bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of Carcinoembryonic Antigen (CEA)-Specific T-Cell Responses in HLA-A*0201 and HLA-A*2402 Late-Stage Colorectal Cancer Patients after Vaccination with Dendritic Cells Loaded with CEA Peptides
Authors: Liu Ko-Jiunn , Wang Chuan-Cheng , Chen Li-Tzong , Cheng Ann-Lii , Lin Dong-Tsamn , Wu Yu-Chen , Yu Wei-Lan , Hung Yi-Mei , Yang Hui-Yu , Juang Shin-Hun , Whang-Peng Jacqueline 
Published: September 2005

Abstract
Purpose: We intranodally immunized metastatic colorectal carcinoma patients, who had failed standard chemotherapy, with dendritic cells (DCs) pulsed with HLA-A*0201- or HLA-A*2402-restricted carcinoembryonic antigen (CEA) peptides to evaluate the safety of this treatment and the immune response against CEA peptides before and after the treatment.
Experimental Design: Six patients with the HLA-A*2402 genotype and 4 patients with the HLA-A*0201 genotype were enrolled. A single CEA peptide (YLSGANLNL) or two CEA peptides (QYSWFVNGTF and TYACFVSNL) were used for patients with the HLA-A*0201 or HLA-A*2402 genotype, respectively. Autologous DCs were generated by culturing adherent mononuclear cells with interleukin 4 and granulocyte macrophage colony-stimulating factor for 6 days. Maturation of DCs was then induced with tumor necrosis factor α for 40 h. Mature DCs were pulsed with appropriate CEA peptides for 2 h. After washing, 1 million peptide-pulsed DCs were injected into one inguinal lymph node under sonographic guidance. Each patient received four injections.
Results: No grade II/III toxicity or autoimmunity was observed. An increase in the number of CEA-specific T cells after DC vaccination could be detected in 7 of 10 (70%) patients. Two (20%) patients had stable disease for at least 12 weeks. One of these 2 patients experienced a transient decrease in CEA levels during the treatment period and also had the most significant T-cell response against the immunizing CEA peptides.
Conclusions: These results suggest that our vaccination procedure can generate or boost specific T-cell responses and may provide clinical benefit in certain cancer patients.
The dl1520 Virus Is Found Preferentially in Tumor Tissue after Direct Intratumoral Injection in Oral Carcinoma
Authors: Morley Stephen , MacDonald Gordon , Kirn David , Kaye Stan , Brown Robert , Soutar David 
Published: September 2005

Abstract
Purpose: dl1520 (also known as Onyx-015) is an E1B-deleted adenovirus designed to selectively lyse p53-deficient cancer cells. Clinical trials involving patients with recurrent squamous cell carcinoma of the head and neck have shown clinical efficacy, but no direct evidence as to the tumor or p53 selectivity of the virus was demonstrated. We wanted to determine whether dl1520 is selective for survival and replication within tumor tissue after direct injection and whether this is determined by p53 status of the tissues. We also wanted to ascertain whether the virus has any macroscopic effect on normal tissue.
Experimental Design: An open-label Phase II trial was devised in which a fixed dose of the virus was administered to 15 patients via a direct intertumoral injection before surgery for untreated oral squamous cell carcinoma. The agent was also delivered into an area of adjacent normal buccal mucosa. Specimens of the excised tumor and of biopsies of the injected normal tissue were assessed for viral presence and p53 status.
Results: We demonstrated that the virus replicates selectively in tumor as opposed to normal tissue after this direct injection. It was not possible to determine whether this selectivity was p53 related. It was found that dl1520 triggers an early rise in apoptosis levels in injected normal tissues. No adverse effects of viral injection were noted.
Conclusions: This is the first report of injection of dl1520 into previously untreated squamous cell cancer. The data support the concept that dl1520 is replication deficient in normal, compared with cancerous, tissues and has potential as a selective anticancer agent against tumor tissues.
Expression of the Forkhead Transcription Factor FOXP1 Is Associated with Estrogen Receptor α and Improved Survival in Primary Human Breast Carcinomas
Authors: Fox Stephen B. , Brown Philip , Han Cheng , Ashe Sally , Leek Russel D. , Harris Adrian L. , Banham Alison H. 
Published: September 2005

Abstract
Purpose: The FOXP1 protein belongs to a functionally diverse family of winged-helix or forkhead transcription factors that have diverse roles in cellular proliferation, differentiation, and neoplastic transformation. The FOXP1 gene, which maps to 3p14, shows common loss of heterozygosity in breast tumors and is a candidate tumor suppressor gene. However, its role in breast cancer is unknown.
Experimental Design: We have therefore investigated the pattern of FOXP1 expression in whole sections from normal (n = 16) and neoplastic (n = 90) breast tissues and correlated the level of expression in 283 invasive breast carcinomas on tissue microarrays with clinicopathological factors and survival. Because a relationship with estrogen receptor (ER) was identified, estrogen (17β-estradiol) regulation and ER/FOXP1 colocalization was also investigated.
Results: Expression of FOXP1 was significantly positively associated with ER (P = 0.03) and negatively with epidermal growth factor receptor (P = 0.01) but no association with age (P = 0.91), lymph node status (P = 0.94), size (P = 0.76), or grade (P = 0.22). In a multivariate analysis of survival, FOXP1 expression was associated with a significantly improved relapse-free (P = 0.03) and borderline overall (P = 0.09) survival. Unlike normal breast, there was common coexpression of FOXP1 and ER in cell lines and tumors, but no 17β-estradiol (10-9 m) regulation of FOXP1 in MCF-7 cells was demonstrated.
Conclusions: Our findings support a role for FOXP1 as a potential ER coregulator in human breast carcinoma and suggest that it may also independently regulate additional important pathways that control the progression of breast cancer.
Expression Pattern of the Novel Gene EG-1 in Cancer
Authors: Zhang Liping , Maul Raymond Scott , Rao JianYu , Apple Sophia , Seligson David , Sartippour Maryam , Rubio Rosalio , Brooks Mai N. 
Published: September 2005

Abstract
Purpose: We recently discovered a novel gene responsive to tumor-conditioned media: endothelial-derived gene 1 (EG-1). Its transcript has been shown to be present in epithelial cells, as well as in endothelial cells. In this study, we examined the levels of EG-1 protein expression in breast, colon, prostate, and lung cancers, which constitute the four most common solid malignancies in the United States.
Experimental Design: Polyclonal antibodies were generated that recognize the EG-1 peptide. These antibodies were used in immunoblot analysis, as well as immunohistochemistry of multiple human clinical specimens of cancer.
Results: In immunoblots of whole cell lysates, EG-1 antibodies revealed the presence of a 22-kDa peptide. Immunohistochemistry of breast, colon, and prostate specimens showed higher levels of EG-1 peptides in cancer tissues, in comparison with their benign counterparts. However, EG-1 expression was minimal in both benign and malignant lung tissues.
Conclusions: Here, we demonstrated that the expression of EG-1 is elevated in cancerous in comparison to benign epithelial cells, as seen in immunohistochemistry of human pathological specimens. These observations collectively support the hypothesis that the novel gene EG-1 is associated with the malignant phenotype of the common epithelial-derived cancers of the breast, colon, and prostate.
Chromatin Remodeling Factors and BRM/BRG1 Expression as Prognostic Indicators in Non-Small Cell Lung Cancer
Authors: Fukuoka Junya , Fujii Takeshi , Shih Joanna H. , Dracheva Tatiana , Meerzaman Daoud , Player Audrey , Hong Kyeong , Settnek Sharon , Gupta Ajay , Buetow Kenneth , Hewitt Stephen , Travis William D. , Jen Jin 
Published: September 2005

Abstract
We immunohistochemically examined 12 core proteins involved in the chromatin remodeling machinery using a tissue microarray composed of 150 lung adenocarcinoma (AD) and 150 squamous cell carcinoma (SCC) cases. Most of the proteins showed nuclear staining, whereas some also showed cytoplasmic or membranous staining. When the expression patterns of all tested antigens were considered, proteins with nuclear staining clustered into two major groups. Nuclear signals of BRM, Ini-1, retinoblastoma, mSin3A, HDAC1, and HAT1 clustered together, whereas nuclear signals of BRG1, BAF155, HDAC2, BAF170, and RbAP48 formed a second cluster. Additionally, two thirds of the cases on the lung tissue array had follow-up information, and survival analysis was performed for each of the tested proteins. Positive nuclear BRM (N-BRM) staining correlated with a favorable prognosis in SCC and AD patients with a 5 year-survival of 53.5% compared with 32.3% for those whose tumors were negative for N-BRM (P = 0.015). Furthermore, patients whose tumors stained positive for both N-BRM and nuclear BRG1 had a 5 year-survival of 72% compared with 33.6% (P = 0.013) for those whose tumors were positive for either or negative for both markers. In contrast, membranous BRM (M-BRM) staining correlated with a poorer prognosis in AD patients with a 5 year-survival of 16.7% compared with those without M-BRM staining (38.1%; P = 0.016). These results support the notion that BRM and BRG1 participate in two distinct chromosome remodeling complexes that are functionally complementary and that the nuclear presence of BRM, its coexpression with nuclear BRG1, and the altered cellular localization of BRM (M-BRM) are useful markers for non-small cell lung cancer prognosis.
Characterization of a New Humanized Anti-CD20 Monoclonal Antibody, IMMU-106, and Its Use in Combination with the Humanized Anti-CD22 Antibody, Epratuzumab, for the Therapy of Non-Hodgkin’s Lymphoma
Authors: Stein Rhona , Qu Zhengxing , Chen Susan , Rosario Adriane , Shi Victoria , Hayes Marianne , Horak Ivan D. , Hansen Hans J. , Goldenberg David M. 
Published: September 2005

Abstract
Purpose: A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in combination with the anti-CD22 MAb, epratuzumab.
Experimental Design: Antiproliferative effects, apoptotic effects, and the ability of IMMU-106 to mediate complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity on a panel of non-Hodgkin’s lymphoma (NHL) cell lines were compared with the chimeric anti-CD20 MAb, rituximab, and evaluated in light of the various levels of antigen expression by the cell lines. In vivo therapy studies were performed in SCID mice bearing disseminated Raji lymphoma.
Results: The mechanisms of cytotoxicity of IMMU-106 were found to be similar to rituximab, and include direct apoptosis, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. IMMU-106 was also found to be very similar to rituximab in terms of antigen-binding specificity, binding avidity, and dissociation constant. Treatment of Raji-bearing SCID mice with IMMU-106 yielded median survival increases of up to 4.2-fold compared with control mice. Survival in mice treated with IMMU-106 plus epratuzumab was compared with IMMU-106 treatment alone. Although the combined treatment did not improve median survival, an increased proportion of long-term survivors was observed. An enhanced antiproliferative effect was also observed in vitro in SU-DHL-6 cells when IMMU-106 was combined with epratuzumab. These findings are consistent with the up-regulation of CD22 expression observed after pretreatment of NHL cells in vitro with CD20 MAb (IMMU-106).
Conclusions: It is expected that in humans IMMU-106 should be at least as effective as rituximab and, due to its human framework construction, it may exhibit different pharmacokinetic, toxicity, and therapy profiles. In addition, it may be possible to enhance efficacy by combination therapy comprised of anti-CD20 and other B-cell lineage targeting MAbs, such as epratuzumab. The current results emphasize that in vitro as well as in vivo studies with many of the NHL cell lines were generally predictive of the known activity of anti-CD20 MAbs in NHL patients, as well as the enhanced efficacy of epratuzumab combined with rituximab observed in early clinical trials.
Induction of Cell Cycle Arrest and Apoptosis by the Proteasome Inhibitor PS-341 in Hodgkin Disease Cell Lines Is Independent of Inhibitor of Nuclear Factor-κB Mutations or Activation of the CD30, CD40, and RANK Receptors
Authors: Zheng Bei , Georgakis Georgios V. , Li Yang , Bharti Alok , McConkey David , Aggarwal Bharat B. , Younes Anas 
Published: September 2005

Abstract
Purpose: The malignant Hodgkin and Reed-Sternberg cells of Hodgkin disease (HD) are known to constitutively express high levels of activated nuclear factor κB (NF-κB), which plays an important role in their survival. The proteasome inhibitor PS-341 has been recently shown to modulate tumor cell proliferation and survival by inhibiting NF-κB and modulating critical cellular regulatory proteins, but its activity in cells carrying IκBα gene mutations has not been reported previously.
Experimental Design: The activity of PS-341 in four well-characterized, HD-derived cell lines. Cell proliferation and apoptosis were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (MTS) and Annexin-V binding methods, respectively. Cell cycle analysis was determined by flow cytometry. Intracellular protein levels were determined by Western blot.
Results: PS-341 demonstrated a strong antiproliferative activity, which was irrespective of the status of mutations in IκBα and even the presence of CD30, CD40, or RANK receptor activation. This effect was attributable to the induction of apoptosis and cell cycle arrest at the G2-M phase. PS-341 not only inhibited nuclear localization of NF-κB but also activated the caspase cascade, increased p21 and Bax levels, and decreased Bcl-2 levels. Furthermore, PS-341 enhanced the effect of gemcitabine chemotherapy and potentiated the effect of tumor necrosis factor-related apoptosis-inducing ligand/APO2L and two agonistic antibodies to tumor necrosis factor-related apoptosis-inducing ligand death receptors R1 and R2.
Conclusions: The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 may have a therapeutic value for the treatment of HD.
Combined Targeting of Epidermal Growth Factor Receptor and MDM2 by Gefitinib and Antisense MDM2 Cooperatively Inhibit Hormone-Independent Prostate Cancer
Authors: Bianco Roberto , Caputo Roberta , Caputo Rosa , Damiano Vincenzo , De Placido Sabino , Ficorella Corrado , Agrawal Sudhir , Bianco A. Raffaele , Ciardiello Fortunato , Tortora Giampaolo 
Published: September 2005

Abstract
Purpose: The epidermal growth factor receptor (EGFR) may play a relevant role in the progression, hormone therapy resistance, and prognosis of prostate cancer patients. Also MDM2, a negative p53 regulator that interacts with retinoblastoma (Rb), E2F, p19arf and the ras-mitogen-activated protein kinase(MAPK) cascade plays an important role in prostate cancer progression and prognosis. On the basis of the EGFR and MDM2 role in integrating signaling pathways critical for prostate cancer progression, we investigated whether their selective combined blockade may have a cooperative antitumor effect in prostate cancer. For this purpose, we have used the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) and a second generation hybrid oligonucleotide antisense MDM2 (AS-MDM2), respectively.
Experimental Design: Gefitinib and AS-MDM2 were administered to hormone-refractory and hormone-dependent human prostate cancer cells in vitro and to mice bearing tumor xenografts, evaluating the effects on growth, apoptosis, and protein expression, in vitro and in vivo.
Results: We demonstrated that the combination of gefitinib and AS-MDM2 synergistically inhibits the growth of hormone-independent prostate cancer cells in vitro. This effect is accompanied by the inhibition of MDM2, phosphorylated Akt (pAkt), phosphorylated MAPK (pMAPK), and vascular endothelial growth factor (VEGF) expression and by Rb hypophosphorylation. The combination of the two agents in nude mice bearing the same hormone-independent tumors caused a potent cooperative antitumor effect. Tumor samples analysis confirmed the inhibition of MDM2, pAkt, pMAPK, VEGF, and basic fibroblast growth factor expression.
Conclusions: This study shows that EGFR and MDM2 play a critical role in the growth of prostate cancer, especially hormone-dependent, and that their combined blockade by gefitinib and AS-MDM2 causes a cooperative antitumor effect, supporting the clinical development of this therapeutic strategy.
Quantification of Colorectal Cancer Micrometastases in Lymph Nodes by Nested and Real-Time Reverse Transcriptase-PCR Analysis for Carcinoembryonic Antigen
Authors: Ho Samuel B. , Hyslop Ann , Albrecht Richard , Jacobson Amanda , Spencer Michael , Rothenberger David A. , Niehans Gloria A. , D’Cunha John , Kratzke Robert A. 
Published: September 2005

Abstract
Purpose: Reverse-transcriptase PCR (RT-PCR) assays for carcinoembryonic antigen (CEA) have been described to identify lymph node micrometastases. These assays are not quantitative and can be confounded by false-positive results. The purpose of this study was to determine whether quantification of CEA in lymph nodes could more readily identify clinically relevant groups.
Experimental Design: Specimens included 400 lymph nodes from 64 patients undergoing colon resections. Specimens were tested by immunohistochemistry and by RT-PCR using nested primers for CEA. Specimens from 59 patients that were positive by nested RT-PCR were further quantified by detection of CEA mRNA fluorescence increase at a threshold PCR cycle.
Results: CEA was detected by nested RT-PCR analysis in 4 of 34 (12%) nodes of nonneoplastic disease, 2 of 13 (15%) nodes from T1N0 patients, 32 of 81 (40%) nodes of T2N0 patients, 49 of 109 (45%) nodes from T3N0 patients, and 92 of 163 (56%) nodes from T1–4N1–2 patients. The overall presence of any RT-PCR–detectable CEA in nodes did not differentiate patient groups. Immunohistochemistry was positive in nodes from 7% of T3N0 patients and 100% of T1–3N1–2 patients. CEA quantification revealed that 0 of 7 patients with nonneoplastic disease and 2 of 17 (12%) patients with stage I T1–2N0 cancers had one or more lymph nodes with ≥1.0 × 102 CEA transcripts per sample. In contrast, 4 of 13 (31%) patients with stage II T3N0 cancer and 10 of 22 (45%) stage III patients with known metastases had lymph nodes with ≥1.0 × 102 CEA transcripts.
Conclusions: These data suggest that quantification of CEA levels in lymph nodes may more accurately identify patients at risk for cancer recurrence than does routine nested RT-PCR or immunohistochemistry.
Phosphorylation/Cytoplasmic Localization of p21Cip1/WAF1 Is Associated with HER2/
neu
Overexpression and Provides a Novel Combination Predictor for Poor Prognosis in Breast Cancer Patients
Authors: Xia Weiya , Chen Jin-Shing , Zhou Xian , Sun Pei-Rong , Lee Dung-Fang , Liao Yong , Zhou Binhua P. , Hung Mien-Chie 
Published: September 2005

Abstract
Purpose: The diversity of biological functions makes p21Cip1/WAF1 (p21) a controversial marker in predicting the prognosis of breast cancer patients. Recent laboratory studies revealed that the regulation of p21 function could be related to different subcellular localizations of p21 by Akt-induced phosphorylation at threonine 145 in HER2/neu-overexpressing breast cancer cells. The purpose of this study was to verify these findings in clinical settings.
Experimental Design: The expression status of the key biological markers in the HER2/neu-Akt-p21 pathway in 130 breast cancer specimens was evaluated by immunohistochemical staining and correlated with patients’ clinical parameters and survival. In addition, an antibody against phospho-p21 at threonine 145 [phospho-p21 (T145)] was also used for better validation of these findings.
Results: Cytoplasmic localization of p21 is highly correlated with overexpression of phospho-p21 (T145). Both cytoplasmic p21 and overexpression of phospho-p21 (T145) are associated with high expression of HER2/neu and phospho-Akt. Cytoplasmic localization of p21 and overexpression of phospho-p21 (T145), HER2/neu, and phospho-Akt are all associated with worse overall survival. Multivariate analysis of the Cox proportional hazard regression model revealed that cytoplasmic p21 and overexpression of HER2/neu are independently associated with increased risk of death. Combining these two factors stratified patients’ survival into four distinct groups, with a 5-year survival rate of 79% in low HER2/neu and negative/nuclear p21 patients, 60% in high HER2/neu and negative/nuclear p21 patients, 29% in low HER2/neu and cytoplasmic p21 patients, and 16% in high HER2/neu and cytoplasmic p21 patients.
Conclusions: The present study, in addition to supporting the mechanisms of p21 regulation derived from laboratory investigation, demonstrates the prognostic importance of phospho-p21 (T145) for the first time and also provides a novel combination of p21 and HER2/neu for better stratification of patients’ survival than any single clinicopathological or biological marker that may play important diagnostic and therapeutic roles for breast cancer patients.
Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors
Authors: Pei Xin-Yan , Dai Yun , Grant Steven 
Published: September 2005

Abstract
Purpose: The purpose of this study was to examine interactions between the proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC) inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple myeloma (MM) cells that are sensitive and resistant to conventional agents.
Experimental Design: MM cells were exposed to bortezomib for 6 h before the addition of HDAC inhibitors (total, 26 h), after which reactive oxygen species (ROS), mitochondrial dysfunction, signaling and cell cycle pathways, and apoptosis were monitored. The functional role of ROS generation was assessed using the free radical scavenger N-acetyl-l-cysteine.
Results: Preincubation with a subtoxic concentration of bortezomib markedly sensitized U266 and MM.1S cells to sodium butyrate- and suberoylanilide hydroxamic acid-induced mitochondrial dysfunction; caspase 9, 8, and 3 activation; and poly(ADP-ribose) polymerase degradation; resulting in synergistic apoptosis induction. These events were associated with nuclear factor κB inactivation, c-Jun NH2-terminal kinase activation, p53 induction, and caspase-dependent cleavage of p21CIP1, p27KIP1, and Bcl-2, as well as Mcl-1, X-linked inhibitor of apoptosis, and cyclin D1 down-regulation. The bortezomib/HDAC inhibitor regimen markedly induced ROS generation; moreover, apoptosis and c-Jun NH2-terminal kinase activation were attenuated by N-acetyl-l-cysteine. Dexamethasone- or doxorubicin-resistant MM cells failed to exhibit cross-resistance to the bortezomib/HDAC inhibitor regimen, nor did exogenous interleukin 6 or insulin-like growth factor I block apoptosis induced by this drug combination. Finally, bortezomib/HDAC inhibitors induced pronounced lethality in primary CD138+ bone marrow cells from MM patients, but not in the CD138− cell population.
Conclusions: Sequential exposure to bortezomib in conjunction with clinically relevant HDAC inhibitors potently induces mitochondrial dysfunction and apoptosis in human MM cells through a ROS-dependent mechanism, suggesting that a strategy combining these agents warrants further investigation in MM.