April 2011

AbstractHuman epididymis protein 4 (HE4) is a new biomarker for the detection of ovarian cancer. We evaluated the analytical performance of a novel automated HE4 assay and established reference ranges of HE4 and CA125. We also compared the diagnostic performance of both biomarkers for ovarian cancer. Precision performances and linearity of the HE4 assay were assessed. Serum samples from 2,182 healthy and 72 pregnant women were also assayed for HE4 and CA125, and the 95%, 97.5% and 99% reference limits for both markers were calculated. Additionally, sera from 66 ovarian cancer and 257 benign gynecologic disease patients were tested to validate reference ranges and diagnostic performances. The total precision of the HE4 assay was <5% coefficient of variation for most of the levels evaluated. The linearity range of this assay was from 15.0 to 1100.0 pmol/L. The 97.5% upper reference limits for HE4 and CA125 were 33.2 pmol/L (95% confidence interval [CI], 32.2–34.0) and 38.3 U/mL (95% CI, 35.1–41.5), respectively. Using these values as cutoff points, the sensitivity and specificity of HE4 for differentiating ovarian cancer from benign gynecologic diseases and healthy individuals were 90.9% and 94.1%, and those of CA125 were 72.7% and 94.4%. The receiver operating characteristic‐area under the curve values of HE4 and CA125 for discriminating ovarian cancer from age‐matched control were 0.94 and 0.86, respectively, and they were statistically different (p = 0.0095). The new automated HE4 assay showed good analytical and diagnostic performances. The reference limits established in our study could be used as cutoff levels to facilitate more accurate diagnosis of ovarian cancer in Asian population.
Potentially functional polymorphisms in IL‐23 receptor and risk of esophageal cancer in a Chinese population
Authors: Chu Hongjun , Cao Weike , Chen Wei , Pan Shandong , Xiao Yong , Liu Yao , Gu Haiyong , Guo Wei , Xu Lin , Hu Zhibin , Shen Hongbing 
Published: April 2011

AbstractInterleukin‐23 (IL‐23)/IL‐23 receptor (IL‐23R) is essential for Th17 cell‐mediated immune response, involved in autoimmune diseases and cancer pathogenesis. Two potentially functional genetic single nucleotide polymorphisms (SNPs; IL‐23R rs6682925 T>C and rs1884444 T>G) were found to contribute to cancer susceptibility. In our study, we conducted a case–control study including 1,645 patients with esophageal cancer and 1,694 cancer‐free controls in a Chinese population to assess the association between the two SNPs and the risk of esophageal cancer. We found that IL‐23R rs6682925 TC/CC and rs1884444 TG/GG variant genotypes were associated with significantly increased risk of esophageal cancer [rs1884444: adjusted odds ratio (OR) = 1.16, 95% confidence intervals (CIs) =1.01–1.33; rs6682925: adjusted OR = 1.23, 95% CIs = 1.07–1.42], compared to their corresponding wild‐type homozygotes. Furthermore, the increased risks associated with the two SNPs were independent from smoking and alcohol drinking status. These findings indicated that genetic variants in IL‐23R may contribute to esophageal cancer risk in our Chinese population.
AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene
Authors: Mimura Mitsuko , Masuda Atsuhiro , Nishiumi Shin , Kawakami Kazuyuki , Fujishima Yoshimi , Yoshie Tomoo , Mizuno Shigeto , Miki Ikuya , Ohno Hiroshi , Hase Koji , Minamoto Toshinari , Azuma Takeshi , Yoshida Masaru 
Published: April 2011

AbstractRecent evidence has suggested that carcinoma is accompanied by the loss of cell polarity. An epithelial cell‐specific form of the AP‐1 clathrin adaptor complex, AP1B, is involved in the polarized transport of membrane proteins to the basolateral surface of epithelial cells. In our study, we investigated whether AP1B is involved in intestinal tumorigenesis. The cellular polarity of intestinal tumor cells was examined using APCMin/+ mice as an in vivo model and SW480 cells with a truncating mutation in the adenomatous polyposis coli (APC) gene as an in vitro model by confocal microscopy. Next, the expression of AP1B in intestinal tumor cells was examined by real‐time polymerase chain reaction (PCR) and Western blotting. The localization of β‐catenin and the expression of AP1B in the tumor tissue of patients with colorectal cancer were evaluated by confocal microscopy and real‐time PCR, respectively, and the relationships among cell polarity, AP1B expression and intestinal tumorigenesis were examined. Cellular polarity was lost in intestinal tumor cells, and the expression of AP1B was downregulated. In addition, the reduction in the expression level of AP1B correlated with the nuclear localization of β‐catenin in human colorectal cancer. Our study indicates the close associations between AP1B, intestinal tumorigenesis and mutations in the APC gene. This is the first report to reveal the relationships among AP1B, cellular polarity and intestinal tumorigenesis, and achieving a detailed understanding of AP1B will hopefully lead to discovery of therapeutic targets and novel biomarkers for intestinal cancer.
[DLys6]‐luteinizing hormone releasing hormone–curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo
Authors: Aggarwal S. , Ndinguri M.W. , Solipuram R. , Wakamatsu N. , Hammer R.P. , Ingram D. , Hansel W. 
Published: April 2011

AbstractPancreatic ductal adenocarcinomas are invariably lethal, and developing effective treatments that have minimal side effects is a challenge. Previous studies from our laboratory have shown that conjugates of cell membrane disrupting lytic peptides and luteinizing hormone releasing hormone (LHRH) target and destroy human prostate and breast cancer cells in xenografts in the nude mouse model (Hansel et al., Mol Cell Endocrinol 2007;260–262:183–9; Hansel et al., Mol Cell Endocrinol 2007;269:26–33), which express LHRH receptors. The objectives of our study were to synthesize a bioconjugate of LHRH analog ([DLys6]‐LHRH) and a dietary microchemical (curcumin) and test the hypothesis that [DLys6]‐LHRH–curcumin targets and inhibits pancreatic cancer cell growth in vitro and in vivo. In in vitro studies, we determined by confocal microscopy, flow cytometry analysis and reverse transcriptase‐polymerase chain reaction that MIAPaCa‐2, Panc‐1 and BxPC‐3 pancreatic cancer cell lines express LHRH receptors. [DLys6]‐LHRH–curcumin inhibited cell proliferation of pancreatic cancer cell lines and induced apoptotic cell death (p < 0.05). Apoptosis was induced by cleavage of polyadenosine‐5′‐diphosphate‐ribose‐polymerase and caspase‐3. The activity of [DLys6]‐LHRH–curcumin was equal to free curcumin at equimolar concentrations in vitro. Unlike curcumin itself, the [DLys6]‐LHRH–curcumin conjugate is water soluble which allows its intravenous administration. In two in vivo studies, [DLys6]‐LHRH–curcumin given intravenously caused a significant (p < 0.01) reduction in tumor weights and volumes, and free curcumin given by gavage at an equal dose failed to cause a significant reduction in tumor weights and volumes in the nude mouse pancreatic cancer model. [DLys6]‐LHRH–curcumin treatment enhanced apoptosis compared to [DLys6]‐LHRH and vehicle‐treated controls in tumor tissue. In conclusion, [DLys6]‐LHRH–curcumin may be useful in treating pancreatic cancer.
Isolation of disseminated neuroblastoma cells from bone marrow aspirates for pretreatment risk assessment by array comparative genomic hybridization
Authors: Vandewoestyne Mado , Kumps Candy , Swerts Katrien , Menten Björn , Lammens Tim , Philippé Jan , De Preter Katleen , Laureys Geneviève , Van Roy Nadine , Speleman Frank , Deforce Dieter 
Published: April 2011

AbstractIn neuroblastoma, tumor biopsies are used for prognostic evaluation and risk assessment by molecular genetic analyses such as fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array CGH). Analysis of primary tumors by array CGH can be hampered by the lack of sufficient tumor cells due to small biopsy size or availability of invaded bone marrow only. Given the importance of accurate assessment of genetic alterations in the diagnostic work‐up of patients with neuroblastoma, we evaluated the possibility to analyze bone marrow metastases in patients with disseminated disease. Disseminated neuroblastoma cells were isolated from bone marrow aspirates by using either laser capture microdissection (LCM) or magnetic activated cell sorting (MACS). The array CGH profiles of these isolated metastases were compared to array CGH profiles and/or FISH data of the corresponding primary tumor. Here, we show that the major recurrent DNA copy number alterations detected in primary neuroblastoma tumors (i.e., 1p, 3p and 11q deletion, 17q gain and MYCN amplification) can be detected, with high sensitivity and specificity, in the disseminated neuroblastoma cells isolated from the bone marrow aspirates, using an array platform with high coverage for these regions. Moreover, we demonstrate that for archived material, for example, for retrospective studies, LCM is the method of choice, while for fresh bone marrow aspirates, acquired at the time of diagnosis, MACS is superior.