bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Therapeutic Responses in a Xenograft Model of Human B Lymphoma (Namalwa) for Liposomal VincristineversusLiposomal Doxorubicin Targeted via Anti-CD19 IgG2a or Fab′ Fragments
Authors: Sapra Puja , Moase Elaine H. , Ma Jie , Allen Theresa M. 
Published: September 2005

AbstractPurpose: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates.Experimental Design: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[αCD19]) or its Fab′ fragments (SIL[Fab′]). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model.Results: SIL[αCD19] or SIL[Fab′] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab′] had longer circulation times than SIL[αCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab′] had better therapeutic outcomes than SIL[αCD19] for the drug DXR but were equally efficacious for the drug VCR.Conclusions: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab′] versus SIL[αCD19] led to superior therapeutics for DXR-loaded immunoliposomes.
A Phase II Trial of Flavopiridol (NSC #649890) in Patients with Previously Untreated Metastatic Androgen-Independent Prostate Cancer
Authors: Liu Glenn , Gandara David R. , Lara Primo N. , Raghavan Derek , Doroshow James H. , Twardowski Przemyslaw , Kantoff Philip , Oh William , Kim KyungMann , Wilding George 
Published: September 2005

Abstract
Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer.
Experimental Design: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m2/day. Dose escalation up to 60 mg/m2/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent.
Results: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident.
Conclusions: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.
Vaccination of Patients with Advanced Ovarian Carcinoma with the Anti-Idiotype ACA125
Authors: Reinartz Silke , Köhler Siegmund , Schlebusch Harald , Krista Karl , Giffels Patrick , Renke Kirsten , Huober Jens , Möbus Volker , Kreienberg Rolf , duBois Andreas , Sabbatini Paul , Wagner Uwe 
Published: September 2005

Abstract
Purpose: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity.
Experimental Design: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses.
Results: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1′) and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5–56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P &lt; 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred.
Conclusions: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.
Autoreactive, Cytotoxic T Lymphocytes Specific for Peptides Derived from Normal B-Cell Differentiation Antigens in Healthy Individuals and Patients with B-Cell Malignancies
Authors: Grube Matthias , Rezvani Katayoun , Wiestner Adrian , Fujiwara Hiroshi , Sconocchia Giuseppe , Melenhorst Jan J. , Hensel Nancy , Marti Gerald E. , Kwak Larry W. , Wilson Wyndham , Barrett John A. 
Published: September 2005

AbstractPurpose: To investigate potential immunotherapeutic strategies in B lymphocytic malignancies we looked for CTLs recognizing CD19 and CD20 epitopes.Experimental Design: Three CD19 and CD20 peptides binding to HLA-A*0201 were identified and used to detect peptide specific CTLs by a quantitative real-time PCR to measure IFN-γ mRNA expression in 23 healthy individuals and 28 patients (18 chronic lymphocytic leukemia (CLL), 7 follicular lymphoma, 2 acute lymphocytic leukemia, and 1 large cell lymphoma). Peptide-specific CTLs were expanded in culture with CD40-activated B cells to test lytic activity in three patients.Results: In healthy individuals, CD8+ T-cell responses were detected in one to CD1974–82, in three to CD20127–135, and three to CD20188–196. Seven of 27 patients (6 with CLL) had CD8+ T cells recognizing CD1974–82. Seven patients responded to CD20127–135 and three to CD20188–196. All were CLL patients. CD1974–82-specific CTLs from three patients were expanded over 4 weeks. These cells were HLA-A*0201 specific and lytic for peptide-loaded antigen-presenting cells but not to malignant or unpulsed B cells.Conclusions: CTLs that recognize CD19 and CD20 epitopes exist in healthy individuals and may be increased in CLL patients. They are of low avidity and require high doses of peptide for activation. Strategies to increase T-cell avidity would be necessary for T-cell immunotherapeutic approaches using the peptides studied.
Clinical Significance of Intracytoplasmic nm23-H1 Expression in Diffuse Large B-Cell Lymphoma
Authors: Niitsu Nozomi , Nakamine Hirokazu , Okamoto Masataka , Akamatsu Hiroko , Higashihara Masaaki , Honma Yoshio , Okabe-Kado Junko , Hirano Masami 
Published: September 2005

Abstract
Purpose: Recently, we established an ELISA technique for measuring nm23-H1 protein in serum and found that the serum nm23-H1 level is a potential prognostic factor for patients with non-Hodgkin’s lymphoma.
Experimental Design: We used immunohistochemistry to examine the expression of nm23-H1 by the lymphoma cells in patients with diffuse large B-cell lymphoma (DLBCL).
Results: By analyzing a consecutive series of 172 untreated DLBCL patients, we found that 100 (58.1%) were strongly positive. The cytoplasmic nm23 expression in lymphoma cells correlated significantly with the serum nm23-H1 level. There was a significant correlation between patients with cytoplasmic nm23-positive lymphoma and those with performance status 2–4, stage III/IV, bulky mass, B symptoms, elevated serum level of soluble interleukin 2 receptor, and elevated serum level of C-reactive protein. Overall and progression-free survival rates were significantly lower in patients with nm23-H1-positive lymphomas than in those with nm23-H1-negative lymphomas. Similar difference was seen between patients with high and low serum levels of nm23-H1. Thus, the correlation between presence or absence of cytoplasmic nm23-H1 expression and serum nm23-H1 levels suggests that serum nm23-H1 is produced directly by lymphoma cells.
Conclusion: We suggest that nm23-H1 expression is a prognostic factor for DLBCL, and that it is as important as serum nm23-H1, both of which are useful for planning a treatment strategy.
Pleomorphic Characteristics of a Germ-Line
KIT
Mutation in a Large Kindred with Gastrointestinal Stromal Tumors, Hyperpigmentation, and Dysphagia
Authors: Robson Mark E. , Glogowski Emily , Sommer Gunhild , Antonescu Cristina R. , Nafa Khedoudja , Maki Robert G. , Ellis Nathan , Besmer Peter , Brennan Murray , Offit Kenneth 
Published: September 2005

Abstract
Purpose: Somatic mutations that result in the activation of the growth factor receptor KIT are commonly found in gastrointestinal stromal tumors (GISTs). Six families have been reported in which a germ-line mutation in KIT is associated with an autosomal dominant predisposition to the development of GISTs. Hyperpigmentation, urticaria pigmentosa, and dysphagia have been described in some, but not all, families. Preliminary correlations between the site of mutation and the clinical phenotype have been proposed, but the strength of these associations is not defined.
Design: A large kindred with multiple GISTs, hyperpigmentation, and dysphagia was identified after the index case presented with multiple GISTs. A germ-line mutation in KIT (W557R) was identified in an affected cousin, after which a large family meeting was held and testing offered. Clinical data were obtained by interview and, whenever possible, medical record documentation.
Results: To date, 19 individuals have been tested, and the mutation has been shown to cosegregate with the syndrome. The phenotypic expression, however, is variable. GISTs, often presenting as upper gastrointestinal bleeding, and hyperpigmentation are common, but not diagnosed in all documented or obligate carriers. Dysphagia is a less prevalent complaint. The diagnosis of GISTs appears to be made at a younger age in more recent generations. Metastatic disease is uncommon.
Conclusions: A germ-line mutation in KIT resulting in an amino acid substitution in the juxtamembrane region is associated with a syndrome of GIST, hyperpigmentation, and dysphagia, although the prominence of each component varies.
Phospho-Serine-118 Estrogen Receptor-α Detection in Human Breast Tumors
in Vivo
Authors: Murphy Leigh , Cherlet Tracy , Adeyinka Adewale , Niu Yulian , Snell Linda , Watson Peter 
Published: September 2005

Abstract
Purpose: To determine whether estrogen receptor (ER)-α specifically phosphorylated at Ser118 is detectable in multiple human breast cancer biopsy samples. To gain insight into possible roles for P-Ser118-ERα in human breast cancer in vivo.
Experimental Design: A specific antibody for P-Ser118-ERα was validated for immunohistochemistry (IHC), and Western blot analysis confirmed IHC results. IHC was used to determine the relationship of P-Ser118-ERα to known prognostic markers and active mitogen-activated protein kinase (MAPK; erk1/2) expression.
Results: P-Ser118-ERα was significantly correlated with the expression of total ER, determined by ligand binding assay (r = 0.442, P = 0.002), but not with progesterone receptor expression or nodal status. P-Ser118-ERα was inversely correlated with histological grade (r = −0.34, P = 0.023), reflecting a similar trend for total ER (r = −0.287, P = 0.056). Categorical contingency analysis confirmed that P-Ser118-ERα was more frequently associated with lower than higher grade breast tumors (P = 0.038). In addition P-Ser118-ERα was significantly associated with detection of active MAPK (Erk1/2; Spearman r = 0.649, P &lt; 0.0001; Fisher’s exact test, P = 0.0004).
Conclusions: P-Ser118-ERα detection is associated with a more differentiated phenotype and other markers of good prognosis in human breast cancer. P-Ser118-ERα is correlated with active MAPK in human breast tumor biopsies, suggesting the possibility that active MAPK either directly or indirectly has a role in the regulation of P-Ser118-ERα expression in vivo. These data provide evidence for a role of P-Ser118-ERα in human breast cancer in vivo.
Detection of Bladder Cancer in Urine by a Tumor Suppressor Gene Hypermethylation Panel
Authors: Dulaimi Essel , Uzzo Robert G. , Greenberg Richard E. , Al-Saleem Tahseen , Cairns Paul 
Published: September 2005

Abstract
Purpose: Bladder cancer is potentially curable in the majority of cases; however, the prognosis for patients with advanced disease at presentation remains poor. Current noninvasive tests such as cytology lack sufficient sensitivity to detect low-grade, low-stage tumors. Silencing of tumor suppressor genes, such as p16INK4a, VHL, and the mismatch repair gene hMLH1, has established promoter hypermethylation as a common mechanism for tumor suppressor inactivation in human cancers. It is also a promising new target for molecular detection in bodily fluids including urine, a readily accessible fluid known to contain bladder cancer cells. Methylation-specific PCR (MSP) can determine the presence or absence of methylation of a gene locus at a sensitivity level of up to 1 methylated allele in 1000 unmethylated alleles, appropriate for identifying cancer cell DNA in a bodily fluid.
Experimental Design: We first determined the frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite sequencing and of the p16INK4a, p14ARF, APC, and RASSF1A tumor suppressor genes by MSP in 45 bladder cancers. We then designed a panel optimal for diagnostic coverage composed of the APC, RASSF1A, and p14ARF tumor suppressor genes. This panel was tested for detection of hypermethylation in matched sediment DNA from urine specimens obtained before surgery from the same 45 bladder cancer patients (2 Tis, 16 Ta, 10 T1, and 17 T2–4) as well as normal and benign control DNAs.
Results: Hypermethylation of at least one of three suppressor genes (APC, RASSF1A, and p14ARF) was found in all 45 tumor DNAs (100% diagnostic coverage). We detected gene hypermethylation in the matched urine DNA from 39 of 45 patients (87% sensitivity), including 16 cases that had negative cytology. No hypermethylation of APC, RASSF1A, or p14ARF was observed in normal transitional cell DNAs or in urine DNAs from normal healthy individuals and patients with inflammatory urinary disease (cystitis). Furthermore, an unmethylated gene in the tumor DNA was always found to be unmethylated in the matched urine DNA (100% specificity).
Conclusions: Promoter hypermethylation of tumor suppressor genes is common in bladder cancer and was found in all grades and stages of tumors examined. Hypermethylation was detected in the urine DNA from 39 of 45 (87%) patients, including cases of early-stage disease amenable to cure. MSP may enhance early detection of bladder cancer using a noninvasive urine test.
Identifying Superficial, Muscle-Invasive, and Metastasizing Transitional Cell Carcinoma of the Bladder
Authors: Modlich Olga , Prisack Hans-Bernd , Pitschke Gerald , Ramp Uwe , Ackermann Rolf , Bojar Hans , Vögeli Thomas A. , Grimm Marc-Oliver 
Published: September 2005

Abstract
Purpose: Expression profiling by DNA microarray technology permits the identification of genes underlying clinical heterogeneity of bladder cancer and which might contribute to disease progression, thereby improving assessment of treatment and prediction of patient outcome.
Experimental Design: Invasive (20) and superficial (22) human bladder tumors from 34 patients with known outcome regarding disease recurrence and progression were analyzed by filter-based cDNA arrays (Atlas Human Cancer 1.2; BD Biosciences Clontech) containing 1185 genes. For 9 genes, array data were confirmed using real-time reverse transcription-PCR. Additionally, Atlas array data were validated using Affymetrix GeneChip oligonucleotide arrays with 22,283 human gene fragments and expressed sequence tags sequences in a subset of three superficial and six invasive bladder tumors.
Results: A two-way clustering algorithm using different subsets of gene expression data, including a subset of 41 genes validated by the oligonucleotide array (Affymetrix), classified tumor samples according to clinical outcome as superficial, invasive, or metastasizing. Furthermore, (a) a clonal origin of superficial tumors, (b) highly similar gene expression patterns in different areas of invasive tumors, and (c) an invasive-like pattern was observed in bladder mucosas derived from patients with locally advanced disease. Several gene clusters that characterized invasive or superficial tumors were identified. In superficial bladder tumors, increased mRNA levels of genes encoding transcription factors, molecules involved in protein synthesis and metabolism, and some proteins involved into cell cycle progression and differentiation were observed, whereas transcripts for immune, extracellular matrix, adhesion, peritumoral stroma and muscle tissue components, proliferation, and cell cycle controllers were up-regulated in invasive tumors.
Conclusions: Gene expression profiling of human bladder cancers provides insight into the biology of bladder cancer progression and identifies patients with distinct clinical phenotypes.
Intratumoral Vaccination and Diversified Subcutaneous/ Intratumoral Vaccination with Recombinant Poxviruses Encoding a Tumor Antigen and Multiple Costimulatory Molecules
Authors: Kudo-Saito Chie , Schlom Jeffrey , Hodge James W. 
Published: September 2005

Abstract
Purpose: Intratumoral (i.t.) vaccination represents a potential modality for the therapy of tumors. Previous i.t. vaccination studies have focused on the efficacy of i.t. vaccination alone. There are no reports that clearly compared i.t. vaccination with systemic vaccination achieved by s.c., intradermal, or i.m. injection, or combining both modalities of systemic and i.t. vaccination. Here, we compared the antitumor effects induced by a systemic vaccination regimen (s.c.) and i.t. vaccination, and a sequential s.c/i.t. vaccination regimen. In this study, we used a recombinant vaccinia virus containing the transgenes for carcinoembryonic antigen (CEA) and a triad of T-cell costimulatory molecules (B7–1, ICAM-1, and LFA-3; designated rV-CEA/TRICOM) for s.c. priming and a replication defective avipox (fowlpox) virus containing the same four transgenes (designated rF-CEA/TRICOM) for i.t. vaccination or s.c. booster vaccinations.
Experimental Design: Vaccination was started on day 8 after s.c. implantation with CEA-positive tumors. We compared the antitumor activity induced by these vaccines when administered via the i.t. route versus the s.c. route. Subsequent therapy studies examined the sequential combination of these routes, s.c. priming with rV-CEA/TRICOM followed by i.t. boosting with rF-CEA/TRICOM. Initial studies were conducted in conventional mice to define optimal vaccine regimens and then in CEA-transgenic mice that expressed CEA as a “self” antigen in a manner similar to that of an advanced colorectal cancer patient.
Results: The results demonstrate that the antitumor activity induced by i.t. vaccination is superior to that induced by s.c. vaccination. For more advanced tumors, a s.c. priming vaccination, followed by i.t. boosting vaccinations was superior to either s.c. or i.t. vaccination alone. Both of these phenomena were observed in tumor models where the tumor-associated antigen is a foreign antigen and in a CEA-transgenic tumor model where the tumor-associated antigen is a self-antigen. The cytokine, granulocyte macrophage colony-stimulating factor admixed in vaccines, was shown to be essential in inducing the antitumor activity.
Conclusions: These studies demonstrate that the diversified vaccine regimens that consisted of s.c. prime and i.t. boosts with CEA/TRICOM vectors could induce antitumor therapy superior to that seen by either route alone.
Loss of Heterozygosity and Internal Tandem Duplication Mutations of the CBP Gene Are Frequent Events in Human Esophageal Squamous Cell Carcinoma
Authors: So Chi-Kwong , Nie Yan , Song Yunlong , Yang Guang-Yu , Chen Suzie , Wei Caroline , Wang Li-Dong , Doggett Norman A. , Yang Chung S. 
Published: September 2005

Abstract
Purpose: Cyclic AMP response element binding protein binding protein (CBP), a nuclear transcriptional coactivator protein, is an important component of the cAMP signal transduction pathway. In this study, we systematically analyzed the pattern and frequency of CBP gene alterations in esophageal squamous cell carcinoma (ESCC) samples from Linzhou (Linxian), China.
Experimental Design: Using microsatellite markers D16S475, D16S2622, and D16S523 within the chromosome 16p13.3 locus flanking the CBP gene, we observed loss of heterozygosity (LOH), microsatellite instability (MSI), or homozygous deletion in 16 of 26 ESCC samples. Additional ESCC samples were analyzed using different sets of microsatellite markers (CS1–CS5) within the introns or in close proximity to the 3′ end of the CBP gene.
Results: The data showed that CBP gene LOH or MSI occurred in 9 of 19 ESCC samples. A detailed genetic alteration map of the CBP gene showed that an LOH or MSI hot spot occurred within intron 2 of the CBP gene. Furthermore, ESCC samples were investigated for CBP gene mutation by conformation sensitive gel electrophoresis and DNA sequencing. These results revealed that most of the shifted fragments contained internal tandem duplication (ITD), frequently in the regions encoding the histone acetyltransferase domain and COOH-terminal transactivating domain one of the CBP gene. The presence of ITD within the CBP gene was additionally confirmed by Southern blot analysis and sequencing.
Conclusions: These studies show that LOH and ITD of the CBP gene are frequent genetic events in human ESCC. These alterations may have functional importance in the development of human ESCC.