bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Cancer Testis Antigen That Is Frequently Expressed in Pancreatic, Lung, and Endometrial Cancers
Authors: Okada Takaho , Akada Masanori , Fujita Tomonobu , Iwata Takashi , Goto Yasufumi , Kido Kenji , Okada Tsutomu , Matsuzaki Yuriko , Kobayashi Kouichi , Matsuno Seiki , Sunamura Makoto , Kawakami Yutaka 
Published: March 2006

Abstract
Purpose: To isolate cancer testis antigens that are expressed in pancreatic cancers and may be useful in clinical applications.
Experimental Design: To efficiently isolate cancer testis antigens, a testis cDNA library was immunoscreened (SEREX) with serum from a patient with pancreatic ductal adenocarcinoma. The expression of isolated antigens in various cancer cell lines and tissues was evaluated by reverse transcription-PCR and Northern blot analyses. The immunogenicity of the antigen in cancer patients was evaluated by detection of the IgG antibody in sera from patients with various cancers.
Results: Of the three clones isolated through screening of a total of 2 × 106 cDNA library clones, one clone (KU-CT-1) was found to be expressed in various cancers but only in testis among normal tissues, indicating that it was a novel cancer testis antigen. The KU-CT-1 gene is located on chromosome 10p12 and produces two splice variants, which encode proteins of 397 and 872 amino acids, respectively. KU-CT-1 was expressed in pancreatic cancer tissues (3 of 9, 33%), lung cancer tissues (9 of 24, 38%), and endometrial cancer tissues (7 of 11, 64%). Specific serum IgG antibodies were detected in 3 of 20 pancreatic cancer patients, 2 of 12 endometrial cancer patients, 1 of 18 colon cancer patients, and 1 of 10 prostate cancer patients but not detected in 30 healthy individuals.
Conclusions: KU-CT-1 is a new cancer testis antigen that is expressed in pancreatic, lung, and endometrial cancers and may be useful for diagnosis and immunotherapy for patients with various cancers.
Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate
Authors: Wardelmann Eva , Merkelbach-Bruse Sabine , Pauls Katharina , Thomas Nadja , Schildhaus Hans-Ulrich , Heinicke Thomas , Speidel Nicola , Pietsch Torsten , Buettner Reinhard , Pink Daniel , Reichardt Peter , Hohenberger Peter 
Published: March 2006

Abstract
Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor α (PDGFRα) gene. Both PDGFRα and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Botulinum toxin potentiates cancer radiotherapy and chemotherapy.
Authors: Ansiaux R√©ginald , Baudelet Christine , Cron Greg O , Segers J√©r√¥me , Dessy Chantal , Martinive Philippe , De Wever Julie , Verrax Julien , Wauthier Val√©rie , Beghein Nelson , Gr√©goire Vincent , Buc Calderon Pedro , Feron Olivier , Gallez Bernard 
Published: March 2006

Abstract
PURPOSE: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. EXPERIMENTAL DESIGN: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. RESULTS: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. CONCLUSIONS: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy.
The Novel Poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons by Increasing the Persistence of DNA Strand Breaks
Authors: Smith Lisa M. , Willmore Elaine , Austin Caroline A. , Curtin Nicola J. 
Published: March 2006

Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors enhance DNA topoisomerase I (topo I) poison-induced cytotoxicity and antitumor activity in vitro and in vivo, but the mechanism has not been defined. We investigated the role of PARP-1 in the response to topo I poisons using PARP-1−/− and PARP-1+/+ mouse embryonic fibroblasts and the potent PARP-1 inhibitor, AG14361 (Ki &lt; 5 nmol/L). PARP-1−/− mouse embryonic fibroblasts were 3-fold more sensitive to topotecan than PARP-1+/+ mouse embryonic fibroblasts (GI50, 21 and 65 nmol/L, respectively). AG14361 caused a &gt;3-fold sensitization of PARP-1+/+ cells to topotecan compared with a &lt;1.4-fold sensitization in PARP-1−/− cells. In human leukemia K562 cells, AG14361 caused a 2-fold sensitization to camptothecin-induced cytotoxicity. AG14361 did not affect the cellular activity of topo I as determined by measurement of cleavable complexes and topo I relaxation activity, showing that sensitization was not due to topo I activation. In contrast, repair of DNA following camptothecin removal, normally very rapid, was significantly retarded by AG14361, resulting in a 62% inhibition of repair 10 minutes after camptothecin removal. This led to a 20% increase in the net accumulation of camptothecin-induced DNA strand break levels in cells coexposed to AG14361 for 16 hours. We investigated the DNA repair mechanism involved using a panel of DNA repair–deficient Chinese hamster ovary cells. AG14361 significantly potentiated camptothecin-mediated cytotoxicity in all cells, except the base excision repair–deficient EM9 cells. Therefore, the most likely mechanism for the potentiation of topo I poison-mediated cytotoxicity by AG14361 is via PARP-1-dependent base excision repair.
Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation
Authors: Yang Muh-Hwa , Chiang Wei-Chung , Chou Teh-Ying , Chang Shyue-Yih , Chen Po-Min , Teng Shu-Chun , Wu Kou-Juey 
Published: March 2006

Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the sixth most frequent type of cancer worldwide. However, the molecular genetic alterations underlying its malignant behavior and progression are little known. We showed previously that c-MYC directly activates the expression of the DNA double-strand break repair gene NBS1, and NBS1 overexpression contributes to transformation. Here, we investigate the role of NBS1 overexpression in HNSCC.
Experimental Design: Immunohistochemistry analysis of NBS1 expression was done in 81 locally advanced HNSCC patients. Real-time PCR and Western blot analysis were used to confirm immunohistochemistry results. Human hypopharyngeal cancer cell lines (FADU) with overexpressing NBS1 (FADUNBS) or inducible short interference RNA to repress endogenous NBS1 (FADUNBSi) were generated by stable transfection. Soft agar clonogenicity assay was used to determine the transformation activity. Western blot analysis and phosphatidylinositol 3-kinase (PI3K) assay were done to evaluate the signaling pathways that were involved.
Results: NBS1 overexpression was identified in 45% of advanced HNSCC patients. It was an independent marker of poor prognosis. NBS1 expression levels correlated with the transformation activity of FADU clones and also correlated with the phosphorylation levels of Akt and its downstream target mammalian target of rapamycin (mTOR). PI3K activity was increased in NBS1-overexpressing FADU clones. NBS1 overexpression also correlated with increased Akt phosphorylation levels in tumor samples.
Conclusions: Increased NBS1 expression is a significant prognostic marker of advanced HNSCC, and the underlying mechanism may involve the activation of the PI3K/Akt pathway.
Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix
Authors: Gombos Zoltan , Xu Xiaowei , Chu Christina S. , Zhang Paul J. , Acs Geza 
Published: March 2006

Abstract
Purpose: Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system.
Experimental Design: We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome.
Results: Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P &lt; 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P &lt; 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival.
Conclusions: Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.
Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft
Authors: Karacay Habibe , Brard Pierre-Yves , Sharkey Robert M. , Chang Chien-Hsing , Rossi Edmund A. , McBride William J. , Ragland Dan R. , Horak Ivan D. , Goldenberg David M. 
Published: March 2006

Abstract
Purpose: To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a 90Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given 90Y-humanized anti-CEA immunoglobulin G (IgG).
Experimental Design: Clearance and biodistribution were monitored by whole-body readings and necropsy. Animals were monitored for 34 weeks with a determination of residual disease and renal pathology in survivors. Hematologic toxicity was assessed separately in non-tumor-bearing NIH Swiss mice.
Results: Hematologic toxicity was severe at doses of 100 to 200 μCi of 90Y-IgG, yet mild in the pretargeted animals given 500 or 700 μCi of the 90Y-peptide. Evidence of end-stage renal disease was found at 900 μCi of the pretargeted 90Y-peptide whereas animals given 700 μCi showed only mild renal pathology, similar to that seen in control animals given 90Y-IgG. Biodistribution data indicated that the average amount of tumor radioactivity by a 700-μCi dose of the pretargeted peptide over a 96-hour period was increased 2.5-fold (48 μCi/g) compared with 150 μCi of 90Y-IgG (18.9 μCi/g). At these doses, survival (i.e., time to progression to 2.5 cm3) was significantly improved (P &lt; 0.04) compared with 90Y-IgG, with ablation of about one third of the tumors, whereas viable tumor was present in all of the 90Y-IgG–treated animals.
Conclusion: Pretargeting increases the amount of radioactivity delivered to colorectal tumors sufficiently to improve the therapeutic index and responses as compared with conventional radioimmunotherapy.
Estrogen Signaling Is Active in Cartilaginous Tumors: Implications for Antiestrogen Therapy as Treatment Option of Metastasized or Irresectable Chondrosarcoma
Authors: Cleton-Jansen Anne-Marie , van Beerendonk Hetty M. , Baelde Hans J. , Bovée Judith V.G.M. , Karperien Marcel , Hogendoorn Pancras C.W. 
Published: March 2006

Abstract
Purpose: Chondrosarcoma is a malignant cartilaginous matrix–producing tumor that can be lethal in 10% to 50% of the patients. Surgery is the only effective treatment known as these tumors are notorious refractory to all types of conventional chemotherapy or radiotherapy. To identify a target for therapy, we want to determine whether estrogen signaling is active in chondrosarcoma because estrogen is important in the regulation of longitudinal growth that is initiated by chondrocyte proliferation and differentiation in the epiphyseal growth plate of long bones.
Experimental Design: We studied protein expression of the estrogen receptor in 35 cartilaginous tumors as well as mRNA levels for the estrogen receptor and for aromatase, an enzyme for estrogen synthesis and another potential therapeutic target. Furthermore, the activity of aromatase was determined in vitro by the tritiated water release assay. Dose-response experiments with chondrosarcoma cultured cells were done with estrogen, androstenedione, and exemestane.
Results: All chondrosarcomas tested showed mRNA and nuclear protein expression of the estrogen receptor. Also, aromatase mRNA was detected. The aromatase activity assay showed a functional aromatase enzyme in primary chondrosarcoma cultures and in a cell line. Growth of chondrosarcoma cell cultures can be stimulated by adding estrogen or androstenedione, which can be inhibited by exemestane.
Conclusions: These results show, on the RNA, protein, and cell biological levels, that the ligand and the receptor are active in estrogen-mediated signal transduction. This observation implicates potential use of targeted drugs that interfere with estrogen signaling, such as those applied for treating breast cancer.
Tumor-Associated Antigen Recognized by the 22-1-1 Monoclonal Antibody Encourages Colorectal Cancer Progression under the Scanty CD8+ T Cells
Authors: Oshikiri Taro , Miyamoto Masaki , Morita Takayuki , Fujita Miyoshi , Miyasaka Yuji , Senmaru Naoto , Yamada Hidehisa , Takahashi Toshiyuki , Horita Shoichi , Kondo Satoshi 
Published: March 2006

Abstract
Purpose: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a novel tumor-associated antigen. Although evidence suggests that RCAS1 suppresses immunity by inducing tumor-infiltrating lymphocyte (TIL) apoptosis, RCAS1 function in humans is controversial. RCAS1 overexpression leads to the generation of the Tn glycan antigen (N-acetyl-d-galactosamine, GalNAc) recognized by the 22-1-1 monoclonal antibody. The objective of this study is to examine Tn glycan antigen function in colorectal cancer and to determine its relationship to CD8+ T cells and prognosis.
Experimental Design: Immunohistochemical analyses examined Tn expression in tumor cells and CD8 on TILs in 146 surgically resected colorectal cancer.
Results: Of 146 samples, 68 tumors (47%) were Tn+; 72 tumors (49%) were CD8+. Using Cox multivariate analysis and the Kaplan-Meier method, Tn and CD8 positivity were determined to be mutually independent prognostic factors (P = 0.0266 and 0.0210, respectively). Tn+ patients with CD8+ TILs exhibited better survival than Tn+/CD8− patients (P = 0.0129). For CD8− patients, Tn positivity was associated with decreased survival from that seen in Tn− patients (P = 0.0097), suggesting that Tn exerts a function independent of CD8+ T cells in tumor progression. In all patients and cases with synchronous liver metastases (n = 29), the Tn+/CD8− survival rate was significantly lower than that seen for other groups (P = 0.0001 and 0.0063, respectively). The average number of liver metastases in Tn+/CD8− cases also increased (mean, 8.2 tumors; P = 0.0032). Multivariate analysis identified Tn+/CD8− status and Dukes' staging as independent prognostic factors (P = 0.0016 and &lt;0.0001, respectively).
Conclusions: Tn may encourage invasion and innidiation through a mechanism independent of CD8+ T cells. Thus, Tn+/CD8− status is a risk factor for multiple liver metastases development and an independent negative prognostic factor for colorectal cancer.
213Bi-[DOTA0, Tyr3]Octreotide Peptide Receptor Radionuclide Therapy of Pancreatic Tumors in a Preclinical Animal Model
Authors: Norenberg Jeffrey P. , Krenning Boudewijn J. , Konings Inge R.H.M. , Kusewitt Donna F. , Nayak Tapan K. , Anderson Tamara L. , de Jong Marion , Garmestani Kayhan , Brechbiel Martin W. , Kvols Larry K. 
Published: March 2006

Abstract
Purpose: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) β-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET α-emitter, 213Bi, was evaluated.
Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/μg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model.
Results: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity &gt;95% and an incorporation yield ≥99.9%. Biodistribution data showed specific binding to somatostatin receptor–expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 ± 1.40% injected dose/g (ID/g) tissue versus 11.15 ± 0.46%, P &lt; 0.0001] and bone marrow (0.31 ± 0.01% ID/g versus 0.06 ± 0.02%, P &lt; 0.0324). A significant decrease in tumor growth rate was observed in rats treated with &gt;11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P &lt; 0.025). Treatment with &gt;20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving &lt;11 MBq (P &lt; 0.02).
Conclusions: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.
Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis.
Authors: Nakamura Yasushi , Yasuoka Hironao , Tsujimoto Masahiko , Yoshidome Katsuhide , Nakahara Masaaki , Nakao Kazuyasu , Nakamura Misa , Kakudo Kennichi 
Published: March 2006

Abstract
PURPOSE: Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. EXPERIMENTAL DESIGN: Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed. RESULTS: Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival. CONCLUSIONS: Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.