bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helicobacter Infection Is Required for Inflammation and Colon Cancer in Smad3-Deficient Mice
Authors: Maggio-Price Lillian , Treuting Piper , Zeng Weiping , Tsang Mark , Bielefeldt-Ohmann Helle , Iritani Brian M. 
Published: January 2006

Abstract
Accumulating evidence suggests that intestinal microbial organisms may play an important role in triggering and sustaining inflammation in individuals afflicted with inflammatory bowel disease (IBD). Moreover, individuals with IBD are at increased risk for developing colorectal cancer, suggesting that chronic inflammation may initiate genetic or epigenetic changes associated with cancer development. We tested the hypothesis that bacteria may contribute to the development of colon cancer by synergizing with defective transforming growth factor-β (TGF-β) signaling, a pathway commonly mutated in human colon cancer. Although others have reported that mice deficient in the TGF-β signaling molecule SMAD3 develop colon cancer, we found that SMAD3-deficient mice maintained free of the Gram-negative enterohepatic bacteria Helicobacter spp. for up to 9 months do not develop colon cancer. Furthermore, infection of SMAD3−/− mice with Helicobacter triggers colon cancer in 50% to 66% of the animals. Using real-time PCR, we found that Helicobacter organisms concentrate in the cecum, the preferred site of tumor development. Mucinous adenocarcinomas develop 5 to 30 weeks after infection and are preceded by an early inflammatory phase, consisting of increased proliferation of epithelial cells; increased numbers of cyclooxygenase-2–positive cells, CD4+ T cells, macrophages; and increased MHC class II expression. Colonic tissue revealed increased transcripts for the oncogene c-myc and the proinflammatory cytokines interleukin-1α (IL-1α), IL-1β, IL-6, IFN-γ, and tumor necrosis factor-α, some of which have been implicated in colon cancer. These results suggest that bacteria may be important in triggering colorectal cancer, notably in the context of gene mutations in the TGF-β signaling pathway, one of the most commonly affected cellular pathways in colorectal cancer in humans. (Cancer Res 2006; 66(2): 828-38)
Increased Expression of Osteopontin Contributes to the Progression of Prostate Cancer
Authors: Khodavirdi Ani C. , Song Zhigang , Yang Shangxin , Zhong Chen , Wang Shunyou , Wu Hong , Pritchard Colin , Nelson Peter S. , Roy-Burman Pradip 
Published: January 2006

Abstract
Osteopontin is a secreted glycosylated phosphoprotein known to be involved in numerous physiologic functions and associated with the late stages of various cancers. We used preneoplastic and neoplastic mouse models of prostate cancer to determine the onset of elevated expression of osteopontin in the development of this disease. Osteopontin alterations occurred early in the disease with dysregulated expression observed in lesions of low-grade prostatic intraepithelial neoplasia (PIN). Over time, osteopontin expressing dysplastic cells seemed to increase in number in high-grade PIN and increased further in adenocarcinoma, and in metastasis, almost all of the cancer cells immunohistochemically stained positive for osteopontin overexpression. We examined the biological properties of human prostate cancer cell lines LNCaP and PC-3, in which osteopontin overexpression was achieved via lentiviral gene transduction. Evidence was obtained that osteopontin could contribute to a proliferative advantage in both cell types, although more significantly in LNCaP than PC-3. Osteopontin also influenced their in vitro invasive ability, and again, most strikingly in the weakly oncogenic LNCaP. Furthermore, excess osteopontin induced the LNCaP cells to acquire a strong intravasation potential in vivo in the chicken embryo chorioallantoic membrane assay for blood vessel penetration. These results establish a correlation between an increased gradient of osteopontin expression throughout the stages of murine prostate cancer, beginning from the preneoplastic lesions to distant metastases that suggests a proliferative and invasive advantages to those prostate tumor cells overexpressing osteopontin. Together, these findings support a strategy designed to target osteopontin in the context of prostate cancer therapy. (Cancer Res 2006; 66(2): 883-8)
Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia
Authors: Li Shu , Zhou Bin , Han Zhong 
Published: January 2006

SummaryAutolougous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized human peripheral blood mononuclear cells (PBMNCs) improves limb ischemia in patients with arteriosclerosis obliterans of lower extremities and with diabetic foot. However, the mechanism of action of PBMNCs remains elusive. Here, we studied comparatively the effects of the G-CSF-mobilized PBMNCs and CD34-depleted G-CSF-mobilized PBMNCs in an ischemia model of athymic nude mice. Fluorescence-labeled human PBMNCs [1×106] were intramuscularly injected into the unilateral ischemic hindlimbs of mice. Laser Doppler imaging analysis revealed a significantly augmented blood perfusion at day 7, 14 and 28 after operation. The capillary density was also markedly increased and the rate of limb loss was significantly reduced in cell-transplanted groups when compared with those in PBS group. In comparison with G-CSF-mobilized PBMNCs, the therapeutic efficiency of G-CSF-mobilized PBMNCs deprived of CD34+ cells was impaired. Transplanted cells were found to accumulate around arterioles and scatter in capillary networks. Incorporation of transplanted cells into new capillaries was observed in the G-CSF-mobilized PBMNCs group, but was not detected in the group deprived of CD34+ cells. There was an elevated expression of VEGF in ischemic tissue. Colocalization of VEGF and transplanted mononuclear cells within adductor tissue was demonstrated. These findings indicate that G-CSF-mobilized PBMNCs promote vascular growth not only by incorporating into vessel walls but also by supplying angiogenic factors. The depletion of CD34+ cells attenuated the therapeutic efficiency of G-CSF-mobilized PBMNCs in response to ischemia-induced neovascularization.
Pre-treatment with clopidogrel and postprocedure troponin elevation after elective percutaneous coronary intervention
Authors: Nienhuis Mark , Miedema Kor , Suryapranata Harry , de Boer Menko-Jan , Dambrink Jan-Henk , Hoorntje Jan , van ’t Hof Arnoud , Gosselink Marcel , Zijlstra Felix , Ottervanger Jan 
Published: January 2006

SummaryElevated troponin after elective percutaneous coronary intervention (PCI) has been associated with a worse prognosis. Pretreatment with clopidogrel may be beneficial in patients undergoing PCI. Therefore, a prospective observational study was conducted to address the potential role of clopidogrel in reducing troponin release after elective PCI. TroponinT was measured 12 hours after elective PCI in 656 patients without elevated troponin before PCI. To assess the independent association between pre-treatment with clopidogrel and increased troponin, multivariate analyses were performed. Mean age of the 656 patients was 63.5 years (SD 10.2), 194 patients (30%) were female and 114 patients (17.4%) had diabetes. In 217 patients (33%) troponin was increased after PCI. Of the 330 patients who were not pre-treated with clopidogrel, 118 patients (34%) had increased troponin after the PCI compared to 99 patients (30%) of the 326 patients who were treated with clopidogrel longer than 24 hours before the procedure (p=0.14). Stratified analyses showed that patients with older age (p=0.03), previous PCI (p=0.013), angina CCS 4 (p=0.03) and multivessel disease (p=0.04) had a significantly lower risk of troponin increase after pre-treatment with clopidogrel compared to patients without pre-treatment. After adjusting for differences in the other variables, patients who were pre-treated with clopidogrel had a significant lower risk of post-PCI increase of troponinT (odds ratio 0.69, 95% confidence interval 0.49–0.99). Pre-treatment with clopidogrel is associated with a significantly lower incidence of increased troponin after elective PCI. Combined with results of other studies, pre-treatment should be advised in patients waiting for elective PCI.
Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C
Authors: Sieghart Wolfgang , Homoncik Monika , Jilma Bernd , Formann Elisabeth , Ferenci Peter , Gangl Alfred , Peck-Radosavljevic Markus 
Published: January 2006

SummaryInterferon alpha (IFN-α) is used to treat haematological and solid malignancies and is the gold standard therapy for chronic hepatitisC infection in combination with ribavirin. It has a well known platelet lowering effect and was recently shown to impair platelet aggregation in the presence of various agonists and has been accused to increase patients’ bleeding risk during IFN-α therapy. Thus, we hypothesised that antiviral treatment decreases GpIIb/IIIa activation and affects global platelet function. In a prospective clinical trial, we examined the effects of combination therapy with pegylated IFN-α 2a (PegIFN-α 2a) and ribavirin on platelet GpIIb/IIIa activation and platelet secretion in 20 patients with chronic hepatitis C at week 2, 4, 8 and 12 after the beginning of therapy. In addition, we determined global platelet function (CEPI-CT) with the PFA-100 and vWF-Ag levels. Antiviral therapy significantly decreased GpIIb/IIIa activation in a time dependent manner, whereas markers of platelet secretion (P-selectin, β-thromboglobulin) remained unchanged. Despite a marked elevation of vWF-Ag levels, CEPI-CT did not change compared to baseline levels. Antiviral therapy significantly decreases GpIIb/IIIa activation in patients with chronic hepatitis C, while vWG-Antigen levels are markedly increased and α-granule secretion is not affected. This does not result in an alteration of global platelet function as assessed by the PFA-100, because elevated vWF-Antigen levels might compensate for the acquired defect.
Characteristics and Outcome of Diffuse Large B-Cell Lymphoma in Hepatitis C Virus–Positive Patients in LNH 93 and LNH 98 Groupe d'Etude des Lymphomes de l'Adulte Programs
Authors: Besson Caroline , Canioni Danielle , Lepage Eric , Pol Stanislas , Morel Pierre , Lederlin Pierre , Van Hoof Achiel , Tilly Hervé , Gaulard Philippe , Coiffier Bertrand , Gisselbrecht Christian , Brousse Nicole , Reyes Félix , Hermine Olivier 
Published: January 2006

Purpose Epidemiologic studies show an association between hepatitis C virus (HCV) and B-cell non-Hodgkin's lymphoma (NHL). Treatment and outcome of patients with diffuse large-cell lymphoma (DLCL) and HCV infection are still a matter of debate. Patients and Methods We studied the HCV-positive patients with B-cell DLCL included in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) programs LNH 93 and LNH 98. They were compared with the other patients with DLCL included in these programs. HCV infection prevalence was 0.5% (26 of 5,586 patients). Results Histologic types of HCV-positive DLCL were more frequently transformed from low-grade lymphoma than DLCL in HCV-negative patients (32% v 6%, P = .02). This is also supported by more frequent spleen involvement in HCV-positive patients (46% v 17%, P < .001). HCV-positive patients had more frequently elevated lactate dehydrogenase levels than other patients (77% v 55%, P = .02). Outcome of HCV-positive patients was poorer for overall survival (P = .02) but not for event-free survival (P = .13). After matching on age and prognosis factors, at 2 years of follow-up, the overall survival was 56% (95% CI, 33% to 76%) among HCV-positive patients, versus 80% (70% to 89%), and the event-free survival was 53% (33% to 72%) versus 74% (64% to 84%). The short-term hepatic toxicity of chemotherapy was strongly increased among HCV-positive patients. After exclusion of the two subjects with chronic hepatitis B virus infection, the overall proportion of subjects undergoing hepatic toxicity was 65% (15 of 23 patients). Conclusion HCV-positive patients with DLCL differ from other patients both at presentation and during chemotherapy. Specific protocols evaluating antiviral therapy should be designed for these patients.
BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications
Authors: Baldus Claudia D. , Thiede Christian , Soucek Silke , Bloomfield Clara D. , Thiel Eckhard , Ehninger Gerhard 
Published: January 2006

Purpose Evaluate the impact of BAALC (brain and acute leukemia, cytoplasmic), a gene whose expression has been associated with adverse outcome in acute myeloid leukemia (AML) with normal cytogenetics, and FLT3 internal tandem duplication (ITD) mutations as independent prognostic factors in a larger study. Patients and Methods BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in pretreatment blood samples of 307 adults ≤ 60 years of age with AML with normal cytogenetics. Patients were dichotomized at BAALC's median expression into low and high expressers. The FLT3 ITD mutant:wild-type ratio was determined by fragment analysis. Results Compared with low-BAALC patients, high-BAALC patients had a higher rate of primary resistant leukemia (16% v 6%; P = .006). High BAALC expression was associated with a higher cumulative incidence of relapse (CIR; P = .018) and an inferior overall survival (OS; 3-year OS, 36% v 54%; P = .001). On multivariable analysis, high BAALC was independently predictive of resistant disease (P = .019), and high BAALC as well as a high FLT3 mutant:wild-type ratio were confirmed as the only factors predicting a high CIR (BAALC, P = .03; FLT3, P = .01) and inferior OS (BAALC, P = .001; FLT3, P = .012). Conclusion This study strengthens BAALC expression as one of the most important prognostic factors in AML patients with normal cytogenetics. BAALC expression and FLT3 mutation status should assist in tailoring induction and postremission therapies.
Endogenous Markers of Two Separate Hypoxia Response Pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) Are Associated With Radiotherapy Failure in Head and Neck Cancer Patients Recruited in the CHART Randomized Trial
Authors: Koukourakis Michael I. , Bentzen Søren M. , Giatromanolaki Alexandra , Wilson George D. , Daley Frances M. , Saunders Michele I. , Dische Stanley , Sivridis Efthimios , Harris Adrian L. 
Published: January 2006

PurposeRandomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial. There are two distinct hypoxia inducible factors (HIFs) that control different gene response pathways and we assessed them both with endogenous markers of hypoxia, hypoxia inducible factor HIF-2 alpha (HIF-2) and carbonic anhydrase CA9, an indicator of HIF-1 alpha (HIF-1) function.MethodsTissue from pre-RT biopsies performed in 198 of 918 patients recruited was analyzed for the immunohistochemical expression of HIF-2 and CA9.ResultsA significant association of high HIF2 and of high CA9 reactivity with poor locoregional control (P < .0001 and P = .0002, respectively) and poor survival (P = .0004 and 0.002, respectively) was noted. In multivariate analysis, HIF-2 and CA9 maintained their independent prognostic significance. Coexpression of both pathways had an additive effect, supporting their independent role. The uni-directional hypothesis, that a benefit from randomization to CHART should be seen in the nonhypoxic tumors, was supported by the data (one-tailed P = .04).ConclusionExpression of endogenous markers of hypoxia for the HIF-1 and HIF-2 pathway is strongly associated with radiotherapy failure. Using immunohistochemical methods it is possible to identify subgroups of HNSCC patients who are highly curable with radiotherapy, or who are excellent candidates for clinical trials on hypoxia-targeting drugs in two distinct pathways.
BCL2 Expression Is a Prognostic Marker for the Activated B-Cell–Like Type of Diffuse Large B-Cell Lymphoma
Authors: Iqbal Javeed , Neppalli Vishala T. , Wright George , Dave Bhavana J. , Horsman Douglas E. , Rosenwald Andreas , Lynch James , Hans Christine P. , Weisenburger Dennis D. , Greiner Timothy C. , Gascoyne Randy D. , Campo Elias , Ott German , Müller-Hermelink H. Konrad , Delabie Jan , Jaffe Elaine S. , Grogan Thomas M. , Connors Joseph M. , Vose Julie M. , Armitage James O. , Staudt Louis M. , Chan Wing C. 
Published: January 2006

Background The role of BCL2 as a predictor of survival in diffuse large B-cell lymphoma (DLBCL) is controversial. DLBCL is heterogeneous, and the expression of BCL2 is variable within the two major subgroups of DLBCL, germinal center B-cell–like (GCB) and activated B-cell–like (ABC) DLBCL, as well as primary mediastinal DLBCL. Patients and Methods In this study, we investigated the correlation of BCL2 expression with survival in the two major subgroups of DLBCL, as well as the mechanisms of BCL2 expression. Results There was no significant correlation between BCL2 protein expression and overall survival within the GCB subgroup, but BCL2 expression had a significant adverse effect on overall survival within the ABC subgroup (P = .008). This correlation was also observed at the mRNA level (P < .04). The difference remained significant when the analyses were performed at different cutoff values. The t(14;18) was frequently observed in the GCB subgroup and was highly associated with BCL2 expression. Patients with ABC DLBCL did not exhibit t(14;18) but had a markedly higher frequency of chromosome 18q21 amplification, on which BCL2 resides. Thus, alternative mechanisms such as 18q21 amplification or activation of the nuclear factor-kappa B pathway, as reported previously, seem to be mainly responsible for the upregulation of BCL2 expression in the ABC subgroup. Conclusion Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.
Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia
Authors: Kröber Alexander , Bloehdorn Johannes , Hafner Sebastian , Bühler Andreas , Seiler Till , Kienle Dirk , Winkler Dirk , Bangerter Markus , Schlenk Richard F. , Benner Axel , Lichter Peter , Döhner Hartmut , Stilgenbauer Stephan 
Published: January 2006

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.
Thromboembolism in Hospitalized Neutropenic Cancer Patients
Authors: Khorana Alok A. , Francis Charles W. , Culakova Eva , Fisher Richard I. , Kuderer Nicole M. , Lyman Gary H. 
Published: January 2006

Purpose Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized cancer patients receiving current chemotherapy regimens is not known. We investigated venous and arterial thromboembolism and associated outcomes in hospitalized cancer patients actively receiving therapy, as identified by neutropenia. Methods We conducted a retrospective cohort study using the discharge database of the University HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074 hospitalizations between 1995 and 2002 at 115 medical centers in the United States. Results Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous thromboembolism and 1.5% developing arterial thromboembolism during the first hospitalization. Patients with lymphoma and leukemia accounted for one third of venous and nearly one half of arterial events. Clinical variables most frequently associated with thromboembolism were age ≥ 65 years; primary site of cancer, including lung, GI, gynecologic, and brain; and comorbidities, including infection, pulmonary and renal disease, and obesity. In-hospital mortality was significantly greater in patients with venous (odds ratio [OR] = 2.01; 95% CI, 1.83 to 2.22) or arterial thromboembolism (OR = 5.04; 95% CI, 4.38 to 5.79). From 1995 to 2002, there was a 36% increase in venous events and a 124% increase in arterial events (P < .0001 for trend). Conclusion Thromboembolism is frequent in hospitalized neutropenic cancer patients, including in perceived low-risk subgroups such as patients with hematologic malignancies and nonmetastatic disease, and seems to be increasing. Thromboembolism is associated with increased in-hospital mortality. Increased efforts at thromboprophylaxis are warranted.