bluuebunny/crossref_metadata_2025_split huggingface dataset:
K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy
Authors: Etienne-Grimaldi Marie-Christine , Formento Jean-Louis , Francoual Mireille , François Eric , Formento Patricia , Renée Nicole , Laurent-Puig Pierre , Chazal Maurice , Benchimol Daniel , Delpero Jean-Robert , Letoublon Christian , Pezet Denis , Seitz Jean-François , Milano Gérard 
Published: August 2008

Abstract
Purpose: K-Ras mutations predict resistance to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.
Experimental Design: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G&gt;C mutation), methylenetetrahydrofolate reductase polymorphism (677C&gt;T, 1298A&gt;C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression.
Results: Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival.
Conclusions: The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.
Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors
Authors: Nickerson Michael L. , Jaeger Erich , Shi Yangu , Durocher Jeffrey A. , Mahurkar Sunil , Zaridze David , Matveev Vsevolod , Janout Vladimir , Kollarova Hellena , Bencko Vladimir , Navratilova Marie , Szeszenia-Dabrowska Neonilia , Mates Dana , Mukeria Anush , Holcatova Ivana , Schmidt Laura S. , Toro Jorge R. , Karami Sara , Hung Rayjean , Gerard Gary F. , Linehan W. Marston , Merino Maria , Zbar Berton , Boffetta Paolo , Brennan Paul , Rothman Nathaniel , Chow Wong-Ho , Waldman Frederic M. , Moore Lee E. 
Published: August 2008

Abstract
Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.
Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.
Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC.
Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
CHEK2 1100delC Is a Susceptibility Allele for HNPCC-Related Colorectal Cancer
Authors: Wasielewski Marijke , Vasen Hans , Wijnen Juul , Hooning Maartje , Dooijes Dennis , Tops Carli , Klijn Jan G.M. , Meijers-Heijboer Hanne , Schutte Mieke 
Published: August 2008

Abstract
Purpose: The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk.
Experimental Design:CHEK2 1100delC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease.
Results: None of the FAP/FAP-related cases carried the CHEK2 1100delC variant. In contrast, CHEK2 1100delC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P = 0.002). Nine of the 10 CHEK2 1100delC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 1100delC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21 cases with other tumor types.
Conclusion: Our analysis provides strong evidence that the 1100delC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.
Delineation of TMPRSS2-ERG Splice Variants in Prostate Cancer
Authors: Hu Ying , Dobi Albert , Sreenath Taduru , Cook Christopher , Tadase Atekelt Y. , Ravindranath Lakshmi , Cullen Jennifer , Furusato Bungo , Chen Yongmei , Thangapazham Rajesh L. , Mohamed Ahmed , Sun Chen , Sesterhenn Isabell A. , McLeod David G. , Petrovics Gyorgy , Srivastava Shiv 
Published: August 2008

Abstract
Purpose: The expression of the ETS-related gene (ERG) is low or undetectable in benign prostate epithelial cells. High prevalence of ERG overexpression in prostate cancer cells due to TMPRSS2-ERG fusions suggest for causal roles of ERG protein in the neoplastic process. TMPRSS2-ERG fusion junctions have been extensively studied in prostate cancer. However, virtually nothing is known about the nature of full-length transcripts and encoded proteins. This study focuses on qualitative and quantitative features of full-length TMPRSS2-ERG transcripts in prostate cancer.
Experimental Design: Full-length TMPRSS2-ERG transcripts were cloned and sequenced from a cDNA library generated from pooled RNA of six TMPRSS2-ERG fusion–positive prostate tumors. The encoded ERG proteins were analyzed in HEK293 cells. Copy numbers of TMPRSS2-ERG splice variants were determined by quantitative reverse transcription-PCR in laser capture microdissected prostate cancer cells.
Results: Two types of TMPRSS2-ERG cDNAs were identified: type I, which encodes full-length prototypical ERG protein (ERG1, ERG2, ERG3), and type II, encoding truncated ERG proteins lacking the ETS domain (ERG8 and a new variant, TEPC). In microdissected prostate tumor cells from 122 patients, relative abundance of these variants was in the following order: ERG8 &gt; TEPC &gt; ERG 3 &gt; ERG1/2 with combined overexpression rate of 62.3% in prostate cancer. Increased ratio of type I over type II splice forms showed a trend of correlation with less favorable pathology and outcome.
Conclusions: Qualitative and quantitative features of specific ERG splice variants defined here promise to enhance the utility of ERG as a biomarker and therapeutic target in prostate cancer.
Three-Gene Expression Signature Predicts Survival in Early-Stage Squamous Cell Carcinoma of the Lung
Authors: Skrzypski Marcin , Jassem Ewa , Taron Miquel , Sanchez Jose Javier , Mendez Pedro , Rzyman Witold , Gulida Grazyna , Raz Dan , Jablons David , Provencio Mariano , Massuti Bartomeu , Chaib Imane , Perez-Roca Laia , Jassem Jacek , Rosell Rafael 
Published: August 2008

Abstract
Purpose: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy.
Experimental Design: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival.
Results: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P &lt; 0.0001), and tumor size &gt;4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05).
Conclusions: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.
Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1
Authors: Ding Chuanlin , Wang Li , Marroquin Jose , Yan Jun 
Published: August 2008

AbstractB cells are antibody (Ab)–secreting cells as well as potent antigen (Ag)–presenting cells that prime T-cell activation, which evokes great interest in their use for vaccine development. Here, we targeted ovalbumin (OVA) to B cells via CD19 and found that a single low dose of anti–CD19-OVA conjugates, but not isotype mAb-OVA, stimulated augmented CD4 and CD8 T-cell proliferation and expansion. Administration of TLR9 agonist CpG could significantly enhance long-term T-cell survival. Similar results were obtained when the tumor-associated Ag MUC1 was delivered to B cells. MUC1 transgenic (Tg) mice were previously found to lack effective T-cell help and produce low-titer of anti-MUC1 Abs after vaccination. Targeting MUC1 to B cells elicited high titer of anti-MUC1 Abs with different isotypes, predominantly IgG2a and IgG2b, in MUC1 Tg mice. The isotype switching of anti-MUC1 Ab was CD4 dependent. In addition, IFN-γ–producing CD8 T cells and in vivo cytolytic activity were significantly increased in these mice. The mice also showed significant resistance to MUC1+ lymphoma cell challenge both in the prophylactic and therapeutic settings. We conclude that Ags targeting to B cells stimulate CD4 and CD8 T-cell responses as well as Th-dependent humoral immune responses.
Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation
Authors: Paiva Bruno , Vidriales Maria-Belén , Cerveró Jorge , Mateo Gema , Pérez Jose J. , Montalbán Maria A. , Sureda Anna , Montejano Laura , Gutiérrez Norma C. , de Coca Alfonso García , de las Heras Natalia , Mateos Maria V. , López-Berges Maria C. , García-Boyero Raimundo , Galende Josefina , Hernández Jose , Palomera Luis , Carrera Dolores , Martínez Rafael , de la Rubia Javier , Martín Alejandro , Bladé Joan , Lahuerta Juan J. , Orfao Alberto , San Miguel Jesús F. 
Published: August 2008

Abstract
Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100 after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD− immunofixation-negative (IFx−) patients and MRD− IFx+ patients had significantly longer PFS than MRD+ IFx− patients. Multivariate analysis identified MRD status by MFC at day 100 after ASCT as the most important independent prognostic factor for PFS (HR = 3.64, P = .002) and OS (HR = 2.02, P = .02). Our findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM re-sponse criteria. This trial is registered at http://clinicaltrials.gov under identifier NCT00560053.
The role of neutrophils in the upper and lower respiratory tract during influenza virus infection of mice
Authors: Tate Michelle D , Brooks Andrew G , Reading Patrick C 
Published: August 2008

AbstractBackgroundNeutrophils have been shown to play a role in host defence against highly virulent and mouse-adapted strains of influenza virus, however it is not clear if an effective neutrophil response is an important factor moderating disease severity during infection with other virus strains. In this study, we have examined the role of neutrophils during infection of mice with influenza virus strain HKx31, a virus strain of the H3N2 subtype and of moderate virulence for mice, to determine the role of neutrophils in the early phase of infection and in clearance of influenza virus from the respiratory tract during the later phase of infection.MethodsThe anti-Gr-1 monoclonal antibody (mAb) RB6-8C5 was used to (i) identify neutrophils in the upper (nasal tissues) and lower (lung) respiratory tract of uninfected and influenza virus-infected mice, and (ii) deplete neutrophils prior to and during influenza virus infection of mice.ResultsNeutrophils were rapidly recruited to the upper and lower airways following influenza virus infection. We demonstrated that use of mAb RB6-8C5 to deplete C57BL/6 (B6) mice of neutrophils is complicated by the ability of this mAb to bind directly to virus-specific CD8+T cells. Thus, we investigated the role of neutrophils in both the early and later phases of infection using CD8+T cell-deficient B6.TAP-/-mice. Infection of B6.TAP-/-mice with a low dose of influenza virus did not induce clinical disease in control animals, however RB6-8C5 treatment led to profound weight loss, severe clinical disease and enhanced virus replication throughout the respiratory tract.ConclusionNeutrophils play a critical role in limiting influenza virus replication during the early and later phases of infection. Furthermore, a virus strain of moderate virulence can induce severe clinical disease in the absence of an effective neutrophil response.
HAPSIMU: a genetic simulation platform for population-based association studies
Authors: Zhang Feng , Liu Jianfeng , Chen Jie , Deng Hong-Wen 
Published: August 2008

Abstract

Background
Population structure is an important cause leading to inconsistent results in population-based association studies (PBAS) of human diseases. Various statistical methods have been proposed to reduce the negative impact of population structure on PBAS. Due to lack of structural information in real populations, it is difficult to evaluate the impact of population structure on PBAS in real populations.

Results
We developed a genetic simulation platform, HAPSIMU, based on real haplotype data from the HapMap ENCODE project. This platform can simulate heterogeneous populations with various known and controllable structures under the continuous migration model or the discrete model. Moreover, both qualitative and quantitative traits can be simulated using additive genetic model with various genetic parameters designated by users.

Conclusion
HAPSIMU provides a common genetic simulation platform to evaluate the impact of population structure on PBAS, and compare the relative performance of various population structure identification and PBAS methods.
Peripheral arterial occlusive disease: Global gene expression analyses suggest a major role for immune and inflammatory responses
Authors: Fu Shijun , Zhao Haiguang , Shi Jiantao , Abzhanov Arhat , Crawford Keith , Ohno-Machado Lucila , Zhou Jianqin , Du Yanzhi , Kuo Winston Patrick , Zhang Ji , Jiang Mier , Jin Jason Gang 
Published: August 2008

Abstract

Background
Peripheral arterial disease (PAD), a major manifestation of atherosclerosis, is associated with significant cardiovascular morbidity, limb loss and death. However, mechanisms underlying the genesis and progression of the disease are far from clear. Genome-wide gene expression profiling of clinical samples may represent an effective approach to gain relevant information.

Results
After histological classification, a total of 30 femoral artery samples, including 11 intermediate lesions, 14 advanced lesions and 5 normal femoral arteries, were profiled using Affymetrix microarray platform. Following real-time RT-PCR validation, different algorithms of gene selection and clustering were applied to identify differentially expressed genes. Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions. Of these, 116 genes were overlapped between intermediate and advanced lesions, including 68 up-regulated genes and 48 down-regulated ones. In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions). Through literature mining and pathway analysis using different databases such as Gene Ontology (GO), and the Kyoto Encyclopedia of Gene and Genomics (KEGG), genes involved in immune/inflammatory responses were significantly enriched in up-regulated genes at different stages of PAD(p < 0.05), revealing a significant correlation between immune/inflammatory responses and disease progression. Moreover, immune-related pathways such as Toll-like receptor signaling and natural killer cell mediated cytotoxicity were particularly enriched in intermediate and advanced lesions (P < 0.05), highlighting their pathogenic significance during disease progression.

Conclusion
Lines of evidence revealed in this study not only support previous hypotheses, primarily based on studies of animal models and other types of arterial disease, that inflammatory responses may influence the development of PAD, but also permit the recognition of a wide spectrum of immune/inflammatory genes that can serve as signatures for disease progression in PAD. Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.
Collagen I but not Matrigel matrices provide an MMP-dependent barrier to ovarian cancer cell penetration
Authors: Sodek Katharine L , Brown Theodore J , Ringuette Maurice J 
Published: August 2008

AbstractBackgroundThe invasive potential of cancer cells is usually assessedin vitrousing Matrigel as a surrogate basement membrane. Yet cancer cell interaction with collagen I matrices is critical, particularly for the peritoneal metastatic route undertaken by several cancer types including ovarian. Matrix metalloprotease (MMP) activity is important to enable cells to overcome the barrier constraints imposed by basement membranes and stromal matricesin vivo. Our objective was to compare matrices reconstituted from collagen I and Matrigel as representative barriers for ovarian cancer cell invasion.MethodsThe requirement of MMP activity for ovarian cancer cell penetration of Matrigel and collagen matrices was assessed in 2D transwell and 3D spheroid culture systems.ResultsThe broad range MMP inhibitor GM6001 completely prevented cell perforation of polymerised collagen I-coated transwell membranes. In contrast, GM6001 decreased ES-2 cell penetration of Matrigel by only ~30% and had no effect on HEY cell Matrigel penetration. In 3D culture, ovarian cancer cells grown as spheroids also migrated into surrounding Matrigel matrices despite MMP blockade. In contrast, MMP activity was required for invasion into 3D matrices of collagen I reconstituted from acid-soluble rat-tail collagen I, but not from pepsin-extracted collagen I (Vitrogen/Purecol), which lacks telopeptide regions.ConclusionMatrigel does not form representative barriers to ovarian cancer cells in either 2D or 3D culture systems. Our findings support the use of collagen I rather than Matrigel as a matrix barrier for invasion studies to better approximate critical interactions and events associated with peritoneal metastasis.
Charting calcium-regulated apoptosis pathways using chemical biology: role of calmodulin kinase II
Authors: Olofsson Maria Hägg , Havelka Aleksandra Mandic , Brnjic Slavica , Shoshan Maria C , Linder Stig 
Published: August 2008

AbstractBackgroundIntracellular free calcium ([Ca2+]i) is a key element in apoptotic signaling and a number of calcium-dependent apoptosis pathways have been described. We here used a chemical biology strategy to elucidate the relative importance of such different pathways.ResultsA set of 40 agents ("bioprobes") that induce apoptosis was first identified by screening of a chemical library. Using p53, AP-1, NFAT and NF-κB reporter cell lines, these bioprobes were verified to induce different patterns of signaling. Experiments using the calcium chelator BAPTA-AM showed that Ca2+was involved in induction of apoptosis by the majority of the bioprobes and that Ca2+was in general required several hours into the apoptosis process. Further studies showed that the calmodulin pathway was an important mediator of the apoptotic response. Inhibition of calmodulin kinase II (CaMKII) resulted in more effective inhibition of apoptosis compared to inhibition of calpain, calcineurin/PP2B or DAP kinase. We used one of the bioprobes, the plant alkaloid helenalin, to study the role of CaMKII in apoptosis. Helenalin induced CaMKII, ASK1 and Jun-N-terminal kinase (JNK) activity, and inhibition of these kinases inhibited apoptosis.ConclusionOur study shows that calcium signaling is generally not an early event during the apoptosis process and suggests that a CaMKII/ASK1 signaling mechanism is important for sustained JNK activation and apoptosis by some types of stimuli.