bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C
Authors: Dharel Narayan , Kato Naoya , Muroyama Ryosuke , Moriyama Masaru , Shao Run-Xuan , Kawabe Takao , Omata Masao 
Published: August 2006

Abstract
Purpose: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection.
Experimental Design: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region.
Results: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age &gt;60 years, male gender, presence of cirrhosis, serum α-fetoprotein &gt;20 μg/L, and serum albumin &lt;3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively.
Conclusions: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.
Characterization and Expression of CT45 in Hodgkin's Lymphoma
Authors: Heidebrecht Hans-Jürgen , Claviez Alexander , Kruse Marie Luise , Pollmann Marc , Buck Friedrich , Harder Sönke , Tiemann Markus , Dörffel Wolfgang , Parwaresch Reza 
Published: August 2006

AbstractPurpose: The monoclonal antibody Ki-A10 (IgG1) generated after immunization of mice with Hodgkin's lymphoma cell line L428 detects a nuclear antigen in human tissues with a restricted distribution pattern similar to cancer/testis antigens. The aim of this study was to characterize the antigen and to determine the expression profile in Hodgkin's lymphoma.Experimental Design: The half-life and phosphorylation of the antigen were determined by radiolabeling. The antigen was characterized by immunopurification and sequencing. Demethylation of genes is used to induce cancer/testis antigens. Ki-A10-negative cells were treated with 5-aza-2′-deoxycytidine. The Ki-A10 expression in paraffin-embedded tumors was determined immunohistochemically.Results: Immunopurification of the 25/22-kDa antigen and sequencing revealed a peptide of 14 amino acids corresponding to the gene product of the newly described gene family MGC27005, located on chromosome Xq26.3, now termed CT45. CT45 is significantly phosphorylated and down-regulated during mitosis. Demethylation of CT45-negative HeLa cells and stimulated peripheral blood lymphocytes induced CT45 expression. Except testis, immunohistochemical stainings of normal tissues, reactive lymphoid lesions, and most malignant tumors were negative. In comparison, 54 of 99 (55%) samples from pediatric and adolescent Hodgkin's lymphoma patients enrolled in the multicenter trial HD-95 stained Ki-A10 positive. Ki-A10 expression correlated with histologic subtypes (nodular sclerosis Hodgkin's lymphoma 68% versus mixed cellularity Hodgkin's lymphoma 40% versus nodular lymphocyte predominant Hodgkin's lymphoma 9%; P &lt; 0.001).Conclusions: Ki-A10 is the first monoclonal antibody that detects CT45. As benign lymphoid lesions did not express CT45, the use of Ki-A10 antibody will facilitate the discrimination of Hodgkin's lymphoma from reactive lymphadenopathies.
Presence of Phosphorylated Hepatocyte Growth Factor Receptor/c-Met Is Associated with Tumor Progression and Survival in Patients with Conventional Renal Cell Carcinoma
Authors: Miyata Yasuyoshi , Kanetake Hiroshi , Kanda Shigeru 
Published: August 2006

Abstract
Purpose: Hepatocyte growth factor receptor (HGFR/c-Met) signaling is associated with tumor progression in various cancers. The clinical significance and pathologic roles of phosphorylated HGFR/c-Met in renal cell carcinoma (RCC) are not fully understood; therefore, this study sought to clarify the possible role of two tyrosine residues (pY1234/pY1235 and pY1349) in HGFR/c-Met.
Experimental Design: The kinetics of tyrosine phosphorylation at these two residues was examined in a human renal carcinoma cell line, ACHN cells. In addition, phosphorylated HGFR/c-Met expression (using phosphorylation site-specific antibodies for pY1234/pY1235 and pY1349) was examined in 114 tumor sections of conventional RCC patients by immunohistochemistry. The relationships between these expressions and clinicopathologic features and survival were also investigated.
Results: Although phosphorylation of Y1349 HGFR/c-Met was observed for 120 minutes after HGF treatment of ACHN cells, maximal phosphorylation of Y1234/Y1235 was observed at 30 minutes followed by a rapid inactivation. Median rates (range) of cancer cells immunopositive for pY1234/pY1235 HGFR/c-Met and pY1349 HGFR/c-Met in the tumor sections were 0% (0-5.2%) and 14.3% (0-64.3%), respectively. Positive expression of pY1349 HGFR/c-Met was significantly associated with high pT stage, presence of metastasis, and high-grade carcinoma. Multivariate Cox analysis revealed that the positive expression of pY1349 HGFR/c-Met was a significant and an independent predictor of cause-specific survival (odds ratio, 2.94; 95% confidence interval, 1.12-7.72; P = 0.028).
Conclusions: Phosphorylated HGFR/c-Met may be important in the tumor progression of RCC. Expression of pY1349 HGFR/c-Met is a useful predictor for metastasis and survival of conventional RCC patients.
Tumor-Directed Radiation and the Immunotoxin SS1P in the Treatment of Mesothelin-Expressing Tumor Xenografts
Authors: Hassan Raffit , Williams-Gould Juanita , Steinberg Seth M. , Liewehr David J. , Yokokawa Junko , Tsang Kwong Y. , Surawski Robert J. , Scott Tamalee , Camphausen Kevin 
Published: August 2006

Abstract
Purpose: Mesothelin is a cell surface protein overexpressed in mesotheliomas and pancreatic and ovarian cancers. The goal of this study was to determine if radiation therapy in combination with the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) would result in enhanced antitumor activity against mesothelin-expressing xenografts in nude mice.
Experimental Design: Female athymic nude mice bearing s.c. mesothelin-expressing xenografts were treated with SS1P alone, tumor-focused radiation alone, or the combination of the two. Two different regimens of the combination therapy were tested. In the low-dose combination schedule, mice were treated with either 5 Gy radiation alone, 0.2 mg/kg SS1P alone, or the same doses of radiation and SS1P in combination. In the high-dose combination experiments, mice were treated with either 15 Gy radiation alone, 0.3 mg/kg SS1P alone, or the combination of radiation and SS1P.
Results: In the low-dose radiation and SS1P combination studies, mice treated with the combination of radiation and SS1P had a statistically significant prolongation in time to tumor doubling or tripling compared with control, SS1P, or radiation alone. A similar increase in time to tumor doubling or tripling was seen in mice treated with high-dose radiation and SS1P combination.
Conclusions: Combination of SS1P with tumor-directed radiation results in enhanced antitumor activity against mesothelin-expressing tumor xenografts. This effect was seen when either low or high doses of radiation were used.
Peptidome from Renal Cell Carcinoma Contains Antigens Recognized by CD4+ T Cells and Shared among Tumors of Different Histology
Authors: Tassi Elena , Facchinetti Valeria , Seresini Samantha , Borri Anna , Dell'Antonio Giacomo , Garavaglia Claudio , Casorati Giulia , Protti Maria Pia 
Published: August 2006

AbstractPurpose: Renal cell carcinoma (RCC) is considered immunogenic; nonetheless, rare tumor-associated antigens have been identified or are expressed in RCC. Peptidome (i.e., the total content of natural peptides of whole cells) from other tumors, such as melanoma, has proved to be immunogenic. The aims of this study were to determine whether peptidome from RCC is immunogenic and whether it contains tumor peptides shared among allogenic RCCs.Experimental Design: Autologous dendritic cells pulsed with RCC peptidome were used to activate in vitro CD4+ T cells from healthy donors and a metastatic RCC patient. CD4+ T-cell polyclonal lines and clones were characterized for tumor cell recognition by proliferation assay, killing activity, and cytokine secretion.Results: CD4+ T-cell lines and clones recognized HLA-DR-matched allogenic RCC and, for the patient, the autologous tumor. RCC-reactive CD4+ T cells showed a heterogeneous Th1 or Th0/Th2 pattern of cytokine secretion. Moreover, RCC-reactive CD4+ T cells recognized also melanoma, colon carcinoma, cervical carcinoma, pancreas carcinoma, lung carcinoma, gastric carcinoma, and lymphoma cells but not autologous T-cell blasts.Conclusions: Our results show that (a) the RCC peptidome contain antigens recognized by CD4+ T cells and (b) shared among tumors of different histology and (c) it induces both Th1-type and Th2/Th0-type immune responses. These data support the use of the peptidome from allogenic RCC for specific immunotherapy in RCC and possibly in other neoplastic diseases. Moreover, the CD4+ T-cell clones generated here are useful tools for tumor antigen identification.
Bcl-2 Protein in 518A2 Melanoma Cells In vivo and In vitro
Authors: Benimetskaya Luba , Ayyanar Kanyalakshmi , Kornblum Noah , Castanotto Daniela , Rossi John , Wu Sijian , Lai Johnathan , Brown Bob D. , Popova Natalia , Miller Paul , McMicken Harilyn , Chen Yin , Stein C.A. 
Published: August 2006

Abstract
Purpose: Bcl-2 is an apoptotic protein that is highly expressed in advanced melanoma. Several strategies have been employed to target the expression of this protein, including G3139, an 18-mer phosphorothioate oligodeoxyribonucleotide targeted to the initiation region of the Bcl-2 mRNA. This compound has recently completed phase III global clinical evaluation, but the function of Bcl-2 as a target in melanoma has not been completely clarified. To help resolve this question, we have permanently and stably down-regulated Bcl-2 protein and mRNA expression in 518A2 cells by two different technologies and evaluated the resulting clones both in vitro and in vivo.
Experimental Design: 518A2 melanoma cells were transfected with plasmids engineered to produce either a single-stranded antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA or a short hairpin RNA also targeted to the Bcl-2 mRNA. In vitro growth, the apoptotic response to G3139, and the G3139-induced release of cytochrome c from isolated mitochondria were evaluated. Cells were then xenografted into severe combined immunodeficient mice and tumor growth was measured.
Results: In vitro, down-regulation of Bcl-2 expression by either method produced no change either in the rate of growth or in sensitivity to standard cytotoxic chemotherapeutic agents. Likewise, the induction of apoptosis by G3139 was entirely Bcl-2 independent. In addition, the G3139-induced release from isolated mitochondria was also relatively independent of Bcl-2 expression. However, when xenografted into severe combined immunodeficient mice, cells with silenced Bcl-2, using either technology, either failed to grow at all or grew to tumors of low volume and then completely regressed. In contrast, control cells with “normal” levels of Bcl-2 protein expression expanded to be large, necrotic tumors.
Conclusions: The presence of Bcl-2 protein profoundly affects the ability of 518A2 melanoma cells to grow as human tumor xenografts in severe combined immunodeficient mice. The in vivo role of Bcl-2 in melanoma cells thus differs significantly from its in vitro role, and these experiments further suggest that Bcl-2 may be an important therapeutic target even in tumors that do not contain the t14:18 translocation.
Outcomes of Stress Fractures of the Talus
Authors: Sormaala Markus J. , Niva Maria H. , Kiuru Martti J. , Mattila Ville M. , Pihlajamäki Harri K. 
Published: August 2006

Background Stress fractures of the talus are rare, and only a few small studies have been published. In the absence of follow-up studies, the outcomes of these injuries are unknown. Hypothesis Traumatic fractures of the talus frequently heal poorly, and stress fracture healing might remain inadequate. The purpose of this study was to determine the outcome of stress fractures of the talus treated in the authors’ institution with reduced exercise and nonweightbearing. Study Design Case series (prognosis); Level of evidence, 4. Methods Patients with a diagnosed stress fracture in the talus by magnetic resonance imaging between April 1997 and March 2005 were recalled for a follow-up inspection by an orthopaedic surgeon, magnetic resonance imaging, and plain radiographs to determine the outcome of the injury. Results One of the 9 patients in our sample declined the invitation, leaving 8 patients with 9 stress fractures in the talus who participated in the follow-up examination. Five patients displayed subchondral degeneration and edema near the original injury area in the follow-up magnetic resonance imaging. In 2 patients, the degeneration was also visible on the plain radiographs. Three patients had mild and 2 moderate symptoms after the mean follow-up time of 45 months (range, 12-74 months). No serious complications in the healing process were seen. Conclusion Stress fractures of the talus do not seem to seriously damage the foot. In a middle-term follow-up, however, minor to moderate symptoms and radiological degeneration of the injured area prevailed in roughly half of the patients.
siRNA silencing of calumenin enhances functional factor IX production
Authors: Wajih Nadeem , Hutson Susan M. , Wallin Reidar 
Published: August 2006

AbstractTo improve production of functional fully γ-carboxylated recombinant human clotting factor IX (r-hFIX), cell lines stably overexpressing r-hFIX have been engineered to also overexpress proteins of the γ-carboxylation system. Here we demonstrate that siRNA silencing of calumenin, an inhibitor of the γ-carboxylation system, enhances production of functional r-hFIX produced by engineered BHK21 cells. The production yield of functional r-hFIX was 80% in engineered cells where calumenin had been silenced 78%. We propose that this high-yield expression system can easily be adapted to overproduce functional forms of all members of the vitamin K–dependent protein family.
Human SLP-65 isoforms contribute differently to activation and apoptosis of B lymphocytes
Authors: Grabbe Annika , Wienands Jürgen 
Published: August 2006

AbstractThe SH2 domain-containing leukocyte adaptor protein of 65 kDa (SLP-65) is the key effector for signaling downstream of the B-cell antigen receptor (BCR). SLP-65 controls not only B lymphopoiesis and humoral immunity but also possesses a yet poorly defined tumor suppressor activity that is lost in many cases of acute lymphoblastic leukemia. We found that the 2 isoforms of human SLP-65 are differentially involved in positive and negative B-cell signaling. Reconstitution experiments revealed that an atypical SH3 domain-binding motif, which is present in the long but not in the short SLP-65 isoform, mediates association to Grb2 and suppresses activation of mitogen-activated protein kinases p38 and JNK as well as up-regulation of c-Fos expression. In turn, the short isoform activates not only AP1-driven but also NF-κB–driven gene transcription more potently than the long isoform. Conversely, the long rather than the short SLP-65 isoform promotes BCR-induced B-cell apoptosis. Our data further delineate the structural requirements of positive and negative SLP-65 signal transduction in normal and neoplastic cells.
EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation
Authors: Pan Jingxuan , Quintás-Cardama Alfonso , Kantarjian Hagop M. , Akin Cem , Manshouri Taghi , Lamb Peter , Cortes Jorge E. , Tefferi Ayalew , Giles Francis J. , Verstovsek Srdan 
Published: August 2006

Abstract
Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.
Coordinated acquisition of inhibitory and activating receptors and functional properties by developing human natural killer cells
Authors: Grzywacz Bartosz , Kataria Nandini , Sikora Magdalena , Oostendorp Robert A. , Dzierzak Elaine A. , Blazar Bruce R. , Miller Jeffrey S. , Verneris Michael R. 
Published: August 2006

AbstractThe stages of human natural killer (NK) cell differentiation are not well established. Culturing CD34+ progenitors with interleukin 7 (IL-7), IL-15, stem cell factor (SCF), FLT-3L, and murine fetal liver cell line (EL08.1D2), we identified 2 nonoverlapping subsets of differentiating CD56+ cells based on CD117 and CD94 (CD117highCD94– and CD117low/–CD94+ cells). Both populations expressed CD161 and NKp44, but differed with respect to NKp30, NKp46, NKG2A, NKG2C, NKG2D, CD8, CD16, and KIR. Only the CD117low/– CD94+ population displayed cytotoxicity and interferon-γ production. Both populations arose from a single CD34+CD38– Lin– cell and their percentages changed over time in a reciprocal fashion, with CD117highCD94– cells predominating early and decreasing due to an increase of the CD117low/–CD94+ population. These 2 subsets represent distinct stages of NKcell differentiation, since purified CD117high CD94– cells give rise to CD117low/–CD94+ cells. The stromal cell line (EL08.1D2) facilitated the transition from CD117highCD94– to CD117low/–CD94+ via an intermediate phenotype (CD117lowCD94low/–). EL08.1D2 also maintained the mature phenotype, preventing the reversion of CD117low/–CD94+ cells to the intermediate (CD117lowCD94low/–) phenotype. An analogous population of CD56+CD117highCD94– cells was found in cord blood. The identified stages of NK-cell differentiation provide evidence for coordinated acquisition of HLA-specific inhibitory receptors (ie, CD94/NKG2A) and function in developing human NK cells.
Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100
Authors: Shepherd Rebecca M. , Capoccia Benjamin J. , Devine Steven M. , DiPersio John , Trinkaus Kathryn M. , Ingram David , Link Daniel C. 
Published: August 2006

AbstractCirculating endothelial progenitor cells (EPCs) are thought to contribute to angiogenesis following vascular injury, stimulating interest in their ability to mediate therapeutic angiogenesis. However, the number of EPCs in the blood is low, limiting endogenous repair, and a method to rapidly mobilize EPCs has not been reported. In this study, healthy donors were mobilized sequentially with the CXCR4 antagonist, AMD3100, and G-CSF. The number of EPCs and circulating angiogenic cells (CACs) in the blood and pheresis product was determined and the angiogenic capacity of each cell population assessed. Compared with baseline, treatment with AMD3100 or G-CSF increased the number of blood CACs 10.0-fold ± 4.4-fold and 8.8-fold ± 3.7-fold, respectively. The number of EPCs in the blood increased 10.2-fold ± 3.3-fold and 21.8-fold ± 5.4-fold, respectively. On a percell basis, CACs harvested from G-CSF–mobilized blood displayed increased in vivo angiogenic potential compared with AMD3100-mobilized CACs. Mobilized EPCs displayed a greater proliferative capacity than EPCs isolated from baseline blood. Both CACs and EPCs were efficiently harvested by leukapheresis. Cryopreserved CACs but not EPCs retained functional activity after thawing. These data show that AMD3100 is a potent and rapid mobilizer of angiogenic cells and demonstrate the feasibility of obtaining and storing large numbers of angiogenic cells by leukapheresis.
Genome comparison using Gene Ontology (GO) with statistical testing
Authors: Cai Zhaotao , Mao Xizeng , Li Songgang , Wei Liping 
Published: August 2006

AbstractBackgroundAutomated comparison of complete sets of genes encoded in two genomes can provide insight on the genetic basis of differences in biological traits between species. Gene ontology (GO) is used as a common vocabulary to annotate genes for comparison. Current approaches calculate the fold of unweighted or weighted differences between two species at the high-level GO functional categories. However, to ensure the reliability of the differences detected, it is important to evaluate their statistical significance. It is also useful to search for differences at all levels of GO.ResultsWe propose a statistical approach to find reliable differences between the complete sets of genes encoded in two genomes at all levels of GO. The genes are first assigned GO terms from BLAST searches against genes with known GO assignments, and for each GO term the abundance of genes in the two genomes is compared using a chi-squared test followed by false discovery rate (FDR) correction. We applied this method to find statistically significant differences between two cyanobacteria,Synechocystissp. PCC6803 andAnabaenasp. PCC7120. We then studied how the set of identified differences vary when different BLAST cutoffs are used. We also studied how the results vary when only subsets of the genes were used in the comparison of humanvs. mouse and that ofSaccharomyces cerevisiaevs.Schizosaccharomyces pombe.ConclusionThere is a surprising lack of statistical approaches for comparing complete genomes at all levels of GO. With the rapid increase of the number of sequenced genomes, we hope that the approach we proposed and tested can make valuable contribution to comparative genomics.