bluuebunny/crossref_metadata_2025_split huggingface dataset:
More Efficient Induction of HLA-A*0201-Restricted and Carcinoembryonic Antigen (CEA)–Specific CTL Response by Immunization with Exosomes Prepared from Heat-Stressed CEA-Positive Tumor Cells
Authors: Dai Shengming , Wan Tao , Wang Baomei , Zhou Xiangyang , Xiu Fangming , Chen Taoyong , Wu Yanfeng , Cao Xuetao 
Published: March 2006

AbstractPurpose: Tumor-derived exosomes are proposed as a new type of cancer vaccine. Heat shock proteins are potent Th1 adjuvant, and heat stress can induce heat shock protein and MHC-I expression in tumor cells, leading to the increased immunogenicity of tumor cells. To improve the immunogenicity of exosomes as cancer vaccine, we prepared exosomes from heat-stressed carcinoembryonic antigen (CEA)–positive tumor cells (CEA+/HS-Exo) and tested the efficacy of these exosomes in the induction of CEA-specific antitumor immunity.Experimental Design: First, we identified the composition of CEA+/HS-Exo and observed their effects on human dendritic cell maturation. Then, we evaluated their ability to induce a CEA-specific immune response in vivo in HLA-A2.1/Kb transgenic mice and CEA-specific CTL response in vitro in HLA-A*0201+ healthy donors and HLA-A*0201+CEA+ cancer patients.Results: CEA+/HS-Exo contained CEA and more heat shock protein 70 and MHC-I and significantly induced dendritic cell maturation. Immunization of HLA-A2.1/Kb transgenic mice with CEA+/HS-Exo was more efficient in priming a CEA-specific CTL, and the CTL showed antitumor effect when adoptively transferred to SW480-bearing nude mice. Moreover, in vitro incubation of lymphocytes from HLA-A*0201+ healthy donors and HLA-A*0201+CEA+ cancer patients with CEA+/HS-Exo-pulsed autologous dendritic cells induces HLA-A*0201-restricted and CEA-specific CTL response.Conclusions: Our results show that CEA+/HS-Exo has superior immunogenicity than CEA+/Exo in inducing CEA-specific CTL response and suggest that exosomes derived from heat-stressed tumor cells may be used as efficient vaccine for cancer immunotherapy.
Enhancement of Sensitivity to Tumor Necrosis Factor α in Non–Small Cell Lung Cancer Cells with Acquired Resistance to Gefitinib
Authors: Ando Koichi , Ohmori Tohru , Inoue Fumiko , Kadofuku Tsuyoki , Hosaka Takamichi , Ishida Hiroo , Shirai Takao , Okuda Kentaro , Hirose Takashi , Horichi Naoya , Nishio Kazuto , Saijo Nagahiro , Adachi Mitsuru , Kuroki Toshio 
Published: March 2006

AbstractTumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor α (TNF-α). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF-α and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF-α was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF-α-induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF-α-induced Akt phosphorylation and IκB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF-α in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF-α sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF-α would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.
Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer
Authors: Morris Michael J. , Divgi Chaitanya R. , Pandit-Taskar Neeta , Batraki Maria , Warren Nyasha , Nacca Angelo , Smith-Jones Peter , Schwartz Lawrence , Kelly W. Kevin , Slovin Susan , Solit David , Halpern Jennifer , Delacruz Anthony , Curley Tracy , Finn Ronald , O'Donoghue Joseph A. , Livingston Philip , Larson Steven , Scher Howard I. 
Published: March 2006

Abstract
Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored.
Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N′,N″,N‴-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed.
Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a &gt;50% prostate-specific antigen decline.
Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.
Prediction of Lymph Node Metastasis in Patients with Endometrioid Endometrial Cancer Using Expression Microarray
Authors: Bidus Michael A. , Risinger John I. , Chandramouli Gadisetti V.R. , Dainty Lou A. , Litzi Tracy J. , Berchuck Andrew , Barrett J. Carl , Maxwell G. Larry 
Published: March 2006

Abstract
Purpose: To characterize the gene expression profiles of endometrioid endometrial cancers associated with lymph node metastasis in an effort to identify genes associated with metastatic spread.
Experimental Design: Tumors from 41 patients with endometrioid endometrial cancer grossly confined to the uterine cavity were evaluated. Positive lymph nodes were noted in 12 of 41 patients. RNA was analyzed for gene expression using the Affymetrix HG133A and HG133B GeneChip set, representing 45,000 array features covering &gt;28,000 UniGene clusters. Data analysis was done using multidimensional scaling, binary comparison, and hierarchical clustering. Gene expression for several differentially expressed genes was examined using quantitative PCR.
Results: Gene expression data was obtained from 30,964 genes that were detected in at least 5% of the cases. Supervised analysis of node-positive versus node-negative cases indicated that 450 genes were significantly differentially expressed between the two classes at P &lt; 0.005, 81 of which were differentially expressed by at least 2-fold at P &lt; 0.005. Overexpressed genes included two cell cycle checkpoint genes, CDC2 and MAD2L1, which have previously been described in association with lymph node metastasis in other cancer types. The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes.
Conclusion: Gene expression profiling of the primary tumors in patients with endometrioid endometrial cancers seems promising for identifying genes associated with lymph node metastasis. Future studies should address whether the status of nodal metastasis can be determined from the expression profiles of preoperative tissue specimens.
Cytotoxic Markers and Frequency Predict Functional Capacity of Natural Killer Cells Infiltrating Renal Cell Carcinoma
Authors: Schleypen Julia S. , Baur Nicole , Kammerer Robert , Nelson Peter J. , Rohrmann Karl , Gröne Elisabeth F. , Hohenfellner Markus , Haferkamp Axel , Pohla Heike , Schendel Dolores J. , Falk Christine S. , Noessner Elfriede 
Published: March 2006

Abstract
Purpose: Renal cell carcinoma harbors high numbers of infiltrating lymphocytes with apparent limited efficacy in tumor control. This study focused on the natural killer (NK) cells infiltrating renal cell carcinoma.
Experimental Design: Tumor-infiltrating lymphocytes (TIL) were isolated from renal cell carcinoma and analyzed for NK cell frequency and phenotype (n = 34). NK cells were enriched and tested for effector function.
Results: Two renal cell carcinoma subtypes were identified, one containing high (&gt;20% of the lymphocyte population, n = 14), the other low (&lt;20%, n = 20), NK cell numbers. NK cells of both groups were noncytolytic ex vivo but differed in CD16 and cytotoxic effector molecule expression as well as in their capacity to acquire cytotoxic activity: The majority of NK cells from tumors with high NK cell content (high NK-TIL) were CD16bright, whereas few CD16bright NK cells were found in tumors with low NK cell frequencies (low NK-TIL). The CD16 dichotomy correlated with different capacities to develop cytotoxicity after short-term activation with interleukin-2 ex vivo: Low NK-TIL remained noncytolytic against K562 and unresponsive to signals via the activating receptor NKp46 despite expression of receptor and adaptor molecules. In contrast, high NK-TIL acquired cytotoxic function. As described for peripheral CD16bright NK cells, NK cells from high-NK tumors showed high per cell expression of granzyme A, granzyme B, and perforin. NK cells from low NK-TIL resembled CD16neg/dim peripheral NK cells with few cytotoxin+ cells and lower expression of perforin.
Conclusion: The extent of NK cell infiltration and the expression of markers (CD16 and cytotoxins) predict the functional capacity of NK cells infiltrating renal cell carcinoma and can be used to characterize subgroups of renal cell carcinoma.
The Nuclear Transcription Factor κB/bcl-2 Pathway Correlates with Pathologic Complete Response to Doxorubicin-Based Neoadjuvant Chemotherapy in Human Breast Cancer
Authors: Buchholz Thomas A. , Garg Amit K. , Chakravarti Nitin , Aggarwal Bharat B. , Esteva Francisco J. , Kuerer Henry M. , Singletary S. Eva , Hortobagyi Gabriel N. , Pusztai Lajos , Cristofanilli Massimo , Sahin Aysegul A. 
Published: March 2006

Abstract
Purpose: Molecular factors involved in apoptosis may affect breast cancer response to chemotherapy. Herein, we studied the nuclear factor κB (NF-κB)/bcl-2 pathway to determine whether or not activation of this antiapoptotic pathway was associated with a poor response of human breast cancer to anthracycline-based neoadjuvant chemotherapy.
Experimental Design: We studied 82 human breast cancer samples from patients treated with neoadjuvant doxorubicin-based chemotherapy and studied whether or not nuclear location of the transcription factor NF-κB was associated with expression of bcl-2 and bax and whether or not expression of these proteins correlated with chemotherapy response. Protein expression was measured with immunohistochemical staining. A dedicated breast cancer pathologist who was unaware of the clinical outcome data dichotomized the slides as positive or negative based on the presence or absence of cytoplasmic staining for bcl-2 and bax or nuclear staining for NF-κB.
Results: Sixty-one percent of the tumors were positive for bcl-2, 85% were positive for bax, and 16% were positive for NF-κB. All bcl-2-positive tumors were also bax positive (P &lt; 0.0001) and all NF-κB-positive tumors were both bcl-2 positive (P = 0.001) and bax positive (P = 0.113). Eleven of the 82 patients (13%) had a pathologic complete response (pCR) to chemotherapy. Patients with positive staining tumors for any of the markers less commonly achieved a pCR to chemotherapy than those with negative tumor staining. The pCR rates were NF-κB positive 0% (0 of 13) versus NF-κB negative 13% (11 of 69; P = 0.130); bcl-2 positive 4% (2 of 49) versus bcl-2 negative 27% (9 of 33; P = 0.004); and bax positive 6% (4 of 69) versus bax negative 58% (7 of 12; P &lt; 0.001).
Conclusion: We conclude that nuclear localization of NF-κB correlates with bcl-2 and bax expression and that the NF-κB/bcl-2 pathway may be associated with a poor response to neoadjuvant doxorubicin-based chemotherapy.
A Phase I Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously Daily for 5 Consecutive Days Every 3 Weeks in Patients with Advanced Solid Tumors
Authors: Ebbinghaus Scot , Rubin Eric , Hersh Evan , Cranmer Lee D. , Bonate Peter L. , Fram Robert J. , Jekunen Antti , Weitman Steve , Hammond Lisa A. 
Published: March 2006

Abstract
Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks.
Experimental Design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m2. Pharmacokinetic samples were collected in cycle 1.
Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m2/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m2, 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m2/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of &lt;45 minutes in most cases.
Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m2/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.
Detection of Mononucleotide Repeat Sequence Alterations in a Large Background of Normal DNA for Screening High-Frequency Microsatellite Instability Cancers
Authors: Sun Xiyuan , Liu Yiding , Lutterbaugh Jim , Chen Wei-Dong , Markowitz Sanford D. , Guo Baochuan 
Published: March 2006

Abstract
Purpose: Mutations in mononucleotide repeat sequence (MRS) are good indicators of high-frequency microsatellite instability (MSI-H) cancers, but it has been a challenge to detect such mutations in a large background of wild-type DNA; as in this setting, PCR errors often generate false positive mutant alleles. In this study, we developed a general strategy, referred to as probe clamping primer extension-PCR (PCPE-PCR), to detect MRS alterations in a large background of wild-type DNA.
Experimental Design: In PCPE-PCR, genomic DNA is first subjected to PCPE, in which mutant single-strand DNA molecules are preferentially produced. Next, genomic DNA is removed to enrich for the mutant DNA fraction. Thereafter, PCR is carried out using the remaining single-strand DNA molecules as templates. Finally, the PCR products are analyzed to reveal the MSI-H status. In this study, the sensitivity of this new method was first examined by spiking mutant DNA into wild-type DNA at specific ratios followed by studying whether this method is applicable to fecal DNA testing.
Results: We showed that PCPE-PCR could detect both mutated BAT26 and transforming growth factor-β-RII (A)10 markers in the presence of 500-fold excess of normal DNA and that as few as three copies of mutated DNA could be detected. In addition, we showed that this technology could detect MSI-H colorectal cancer by fecal DNA analysis.
Conclusion: PCPE-PCR is sensitive. In addition, PCPE-PCR is simple and amendable to a cost-effective and high-throughput screening operation. This technology may be applicable to noninvasive screening of MSI-H cancer.
Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients
Authors: Hastings Randolph H. , Laux Ann M.P. , Casillas Andrea , Xu Ronghui , Lukas Zenaida , Ernstrom Karin , Deftos Leonard J. 
Published: March 2006

Abstract
Purpose: Parathyroid hormone–related protein (PTHrP) is commonly expressed in non–small cell lung carcinomas (NSCLC). Expression of the protein could have implications for progression of the disease because it regulates cancer cell growth, apoptosis, and angiogenesis. However, its relationship with survival has not been evaluated in a large-scale investigation.
Experimental Design: PTHrP expression was assessed in paraffin-embedded tumor samples from 407 patients with NSCLC by immunohistochemistry. A pathologist unaware of the clinical history classified specimens as PTHrP positive or PTHrP negative. The log-rank test was used to compare survivals of PTHrP-positive and PTHrP-negative groups, and Cox regression was used to adjust for additional covariates.
Results: Median survival was 55 versus 22 months (P &lt; 0.001) in female patients with and without tumor PTHrP, respectively. Male survival was 38 months independent of PTHrP status. Stage, histology, age, and smoking history were also associated with increased longevity. PTHrP remained a significant predictor of survival for female patients after controlling for stage, histology, and age.
Conclusions: In this study, PTHrP expression was associated with a survival advantage in female patients. Additional investigations must be done to ascertain whether the result is reproducible and independent of potential confounding covariates. Sex-dependent effects of PTHrP in lung cancer would open new avenues of research into the role of sex in cancer progression.
mdr-1Single Nucleotide Polymorphisms in Ovarian Cancer Tissue: G2677T/A Correlates with Response to Paclitaxel Chemotherapy
Authors: Gréen Henrik , Söderkvist Peter , Rosenberg Per , Horvath György , Peterson Curt 
Published: March 2006

AbstractPurpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P &lt; 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P &lt; 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (χ2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.
Natural Killer Cells License Dendritic Cell Cross-Presentation of B Lymphoma Cell–Associated Antigens
Authors: Dao Tao , Gomez-Nunez Marta , Antczak Christophe , Kappel Barry , Jaggi Jaspreet Singh , Korontsvit Tatyana , Zakhaleva Victoriya , Scheinberg David A. 
Published: March 2006

AbstractPurpose: Presentation of exogenous antigen by MHC class I molecules, or cross-presentation, is a property of dendritic cells, which is considered crucial for the priming of cytotoxic T-cell response to tumor antigens. However, the precise mechanisms of this process are not fully understood.Experimental Design and Results: We show here in a human in vitro system, using B lymphoma cells as a tumor model, that the cross-presentation of cell-associated antigens to T cells by dendritic cells requires “help” from natural killer cells. When autologous dendritic cells that had taken up apoptotic B lymphoma cells and induced to a fully mature state were used to stimulate nonadherent cells of peripheral blood mononuclear cells from healthy donors, they induced strong cytotoxicity against B lymphoma cells in a HLA-A0201-restricted manner. The cells failed to induce cytotoxicity, however, when purified T cells were used as effector cells. Depletion of CD56+ cells, but not CD14+ or CD19+ cells, abrogated the cytotoxicity of nonadherent cells, showing that the help was provided by natural killer cells. Further, when natural killer cells were present in the cultures, a strong and persistent production of interleukin-18, but not interleukin-12 and interleukin-15, was observed. Blocking interleukin-18 significantly reduced the cytotoxicity of nonadherent cells against B lymphoma cells.Conclusions: These results suggest that capture of tumor cells and a full maturation status of dendritic cells are not sufficient to cross-prime CD8 T cells. Effective cross-priming requires further activation of dendritic cells by natural killer cells and an abundant production of interleukin-18, which, along with other yet undefined mechanisms, contribute to the generation of CTL response against B-cell lymphoma.