bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrinsic Chemoresistance to Gemcitabine Is Associated with Decreased Expression of BNIP3 in Pancreatic Cancer
Authors: Akada Masanori , Crnogorac-Jurcevic Tatjana , Lattimore Samuel , Mahon Patrick , Lopes Rita , Sunamura Makoto , Matsuno Seiki , Lemoine Nicholas R. 
Published: September 2005

AbstractPurpose: Although chemotherapy with gemcitabine is a common mode of treatment of pancreatic cancer, 75% of patients do not benefit from this therapy. It is likely that the sensitivity of cancer cells to gemcitabine is determined by a number of different factors.Experimental Design: To identify genes that might contribute to resistance to gemcitabine, 15 pancreatic cancer cell lines were subjected to gemcitabine treatment. Simultaneously, gene expression profiling using a cDNA microarray to identify genes responsible for gemcitabine sensitivity was performed.Results: The pancreatic cancer cell lines could be classified into three groups: a gemcitabine “sensitive,” an “intermediate sensitive,” and a “resistant” group. Microarray analysis identified 71 genes that show differential expression between gemcitabine-sensitive and -resistant cell lines including 27 genes relatively overexpressed in sensitive cell lines whereas 44 genes are relatively overexpressed in resistant cell lines. Among these genes, 7 genes are potentially involved in the phosphatidylinositol 3-kinase/Akt pathway. In addition to this major signaling pathway, Bcl2/adenovirus E1B 19 kDa protein interacting protein (BNIP3), a Bcl-2 family proapoptotic protein, was identified as being expressed at lower levels in drug-resistant pancreatic cancer cell lines. In an analysis of 21 pancreatic cancer tissue specimens, more than 90% showed down-regulated expression of BNIP3. When expression of BNIP3 was suppressed using small interfering RNA, gemcitabine-induced cytotoxicity in vitro was much reduced.Conclusions: These results suggest that BNIP3 and the phosphatidylinositol 3-kinase/Akt pathway may play an important role in the poor response to gemcitabine treatment in pancreatic cancer patients.
Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis
Authors: Jin Qianren , Hemminki Kari , Enquist Kerstin , Lenner Per , Grzybowska Ewa , Klaes Rüdiger , Henriksson Roger , Chen Bowang , Pamula Jolanta , Pekala Wioletta , Zientek Helena , Rogozinska-Szczepka Jadwiga , Utracka-Hutka Beata , Hallmans Göran , Försti Asta 
Published: September 2005

Abstract
Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study.
Experimental Design: We examined three polymorphisms in the VEGF gene (−2578C/A, −1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and −2578C/A, −634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls.
Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The −634CC genotype and the −2578/−634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P &lt; 0.01) and the −2578AA genotype and the −2578/−634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status.
Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.
A Rare Transporter Associated with Antigen Processing Polymorphism Overpresented in HLAlow Colon Cancer Reveals the Functional Significance of the Signature Domain in Antigen Processing
Authors: Yang Tianyu , Lapinski Philip E. , Zhao Haotian , Zhou Qunmin , Zhang Huiming , Raghavan Malini , Liu Yang , Zheng Pan 
Published: September 2005

AbstractTransporter associated with antigen processing (TAP), a member of the ATP-binding cassette transporter superfamily, is composed of two integral membrane proteins, TAP-1 and TAP-2. Each subunit has a C-terminal nucleotide-binding domain that binds and hydrolyzes ATP to energize peptide translocation across the endoplasmic reticulum membrane. A motif comprising the sequence LSGGQ (called the signature motif) and the amino acid that is immediately C-terminal to this motif are highly conserved in the nucleotide-binding domains of ATP-binding cassette transporters. To search for natural variants of TAP-1 with alterations in or near the signature motif, we sequenced the TAP-1 exon 10 amplified from 103 human colon cancer samples. We found a rare TAP-1 allele with an R&gt;Q alteration at a residue immediately C-terminal to the signature motif (R648) that occurred 17.5 times more frequently in colon cancers with down-regulated surface class I MHC than those with normal MHC levels (P = 0.01). Functional analysis revealed that the Q648 variant had significantly reduced peptide translocation activity compared with TAP-1(R648). In addition, we found that mutations S644R, G645R, G646S, and G646D interfered with TAP-1 activity. TAP-1 G646D, which showed the most severe defect, resided normally in the endoplasmic reticulum and associated with the peptide loading complex, but failed to transport peptide across the endoplasmic reticulum membrane. Thus, a TAP-1 polymorphism adjacent to the signature motif may be a contributing factor for MHC class I down-regulation in colon cancer. Given the widespread defects in DNA mismatch repair in colon cancer, mutations at or near the signature domain can potentially modulate antigen processing.
Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Oxaliplatin, Cisplatin, and Carboplatin in Nonhuman Primates
Authors: Jacobs Shana S. , Fox Elizabeth , Dennie Christopher , Morgan Lindsey B. , McCully Cynthia L. , Balis Frank M. 
Published: September 2005

Abstract
Purpose: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species.
Experimental Design: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration × time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC0-24/plasma ultrafiltrate AUC0-24 ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites.
Results: The mean ± SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 ± 22, 18 ± 6, and 211 ± 64 μmol/L hour, respectively. The AUCs in CSF were 1.2 ± 0.4 μmol/L hour for oxaliplatin, 0.56 ± 0.08 μmol/L hour for cisplatin, and 8 ± 2.2 μmol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin.
Conclusions: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.
Expression Levels of TEL, AML1, and the Fusion Products TEL-AML1 and AML1-TEL versus Drug Sensitivity and Clinical Outcome in t(12;21)-Positive Pediatric Acute Lymphoblastic Leukemia
Authors: Stams Wendy A.G. , den Boer Monique L. , Beverloo H. Berna , Meijerink Jules P.P. , van Wering Elisabeth R. , Janka-Schaub Gritta E. , Pieters Rob 
Published: September 2005

Abstract
Purpose: t(12;21)(p13; q22), present in ∼25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients.
Experimental Design: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.
Results: A significant ∼3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)− ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)− ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.
Conclusion: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.
Signet-Ring Cell or Mucinous Histology after Preoperative Chemoradiation and Survival in Patients with Esophageal or Esophagogastric Junction Adenocarcinoma
Authors: Chirieac Lucian R. , Swisher Stephen G. , Correa Arlene M. , Ajani Jaffer A. , Komaki Ritsuko R. , Rashid Asif , Hamilton Stanley R. , Wu Tsung-Teh 
Published: September 2005

Abstract
Purpose: The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is much better in patients with pathologic complete response than those with residual tumor. Some adenocarcinomas have mixed patterns, including signet-ring cell and mucinous histology, but the clinical significance of these subtypes is unknown.
Experimental Design: We studied 412 consecutive patients with esophageal or EGJ adenocarcinoma treated with chemoradiation followed by esophagectomy (193 patients) or surgery alone (219 patients). We evaluated signet-ring cell and mucinous histology in the resection and pretherapy biopsy specimens and compared clinicopathologic features with overall survival.
Results: The fraction of signet-ring cell and mucinous histology was similar in evaluated specimens of patients treated with preoperative chemoradiation or surgery alone (17% and 18%, respectively). The overall survival rate at 5 years of patients treated with preoperative chemoradiation was significantly better if residual signet-ring cell or mucinous histology was present in the esophagectomy specimen (63% versus 28%; P = 0.02). All 13 patients with acellular mucin pools and no residual carcinoma are still alive after an average follow-up time of 36 months. By contrast, in patients treated with surgery alone, overall survival rate was significantly worse if signet-ring cell or mucinous histology was present (14% versus 30%; P = 0.05). In multivariate analysis, overall survival was independently predicted by presence of signet-ring cell or mucinous histology (P = 0.04).
Conclusions: Our study showed that patients with esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from preoperative chemoradiation and esophagectomy.
Prostate Stem Cell Antigen Is Overexpressed in Prostate Cancer Metastases
Authors: Lam John S. , Yamashiro Joyce , Shintaku I. Peter , Vessella Robert L. , Jenkins Robert B. , Horvath Steve , Said Jonathan W. , Reiter Robert E. 
Published: September 2005

Abstract
Purpose: Prostate stem cell antigen (PSCA) is expressed by a majority of prostate cancers and is a promising therapeutic target. PSCA protein and mRNA expression was examined in prostate cancer bone, lymph node, and visceral metastases to assess the potential of PSCA as an immunotherapeutic target in advanced prostate cancer.
Experimental Design: Immunohistochemical analysis of PSCA protein expression and quantitative mRNA expression analysis of PSCA was done on clinical specimens of prostate cancer bone, lymph node, and visceral metastases. PSCA protein and mRNA expression levels were quantified and compared between available matched pairs of bone and lymph node or visceral metastases.
Results: Bone metastases stained with higher intensity of PSCA compared with lymph node or liver metastases in seven of eight (87.5%) matched pairs (P = 0.035). PSCA mRNA expression was equal or greater than that of LAPC-9, a PSCA expressing xenograft, in 12 of 24 (50%) cases of prostate cancer metastases and was significantly correlated with PSCA protein expression (σ = 0.84, P = 0.0019). Overall, PSCA protein expression was detected in 41 of 47 (87.2%), four of six (66.7%), and two of three (66.7%) cases of bone, lymph node, and liver metastases, respectively. Mean PSCA staining intensity was significantly higher in prostate cancer bone metastases compared with lymph node metastases (2.0 ± 0.02 versus 0.83 ± 0.31, P = 0.014).
Conclusions: Prostate cancer metastases express PSCA. However, greater PSCA staining intensity and level of PSCA mRNA expression was associated with bone metastases compared with lymph node metastases. This study suggests that PSCA is a promising tumor marker and potential therapeutic target for patients with metastatic prostate cancer.
Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer
Authors: Yang Sei Hoon , Mechanic Leah E. , Yang Ping , Landi Maria Teresa , Bowman Elise D. , Wampfler Jason , Meerzaman Daoud , Hong Kyeong Man , Mann Felicia , Dracheva Tatiana , Fukuoka Junya , Travis William , Caporaso Neil E. , Harris Curtis C. , Jen Jin 
Published: September 2005

Abstract
We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non–small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.
Enhanced Apoptosis and Tumor Regression Induced by a Direct Agonist Antibody to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor 2
Authors: Motoki Kazuhiro , Mori Eiji , Matsumoto Atsushi , Thomas Mayumi , Tomura Takafumi , Humphreys Robin , Albert Vivian , Muto Mari , Yoshida Hitoshi , Aoki Masami , Tamada Taro , Kuroki Ryota , Yoshida Hideaki , Ishida Isao , Ware Carl F. , Kataoka Shiro 
Published: September 2005

AbstractPurpose: Substantial evidence indicates that supraoligomerization of the death receptors for Fas ligand and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is necessary for efficient activation of the apoptotic pathway. Bivalent IgG antibodies can induce the efficient apoptosis by mimicking the natural ligands but only after these antibodies are further oligomerized by cross-linking. In this study, we generated a novel agonist antibody to TRAIL receptor 2 (TRAIL-R2) capable of inducing apoptosis without cross-linking and elucidated its mode of action and efficacy.Experimental Design: A fully human antibody to TRAIL-R2, KMTR2, was generated from KM Mouse immunized with TRAIL-R2 ectodomain. Apoptosis-inducing activities of unfractionated or purified monomeric IgG of KMTR2 was evaluated in the presence or absence of cross-linkers, secondary antibodies or Fc receptor–expressing effector cells, against human colorectal adenocarcinoma Colo205. Oligomerization of TRAIL-R2 was analyzed by size exclusion chromatography and confocal microscopy, and in vivo efficacy was examined in Colo205 xenograft model.Results: KMTR2 specifically recognized TRAIL-R2 and induced apoptosis with or without cross-linking. Size exclusion chromatography showed that the apoptosis activity coeluted with monomeric IgG and was effective independent of secondary antibody or Fc receptor–expressing effector cells. The antibody formed supracomplexes with soluble recombinant and membrane-anchored TRAIL-R2 and enhanced clustering of TRAIL-R2 on cell surface without cross-linking. KMTR2 was dramatically efficacious in reducing established human tumor.Conclusion: Our findings indicate that novel agonist antibody KMTR2 can direct antibody-dependent oligomerization of TRAIL-R2 and initiates efficient apoptotic signaling and tumor regression independent of host effector function. Thus, the direct agonist would be a lead candidate for cancer therapeutics.
P16 Loss and Mitotic Activity Predict Poor Survival in Patients with Peritoneal Malignant Mesothelioma
Authors: Borczuk Alain C. , Taub Robert N. , Hesdorffer Mary , Hibshoosh Hanina , Chabot John A. , Keohan Mary L. , Alsberry Ritchie , Alexis Diane , Powell Charles A. 
Published: September 2005

Abstract
Purpose: Peritoneal malignant mesothelioma is an aggressive neoplasm for which intensive therapy improves survival in a subset of patients. We hypothesized that pathologic variables would stratify patients into favorable and unfavorable survival subgroups.
Experimental Design: Fifty-four patients with peritoneal malignant mesothelioma were evaluated for trimodal therapy from 1995 to 2003. Two pathologists evaluated pathologic variables independently, and p16 status was analyzed by immunohistochemistry.
Results: Patients not receiving trimodal therapy had a significantly increased risk of death [hazard ratio (HR), 9.6; 4.3-21.6; P &lt; 0.0001]. Biphasic histology was also associated with increased risk of death (HR, 8.5; 3.4-21.8; P &lt; 0.0001). In multivariate analysis adjusting for treatment modality and histologic type, high mitotic rate and p16 loss were associated with increased risk of death (HR, 3.074; 1.05-9.0; P &lt; 0.04 and HR, 3.65; 1.3-10.2; P &lt; 0.014, respectively).
Conclusions: Biphasic histology, increased mitotic rate, and p16 loss were independently associated with poorer survival in peritoneal malignant mesothelioma. Among the trimodal treated patients, increased mitotic rate was associated with increased risk of death.
Antiangiogenic Treatment with the Three Thrombospondin-1 Type 1 Repeats Recombinant Protein in an Orthotopic Human Pancreatic Cancer Model
Authors: Zhang Xuefeng , Galardi Eric , Duquette Mark , Delic Marko , Lawler Jack , Parangi Sareh 
Published: September 2005

Abstract
Purpose: This study investigates the antiangiogenesis and antitumor efficacy of a recombinant protein composed of the three type 1 repeats (3TSR) of thrombospondin-1 in an orthotopic human pancreatic cancer model and provides useful preclinical data for pancreatic cancer treatment.
Experimental Design: Human pancreatic cancer cells (AsPC-1) were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR (3 mg per kg per day) or PBS for 3 weeks. Subsequently, the effects of 3TSR on tumor growth, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed. The in vitro effects of 3TSR on human pancreatic cancer cells were also studied.
Results: 3TSR treatment significantly reduced angiogenesis and tumor growth of orthotopic pancreatic cancer. 3TSR-treated mice had a 69% reduction in tumor volume (316.6 ± 79.3 versus 1,012.2 ± 364.5 mm3; P = 0.0001), and a significant increase in tumor necrotic area. After 3TSR treatment, both the vessel number and average microvessel size were significantly decreased, and microvessel density was decreased from 8.0% to 3.7% (P &lt; 0.0001). The apoptotic rate of tumoral endothelial cells in 3TSR-treated tumors increased to 14.7% comparing to 4.2% in control tumors (P &lt; 0.0001). 3TSR showed no direct effects on pancreatic cancer cell proliferation or apoptosis either in vivo or in vitro.
Conclusion: 3TSR, a domain of a natural occurring angiogenesis inhibitor, showed potent therapeutic effect in pancreatic cancer by inhibiting tumor angiogenesis and may prove to be a promising agent for clinical pancreatic cancer treatment.
Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study
Authors: Savellano Mark D. , Hasan Tayyaba 
Published: September 2005

AbstractPurpose: Photoimmunotherapy may allow target-specific photodynamic destruction of malignancies and may also potentiate anticancer antibody therapies. However, clinical use of either of the two modalities is limited for different reasons. Antibody therapies suffer from being primarily cytostatic and the need for prolonged administration with consequent side effects. In the case of photoimmunotherapy, a major impediment has been the absence of well-characterized photosensitizer immunoconjugates (PIC). In this investigation, we suggest a strategy to overcome these limitations and present the successful targeting of epidermal growth factor receptor (EGFR) using a well-characterized PIC.Experimental Design: The PIC consisted of the EGFR-recognizing chimeric monoclonal antibody, C225, conjugated with a two-branched polyethylene glycol and benzoporphyrin derivative (BPD, Verteporfin). Mechanistic studies included photophysics, phototoxicity, cellular uptake, and catabolism experiments to yield dosimetric parameters. Target cells included two EGFR-overexpressing human cancer cell lines, OVCAR-5 and A-431. Nontarget cells included an EGFR-negative fibroblast cell line, 3T3-NR6, and a monocyte-macrophage cell line, J774.Results: BPD-C225 PICs targeted and photodynamically killed EGFR-overexpressing cells, whereas free BPD exhibited no specificity. On a per mole basis, PICs were less phototoxic than free BPD, but PICs were very selective for target cells, whereas free BPD was not. Phototoxicity of the PICs increased at prolonged incubations. Photodynamic dose calculations indicated that PIC photophysics, photochemistry, catabolism, and subcellular localization were important determinants of PIC phototoxic potency.Conclusions: This study shows the efficacy of EGFR targeting with PIC constructs and suggests approaches to improve PIC designs and targeting strategies for in vivo photoimmunotherapy. The approach offers the possibility of dual effects via antibody-mediated cytostasis and photoimmunotherapy-based cytotoxicity.