bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood and lymphatic vessel invasion in pT1 colorectal cancer: an international concordance study
Authors: Kojima Motohiro , Puppa Giacomo , Kirsch Richard , Basturk Olca , Frankel Wendy L , Vieth Michael , Lugli Alessandro , Sheahan Kieran , Yeh Matthew , Lauwers Greg Y , Risio Mauro , Shimazaki Hideyuki , Iwaya Keiichi , Kage Masayoshi , Akiba Jun , Ohkura Yasuo , Horiguchi Shinichiro , Shomori Kohei , Kushima Ryoji , Nomura Shogo , Ajioka Yoichi , Adsay Volkan , Ochiai Atsushi 
Published: May 2015

AimThis study was performed to evaluate the concordance in pathological assessments of blood and lymphatic vessel invasion (BLI) in pT1 colorectal cancers and to assess the effect of diagnostic criterion on consistency in the assessment of BLI.MethodsForty consecutive patients undergoing surgical resection of pT1 colorectal cancers were entered into this study. H&E-stained, D2-40-stained and elastica-stained slides from the tumours were examined by 18 pathologists from seven countries. The 40 cases were divided into two cohorts with 20 cases each. In cohort 1, pathologists diagnosed BLI using criteria familiar to them; all Japanese pathologists used a criterion of BLI from the Japanese Society for Cancer of the Colon and Rectum (JSCCR). In cohort 2, all pathologists used the JSCCR diagnostic criterion.ResultsIn cohort 1, diagnostic concordance was moderate in the US/Canadian and European pathologists. There were no differences in the consistency compared with results for Japanese pathologists, and no improvement in the diagnostic concordance was found for using the JSCCR criterion. However, in cohort 2, the JSCCR criterion decreased the consistency of BLI diagnosis in the US/Canadian and European pathologists. The level of decreased consistency in the assessment of BLI was different between the US/Canadian and European pathologists.ConclusionsA uniform criterion strongly influences the diagnostic consistency of BLI but may not always improve the concordance. Further study is required to achieve an objective diagnosis of BLI in colorectal cancer. The varying effects of diagnostic criterion on the pathologists from Japan, the USA/Canada and Europe might reflect varied interpretations of the criterion. Internationally accepted criterion should be developed by participants from around the world.
Infective endocarditis in the Pacific: clinical characteristics, treatment and long-term outcomes
Authors: Mirabel Mariana , André Romain , Barsoum Mikhaïl Paul , Colboc Hester , Lacassin Flore , Noël Baptiste , Robert Jacques , Nadra Marie , Braunstein Corinne , Gervolino Shirley , Marijon Eloi , Iung Bernard , Jouven Xavier 
Published: May 2015

IntroductionData on clinical characteristics and outcomes of infective endocarditis (IE) in the Pacific are scarce.MethodsRetrospective hospital-based study in New Caledonia, a high-income country, on patients aged over 18 years with definite IE according to the modified Duke criteria (2005–2010).Results51 patients were included: 31 (60.8%) men; median age of 52.4 years (IQR 33.0–70.0). Left-sided IE accounted for 47 (92.2%) patients: native valve IE in 34 (66.7%) and prosthetic valve IE in 13 (25.5%). The main underlying heart disease included: rheumatic valve disease in 19 (37.3%), degenerative heart valve disease in 12 (23.5%) and congenital heart disease in 6 (11.8%). Significant comorbidities (Charlson's score >3) were observed in 20 (38.7%) patients. Infection was community acquired in 43 (84.3%) patients. Leading pathogens includedStaphylococcus aureusin 16 (31.4%) andStreptococcusspp in 15 (29.4%) patients. Complications were noted in 33 patients (64.7%) and 24 (47.1%) were admitted to the intensive care unit. Cardiac surgery was eventually performed in 22 of 40 (55.0%) patients with a theoretical indication. None underwent emergent cardiac surgery (ie, first 24 h); 2 (3.9%) were operated within 7 days; and 20 (39.2%) beyond 7 days. 11 (21.6%) patients died in hospital and 21 (42.9%) were dead after a median follow-up of 28.8 months (IQR 4.6–51.2). Two (3.9%) were lost to follow-up.ConclusionsIn New Caledonia, IE afflicts relatively young patients with rheumatic heart disease, and carries high complication and mortality rates. Access to heart surgery remains relatively limited in this remote archipelago.
The impact of patient heterogeneity and socioeconomic factors on abatacept retention in rheumatoid arthritis across nine European countries
Authors: Finckh A , Neto D , Iannone F , Loza E , Lie E , van Riel P , Hetland M L , Pavelka K , Gottenberg J E , Canhão H , Mariette X , Turesson C 
Published: May 2015

BackgroundThere are substantial differences in accessibility to biological disease modifying antirheumatic drugs (bDMARDs) across countries. The objective of this study was to analyse the impact of patient demographics, disease characteristics and gross domestic product (GDP) on abatacept (ABA) retention in patients with rheumatoid arthritis (RA) treated in clinical practice.MethodsData from nine European observational RA cohorts of patients treated with ABA were pooled. Kaplan-Meier analysis was used to compare drug retention across registries. Specific causes of drug retention were investigated using competing risks multivariate Cox regression.ResultsA total of 3961 patients treated with ABA, with 6188 patient-years of follow-up, were included. Patients in the different national registries had similar demographic features, but varied in baseline disease characteristics. ABA drug retention differed between countries, with median drug retention rates ranging from 1.2 to more than 6 years. The differences in drug retention were marginally explained by disparities in disease characteristics, while the national GDP per capita was strongly associated with drug retention (correlation coefficient −0.74; p=0.02).ConclusionsPatient characteristics at ABA initiation vary across Europe, probably reflecting differences in eligibility criteria and prescription patterns. However, the difference in ABA drug retention between countries was not primarily explained by disparities in patient characteristics. Lower ABA retention was observed in countries with a more liberal access to bDMARDs and higher GDP. National differences need to be accounted for when pooling data on treatment with bDMARDs from various countries.
Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D
Authors: Jeong Youngtae , Swami Srilatha , Krishnan Aruna V. , Williams Jasmaine D. , Martin Shanique , Horst Ronald L. , Albertelli Megan A. , Feldman Brian J. , Feldman David , Diehn Maximilian 
Published: May 2015

Abstract
The anticancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and preclinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here, we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor–initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors and estrogen receptors (ER) and exhibited calcitriol-induced molecular responses including ER downregulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D–supplemented diet caused a striking delay in tumor appearance and growth, whereas a vitamin D–deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies may enhance anticancer activity and improve therapeutic outcomes. Mol Cancer Ther; 14(8); 1951–61. ©2015 AACR.
AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody–Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML
Authors: Pereira Daniel S. , Guevara Claudia I. , Jin Liqing , Mbong Nathan , Verlinsky Alla , Hsu Ssucheng J. , Aviña Hector , Karki Sher , Abad Joseph D. , Yang Peng , Moon Sung-Ju , Malik Faisal , Choi Michael Y. , An Zili , Morrison Kendall , Challita-Eid Pia M. , Doñate Fernando , Joseph Ingrid B.J. , Kipps Thomas J. , Dick John E. , Stover David R. 
Published: May 2015

AbstractCD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody–drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to &gt;80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34+CD38− leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML. Mol Cancer Ther; 14(7); 1650–60. ©2015 AACR.
Abstract 1459: miR-221: A potential therapeutic target for hepatocellular carcinoma
Authors: Lee Edmund C. , Xu Jessica , Vincent Thomas , Chen Jie , Nelson Michael , Huang Xinqiang , Marcusson Eric , Androsavich John , Davis Scott , Pavlicek Adam , Gibson Neil , Zabludoff Sonya 
Published: May 2015

Abstract
microRNAs, which control post-transcriptional gene expression by repressing mRNA translation and/or causing mRNA degradation, play important roles in human cancers. miR-221 is one of the two microRNAs in the miR-221/222 cluster located in chromosome-X, targets key cancer pathways and inhibit translation of several tumor suppressors including p27, p57, and PTEN. miR-221 is up-regulated by &gt;2-fold in 55% and &gt;5-fold in 14% of human hepatocellular carcinoma (HCC) tumor samples. Importantly, it has been shown in preclinical HCC models that miR-221 overexpression accelerated tumorigenesis, while miR-221 inhibition reduced tumor growth. To identify novel microRNA antagonists that specifically inhibit miR-221 (refer to as miR-221 anti-miRs) for the treatment of HCC, we have generated a number of chemically-modified oligonucleotides and screened for their ability to inhibit miR-221 functions. A number of potent and metabolically stable miR-221 anti-miRs devoid of proinflammatory potential were identified. These miR-221 anti-miRs were tested in a number of human HCC cell lines that highly express miR-221 compare to normal adult human hepatocytes. We demonstrated the de-repression of both p27 mRNA and p27 protein in HCC cells following treatment with miR-221 anti-miRs. We also showed in HCC cells the de-repression of a novel miR-221 target gene recently identified through an argonuate pull-down assay (Ago-IP), alongside with the enrichment of global miR-221 target seeds (as defined by TargetScan) following miR-221 anti-miRs treatment. We then sought to determine the biologic consequences following miR-221 inhibition in HCC cells. In standard cell proliferation assays, we demonstrated that HCC cells responded to miR-221 anti-miRs treatment with IC50s of 125 to 500nM under free-uptake conditions and IC50s of 5 to 75 nM under transfection conditions. In addition, we also showed that miR-221 anti-miRs treatment disrupted HCC cell cycle transition. Altogether, our data showed that miR-221 inhibition de-repressed p27, blocked cell cycle progression and reduced cell proliferation in HCC cells, and supports the notion of miR-221 as a potential therapeutic target for the treatment of HCC. Further preclinical testing of our miR-221 anti-miRs is currently in progress.
Citation Format: Edmund C. Lee, Jessica Xu, Thomas Vincent, Jie Chen, Michael Nelson, Xinqiang Huang, Eric Marcusson, John Androsavich, Scott Davis, Adam Pavlicek, Neil Gibson, Sonya Zabludoff. miR-221: A potential therapeutic target for hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1459. doi:10.1158/1538-7445.AM2014-1459
Abstract 1671: Immunosuppressive myeloid-derived suppressor cells expressing PDL1 are increased in human melanoma tumor tissue
Authors: Jordan Kimberly Rae , Borges Virginia , McCarter Martin D. 
Published: May 2015

Abstract
Despite the ability to elicit active immune responses, most immunotherapies fail to eliminate tumors in human cancer patients. One reason immunotherapy has not met expectations may be due to immunosuppression in the local environment of the tumor. Immunosuppressive myeloid-derived suppressor cells (MDSCs) are increased in the peripheral blood of melanoma patients and the frequency of MDSCs correlates with overall survival and disease progression. Furthermore, cytokines related to the recruitment and differentiation of MDSCs are also increased in melanoma patient serum and changes in these cytokine levels may correlate with disease progression. We find an increased frequency of regulatory T cells, PD-1-expressing T cells, and PD-L1 expressing MDSCs in primary melanoma tumors, suggesting that PD-1/PD-L1 interactions may play a role in immunosuppression in the microenvironment of the tumor. We are currently investigating the mechanisms of immunosuppression used by human MDSCs and whether the suppressive function of MDSCs can be blocked with antibodies targeting PD-L1. In conclusion, we have established MDSCs as an important player in immunosuppression in melanoma patients suggesting that combinatorial treatments that reduce the frequency or activity of MDSCs may improve the effectiveness of future immunotherapies.
Citation Format: Kimberly Rae Jordan, Virginia Borges, Martin D. McCarter. Immunosuppressive myeloid-derived suppressor cells expressing PDL1 are increased in human melanoma tumor tissue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2014-1671
Abstract 1760: Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition
Authors: Moore Zachary , Boothman David A. 
Published: May 2015

Abstract
Cancer cells require increased NAD+ synthesis to support anabolic metabolism, to sustain signaling processes such as sirtuin activity and ADP-ribosylation, and to maintain redox balance. Inhibitors of Nicotinamide phosphoribosyltransferase (NamPT), the rate-limiting step in NAD+ biosynthesis, have modest anti-tumor activity in monotherapy in vitro and in vivo, but failed clinical trials due to a lack of tumor specificity attributed to the necessity of NAD+ synthesis in normal proliferating cells. We found that the tumor specificity and efficacy of NamPT inhibition can be greatly increased when small molecule NamPT inhibitors, such as FK866, are used in combination with the NQO1 bioactivated therapeutic ß-lapachone (ß-lap). Most solid tumor cells overexpress NQO1, which catalyzes a futile redox cycle with ß-lap, resulting in the formation of a burst of reactive oxygen species (ROS). This results in substantial DNA single strand breaks and base damage in a tumor-specific manner, which hyperactivates poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme that utilizes NAD+ to generate poly(ADP-ribose) (PAR)-protein moieties. Rapid NAD+ and ATP loss occurs and tumor cells die through programmed necrosis. PARP-1-mediated NAD+ depletion caused by ß-lap treatment synergizes with reduced NAD+ synthesis as a result of FK866-mediated NamPT inhibition. Enhanced cancer cell death in terms of loss of viability and clonogenicity at lower ß-lap doses was noted, while tumor specificity for NQO1 overexpressing cells was maintained. With combination treatment, cells are primed for ROS-mediated damage due to reduced glutathione and NAD(P)+ levels, they are unable to recover ATP, NAD+, and NADP+ synthesis even after only a 2 hour treatment, and they rapidly die through a caspase-independent mechanism. This therapeutic approach is highly effective against a variety of tumor cell lines from pancreatic, breast, and non-small cell lung, and is expected to improve the efficacy and tumor specificity of both of these drugs by allowing their use at lower doses in vivo. These studies were supported by an AACR/PanCan Innovator Award and NIH R01 CA102972 to DAB.
Citation Format: Zachary Moore, David A. Boothman. Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1760. doi:10.1158/1538-7445.AM2014-1760
Abstract 1882: The expression phenotype of SNPs linked to the risk for prostate cancer
Authors: Chen Xin , Jia Zhenyu , McClelland Michael , Rahmatpanah Farah , Mercola Dan 
Published: May 2015

Abstract
Numerous Genome Wide Association (GWA) studies of large populations have provided limited biomarkers for cancer and few linkages to phenotype. We investigated whether SNPs that are known to be associated with prostate cancer (PCa) affect expression in prostate stroma. The stroma of prostate tumors provides genetically homogenous tissue type with hundreds of tumor-dependent expression changes [1] which favors linkage identification. We surveyed published GWA studies covering a total of ∼90,000 patients and selected the most significant 35 susceptibility loci for further linkage analysis. We also selected 4030 transcripts previously associated with PCa diagnosis and prognosis. We then investigated 47 PCa cases using genetic variations in nontumor DNA (Illumina Human1M-Duov3_B snp arrays) and correlating the genotypes with RNA gene expression data from the same patients (U133 plus 2.0 arrays). A novel eQTL (Expression Quantitative Trait Loci) analysis was carried out by a modified BAYES method to analyze the associations between the risk variants and expressed transcripts jointly in a single model. The model assumed that a risk variant can be associated with multiple RNA expression changes and vice versa. We observed 47 significant linkages between 8 risk variants and 46 significant expression changes. The false discovery rates of two resampling studies are 0.03 and 0.05, respectively, which indicated the 47 linkages are significant. All linkages are “trans' linkages indicating remote effects of key SNPs on expressing genes. This is the first study to identify trans-linkages between multiple SNPs and multiple significant expression changes identified in cancer stroma. The linkages also associated with trends in clinical phenotypes. The strongest trend is between linkage rs9623117(C)-FOXD1 and biochemical relapse (p=0.01). The study reveals links between SNPs associated with PCa risk and transcription, which may identify the subset of patients where these genotypes may affect relevant phenotypes.
[1] Jia et al., Cancer Research 2011; 71:2476-2487.
Citation Format: Xin Chen, Zhenyu Jia, Michael McClelland, Farah Rahmatpanah, Dan Mercola. The expression phenotype of SNPs linked to the risk for prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2014-1882
Abstract 2624: The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model
Authors: Niemann Carsten U. , Montraveta Arnau , Herman Sarah E. M. , Ingallinera Tim , Barf Tjeerd , Colomer Dolors , Wiestner Adrian 
Published: May 2015

Abstract
Background: Targeting Bruton's tyrosine kinase (BTK), an essential kinase in the B cell receptor (BCR) pathway in patients with chronic lymphocytic leukemia (CLL) has proven very effective. For the first generation BTK inhibitor ibrutinib, clinical response rates &gt;70% and 75% progression free survival &gt;2 years have been reported for previously treated patients (Byrd, NEJM, 2013). ACP-196 is a novel, second generation, irreversible BTK inhibitor that may show advantages in terms of binding specificity and drug-drug interactions compared to the first generation BTK inhibitor. Survival and proliferation of CLL cells is highly dependent on microenvironment interaction, which must be taken into consideration when testing new drugs for CLL. We have previously shown that human CLL cells engrafted in the spleen of NSG mice have comparable tumor biology to human lymph node resident CLL cells (Herman, Leukemia, 2013). We here demonstrate the in vivo effects of ACP-196 monotherapy against CLL cells in the NSG xenograft model.
Methods: Peripheral blood mononuclear cells from previously untreated CLL patients were injected intravenously into NSG mice. Mice received ACP-196 through the drinking water. The effect of ACP-196 on xenografted CLL cells from peripheral blood and spleen was assessed by flow cytometry.
Results: At all dose levels tested, ACP-196 significantly inhibited proliferation of human CLL cells in the spleens of NSG mice, as measured by Ki67 expression (P=0.002). The mean Ki67 decrease was 58%, 70% and 73%, respectively for the low, intermediate, and high dose level compared with vehicle. Tumor burden in spleens from mice treated with the high dose of ACP-196 decreased compared with the vehicle treated group (P=0.007). As seen with other BCR inhibitors, ACP-196 transiently increased CLL cell counts in the peripheral blood in a dose dependent manner (p=0.01). ACP-196 inhibited BCR signaling in vivo, as demonstrated by reduced phosphorylation of PLCγ2.
Conclusions: Results presented here for ACP-196 are in accordance with the expected profile of an irreversible BTK inhibitor. The NSG CLL xenograft model will be used for comparative testing of different BTK inhibitors and exploration of combination therapies.
Citation Format: Carsten U. Niemann, Arnau Montraveta, Sarah E. M. Herman, Tim Ingallinera, Tjeerd Barf, Dolors Colomer, Adrian Wiestner. The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2014-2624