bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design of a pH-Sensitive Polymeric Carrier for Drug Release and Its Application in Cancer Therapy
Authors: Kamada Haruhiko , Tsutsumi Yasuo , Yoshioka Yasuo , Yamamoto Yoko , Kodaira Hiroshi , Tsunoda Shin-ichi , Okamoto Takayuki , Mukai Yohei , Shibata Hiroko , Nakagawa Shinsaku , Mayumi Tadanori 
Published: September 2005

Abstract
Purpose: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier.
Experimental Design: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined.
Results: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo.
Conclusions: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.
Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity
Authors: Rouits Elisabeth , Boisdron-Celle Michèle , Dumont Agnès , Guérin Olivier , Morel Alain , Gamelin Erick 
Published: September 2005

Abstract
Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert’s syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients.
Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment.
Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert’s syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity.
Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert’s syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.
Prognostic Significance of
c-kit
Mutation in Localized Gastrointestinal Stromal Tumors
Authors: Kim Tae Won , Lee Hyoungnam , Kang Yoon-Koo , Choe Mi Sun , Ryu Min-Hee , Chang Heung Moon , Kim Jung Sun , Yook Jeong Hwan , Kim Byung Sik , Lee Jung Shin 
Published: September 2005

Abstract
Purpose: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial.
Experimental Design: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced.
Results: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts &lt; 5 mitoses/50 high power field, spindle-cell histology, tumor size &lt; 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count [≥5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (≥5 cm; OR = 4.2).
Conclusions: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.
Suppression of Constitutive and Tumor Necrosis Factor α-Induced Nuclear Factor (NF)-κB Activation and Induction of Apoptosis by Apigenin in Human Prostate Carcinoma PC-3 Cells: Correlation with Down-Regulation of NF-κB-Responsive Genes
Authors: Shukla Sanjeev , Gupta Sanjay 
Published: September 2005

Abstract
Purpose: Development of androgen independence and resistance to apoptosis in prostate cancer are often correlated with high levels of serum tumor necrosis factor (TNF)-α in these patients. The loss of sensitivity to TNF-α-induced apoptosis in androgen-insensitive prostate carcinoma cells is due in part to constitutive activation of Rel/nuclear factor (NF)-κB transcription factors that regulate several cell survival and antiapoptotic genes. Our previous studies have demonstrated growth inhibitory and apoptotic effects of apigenin, a common plant flavonoid, in a variety of human prostate carcinoma cells. Here we examined whether apigenin is effective in inhibiting NF-κB expression in androgen-insensitive human prostate carcinoma cells exhibiting high constitutive levels of NF-κB.
Experimental Design: Using androgen-insensitive human prostate carcinoma PC-3 cells, the effect of apigenin was assessed on NF-κB activation by electrophoretic mobility shift assay and reporter gene assay. Expression of NF-κB subunits p65 and p50, IκBα, p-IκBα, in-beads kinase assay and NF-κB-regulated genes were determined by Western blot analysis. Apoptosis was determined by annexin V/propidium iodide staining after fluorescence-activated cell-sorting analysis.
Results: Treatment of cells with 10–40-μm doses of apigenin inhibited DNA binding and reduced nuclear levels of the p65 and p50 subunits of NF-κB. Apigenin inhibited IκBα degradation and IκBα phosphorylation and significantly decreased IKKα kinase activity. Apigenin also inhibited TNF-α-induced activation of NF-κB via the IκBα pathway, thereby sensitizing the cells to TNF-α-induced apoptosis. The inhibition of NF-κB activation correlated with a decreased expression of NF-κB-dependent reporter gene and suppressed expression of NF-κB-regulated genes [specifically, Bcl2, cyclin D1, cyclooxygenase-2, matrix metalloproteinase 9, nitric oxide synthase-2 (NOS-2), and vascular endothelial growth factor].
Conclusions: Our results indicate that inhibition of NF-κB by apigenin may lead to prostate cancer suppression by transcriptional repression of NF-κB-responsive genes as well as selective sensitization of prostate carcinoma cells to TNF-α-induced apoptosis.
BRCA
Mutations and Risk of Prostate Cancer in Ashkenazi Jews
Authors: Kirchhoff Tomas , Kauff Noah D. , Mitra Nandita , Nafa Kedoudja , Huang Helen , Palmer Crystal , Gulati Tony , Wadsworth Eve , Donat Sheri , Robson Mark E. , Ellis Nathan A. , Offit Kenneth 
Published: September 2005

Abstract
Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study.
Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age.
Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64–7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87–12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased.
Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.
Methylation of
p16
CpG Islands Associated with Malignant Transformation of Gastric Dysplasia in a Population-Based Study
Authors: Sun Yu , Deng Dajun , You Wei-Cheng , Bai Hua , Zhang Lian , Zhou Jing , Shen Lin , Ma Jun-Ling , Xie Yu-Quan , Li Ji-You 
Published: September 2005

Abstract
Purpose: Inactivation of p16 by aberrant methylation of CpG islands is a frequent event in carcinomas and precancerous lesions of various organs, including the stomach. The aim of this study is to investigate the relationship between p16 methylation and malignant transformation of human gastric dysplasia (DYS) based on follow-up endoscopic screening in a high-risk population.
Experimental Design: Genomic DNA samples were extracted from paraffin blocks of gastric mucosal biopsies that were histopathologically diagnosed as low-grade DYS from patients who developed gastric carcinomas [GCs (n = 21)] and those that did not do so (n = 21) during 5 years of follow-up. The methylation status of p16 CpG islands of each sample was detected by methylation-specific PCR, denatured high-performance liquid chromatography, and sequencing.
Results: Aberrant p16 methylation was observed in 5 of 21 samples of DYS that progressed to GC but in 0 of 21 samples that did not progress to GC (P = 0.048, two-sided). Sequencing results confirmed that all CpG sites were methylated in the analyzed sequence from these five p16-methylated cases. Furthermore, p16 methylation was also observed in the five subsequent GCs. Unmethylated p16 CpG islands were detected in all of the samples without p16 methylation.
Conclusions: Our findings suggest p16 methylation is correlated with the malignant transformation of gastric DYS, and p16 methylation might be a useful biomarker for prediction of malignant potential of gastric DYS.
Genetically Altered Fields as Origin of Locally Recurrent Head and Neck Cancer
Authors: Tabor Maarten P. , Brakenhoff Ruud H. , Ruijter-Schippers Henrique J. , Kummer J. Alain , Leemans C. René , Braakhuis Boudewijn J. M. 
Published: September 2005

AbstractPurpose: Surgeons treating patients with head and neck squamous cell carcinoma (HNSCC) rely heavily on histology to decide whether the resection margins are tumor free and subsequent adjuvant treatments can be omitted. However, despite the presence of tumor-free margins, 10–30% of HNSCC patients still develop a locally recurrent tumor. Evidence is available that recurrent cancer develops from either (a) outgrowth of a relatively small number of tumor cells that have not been detected by the pathologist or (b) a precursor lesion in which additional genetic alterations have led again to invasive cancer.Experimental Design: In a retrospective study on 13 HNSCC cases, we analyzed the primary tumor, its surrounding histologically tumor-free resection margins, and local recurrences for loss of heterozygosity (22 microsatellite markers on 6 chromosomes) and TP53 mutations to determine the origin of the recurrent cancer.Results: A precursor lesion was absent in 5 of 13 (39%) cases, and the genetic similarity of the primary and recurrent cancer was high, providing evidence that residual cancer cells were the origin of recurrence. For the remaining eight cases (61%) a genetically related precursor lesion (field) was detected, and for five of these cases, evidence was found that both the primary and recurrent carcinoma originated from this field. The remaining three cases were less conclusive.Conclusions: This study explains the pathobiology of locally recurrent HNSCC in patients with histologically tumor-free resection margins and indicates that the development of novel therapies to decrease the local recurrence rates in HNSCC should not only be focused on eradicating residual cancer cells but also on the precursor lesions that are left behind.
Ability to Predict Metastasis Based On Pathology Findings and Alterations in Nuclear Structure Of Normal-Appearing and Cancer Peripheral Zone Epithelium in the Prostate
Authors: Veltri Robert W. , Khan Masood A. , Miller M. Craig , Epstein Jonathan I. , Mangold Leslie A. , Walsh Patrick C. , Partin Alan W. 
Published: September 2005

Abstract
Purpose: Malignant transformation in the prostate produces significant alterations in glandular architecture (Gleason grade) and nuclear structure that provide valuable prognostic information. Normal-appearing nuclei (NN) adjacent to cancer may also have altered functions in response to malignancy. We studied NN adjacent to peripheral zone (PZ) prostate cancer (PCa), as well as the PZ cancer nuclei (CaN) using quantitative image cytometry. The nuclear structure information was combined with routine pathological findings to predict metastatic PCa progression and/or death.
Experimental Design: Tissue microarrays of normal-appearing and cancer areas were prepared from 182 pathologist-selected paraffin blocks. Feulgen-stained CaN and NN were captured from the tissue microarrays using the AutoCyte Pathology Workstation. Multivariate logistic regression was used to calculate quantitative nuclear grade (QNG) solutions based on nuclear morphometric descriptors determined from NN and CaN. Multivariate logistic regression and Kaplan-Meier plots were also used to predict risk for distant metastasis and/or PCa-specific death using QNG solutions and routine pathology.
Results: The pathology model yielded an area under the receiver operator characteristic curve of 72.5%. The QNG-NN and QNG-CaN solutions yielded an area under the receiver operator characteristic curve of 81.6 and 79.9%, respectively, but used different sets of nuclear morphometric descriptors. Kaplan-Meier plots for the pathology variables, the QNG-NN and QNG-CaN solutions, were combined with pathology to defined three statistically significantly distinct risk groups for distant metastasis and/or death (P &lt; 0.0001).
Conclusions: Alterations in cancer or normal-appearing nuclei adjacent to peripheral zone cancer areas can predict PCa progression and/or death. The QNG-NN and QNG-CA solutions could be combined with pathology variables to improve the prediction of distant metastasis.
Identification of C-Met Oncogene as a Broadly Expressed Tumor-Associated Antigen Recognized by Cytotoxic T-Lymphocytes
Authors: Schag Kerstin , Schmidt Susanne M. , Müller Martin R. , Weinschenk Toni , Appel Silke , Weck Markus M. , Grünebach Frank , Stevanovic Stefan , Rammensee Hans-Georg , Brossart Peter 
Published: September 2005

Abstract
Purpose: C-Met proto-oncogene is a receptor tyrosine kinase that mediates the oncogenic activities of the hepatocyte growth factor. Using a DNA chip analysis of tumor samples from patients with renal cell carcinoma and sequencing of peptides bound to the HLA-A*0201 molecules on tumor cells a peptide derived from the c-Met protein was identified recently.
Experimental Design: We used this novel HLA-A*0201 peptide for the induction of specific CTLs to analyze the presentation of this epitope by malignant cells.
Results: The induced CTL efficiently lysed target cells pulsed with the cognate peptide, as well as HLA-A*0201-matched tumor cell lines in an antigen-specific and HLA-restricted manner. Furthermore, the induced c-Met-specific CTLs recognized autologous dendritic cells (DCs) pulsed with the peptide or transfected with whole-tumor mRNA purified from c-Met-expressing cell lines. We next induced c-Met-specific CTLs using peripheral blood mononuclear cells and DC from an HLA-A*0201-positive patient with plasma cell leukemia to determine the recognition of primary autologous malignant cells. These CTLs lysed malignant plasma cells while sparing nonmalignant B- and T-lymphocytes, monocytes, and DCs.
Conclusion: Our results demonstrate that c-Met oncogene is a novel tumor rejection antigen recognized by CTL and expressed on a broad variety of epithelial and hematopoietic malignant cells.
Selective Tyrosine Hyperphosphorylation of Cytoskeletal and Stress Proteins in Primary Human Breast Cancers
Authors: Lim Yoon-Pin , Wong Chow Yin , Ooi London Lucien , Druker Brian J. , Epstein Richard J. 
Published: September 2005

Abstract
Purpose: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors.
Experimental Design: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells.
Results: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exhibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-γ, and phosphatidylinositol 3′-kinase).
Conclusions: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.
HER-2 Gene Amplification Correlates with Higher Levels of Angiogenesis and Lower Levels of Hypoxia in Primary Breast Tumors
Authors: Blackwell Kimberly L. , Dewhirst Mark W. , Liotcheva Vlayka , Snyder Stacey , Broadwater Gloria , Bentley Rex , Lal Anita , Riggins Gregory , Anderson Steve , Vredenburgh Jim , Proia Alan , Harris Lyndsay N. 
Published: September 2005

Abstract
Purpose: This study investigated the connection among HER-2 gene amplification, HER-2 protein expression, and markers of tumor angiogenesis and oxygenation in patients with operable, invasive breast tumors.
Experimental Design: From 1988 to 1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks were obtained and evaluated using immunohistochemistry (IHC) staining of vessels with von Willebrand factor antibody. Mean microvessel densities (MVD) were determined by counting von Willebrand factor stained cells in three separate “vascular hot spots” using image analysis. Tumor samples were also stained for HER-2 by IHC, HER-2 gene amplification by fluorescence in situ hybridization, carbonic anhydrase 9 by IHC, and vascular endothelial growth factor (VEGF) by IHC. Plasma from 36 patients with primary tumor samples had VEGF (R&D Systems, MN) and d-dimer (American Diagnostica, Greenwich, CT) levels determined.
Results: There was a significant positive correlation between HER-2 gene amplification and both maximum and average MVD (Spearman coefficient = 0.51 and 0.50; P = 0.03 and 0.05, respectively). There was an inverse correlation with HER-2 gene amplification and expression of the tumor hypoxia marker CA-9 (χ2 P = 0.02). The level of HER-2 gene amplification correlated with plasma d-dimer levels (Spearman coefficient = 0.43; P = 0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (χ2 = 5.81; P = 0.01). There was no correlation between HER-2 by IHC and MVD or d-dimer. Of all of the variables examined, only average (P = 0.0016) and maximum MVD (P = 0.0128) predicted disease-free survival (Cox univariate model).
Conclusions: HER-2-amplified breast cancers have increased amounts of angiogenesis, decreased amounts of hypoxia, and increased markers of fibrin degradation. These findings have prognostic, predictive, and therapeutic implications in breast cancer treatment.