bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Selective Small Molecule c-MET Inhibitor, PHA665752, Cooperates with Rapamycin
Authors: Ma Patrick C. , Schaefer Erik , Christensen James G. , Salgia Ravi 
Published: September 2005

Abstract
Purpose: c-MET is believed to be an attractive receptor target for molecular therapeutic inhibition. TPR-MET, a constitutively active oncogenic variant of MET, serves as excellent model for testing c-MET inhibitors. Here, we characterized a small molecule c-MET inhibitor, PHA665752, and tested its cooperation with the mammalian target of rapamycin inhibitor as potential targeted therapy.
Experimental Design: The effect of PHA665752 treatment was determined on cell growth, motility and migration, apoptosis, and cell-cycle arrest of TPR-MET-transformed cells. Moreover, the effect of PHA665752 on the phosphorylation on MET, as well as its downstream effectors, p-AKT and p-S6K, was also determined. Finally, growth of TPR-MET-transformed cells was tested in the presence of PHA665752 and rapamycin. H441 non–small cell lung cancer (NSCLC) cells (with activated c-Met) were also tested against both PHA665752 and rapamycin.
Results: PHA665752 specifically inhibited cell growth in BaF3. TPR-MET cells (IC50 &lt; 0.06 μmol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3. TPR-MET cells was also inhibited. PHA665752 inhibited specific phosphorylation of TPR-MET as well as phosphorylation of downstream targets of the mammalian target of rapamycin pathway. When combined with PHA665752, rapamycin showed cooperative inhibition to reduce growth of BaF3. TPR-MET- and c-MET-expressing H441 NSCLC cells.
Conclusions: PHA665752 is a potent small molecule–selective c-MET inhibitor and is highly active against TPR-MET-transformed cells both biologically and biochemically. PHA665752 is also active against H441 NSCLC cells. The c-MET inhibitor can cooperate with rapamycin in therapeutic inhibition of NSCLC, and in vivo studies of this combination against c-MET expressing cancers would be merited.
Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine
Authors: Yamane Kazuhiko , Kinsella Timothy J. 
Published: September 2005

Abstract
Purpose: The purine antimetabolite, 6-thioguanine (6-TG), is an effective drug in the management of acute leukemias. In this study, we analyze the mechanisms of apoptosis associated with 6-TG treatment and casein kinase 2 (CK2 or CKII) in human tumor cells.
Experimental Design: Small interfering RNA and chemical CK2 inhibitors were used to reduce CK2 activity. Control and CK2 activity–reduced cells were cultured with 6-TG and assessed by flow cytometry to measure apoptosis and cell cycle profiles. Additionally, confocal microscopy was used to assess localization of CK2 catalytic units following 6-TG treatment.
Results: Transfection of small interfering RNA against the CK2 α and/or α′ catalytic subunits results in marked apoptosis of HeLa cells following treatment with 6-TG. Chemical inhibitors of CK2 also induce apoptosis following 6-TG treatment. Apoptosis induced by 6-TG is similarly observed in both mismatch repair-proficient and -deficient HCT116 and HeLa cells. Concomitant treatment with a pan-caspase inhibitor or transfection of apoptosis repressor with caspase recruitment domain markedly suppresses the apoptotic response to DNA damage by 6-TG in the CK2-reduced cells, indicating caspase regulation by CK2. CK2 α relocalizes to the endoplasmic reticulum after 6-TG treatment. Additionally, transfection of Cdc2 with a mutation at Ser39 to Ala, which is the CK2 phosphorylation site, partially inhibits cell cycle progression in G1 to G2 phase following 6-TG treatment.
Conclusion: CK2 is essential for apoptosis inhibition following DNA damage induced by 6-TG, controlling caspase activity.
Prognostic Effect of Epidermal Growth Factor Receptor and EGFRvIII in Glioblastoma Multiforme Patients
Authors: Heimberger Amy B. , Hlatky Roman , Suki Dima , Yang David , Weinberg Jeff , Gilbert Mark , Sawaya Raymond , Aldape Kenneth 
Published: September 2005

Abstract
Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in ∼50% to 60% of glioblastoma multiforme tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24% to 67% of cases. We sought to determine whether glioblastoma multiforme expression of either overexpressed wild-type EGFR or the mutant EGFRvIII is an independent predictor of overall patient survival.
Experimental Design: Glioblastoma multiforme patients (n = 196) underwent a ≥95% volumetric tumor resection followed by conformal radiation. Their EGFR and EGFRvIII status was determined by immunohistochemistry and survival analyses were done.
Results: In our study of glioblastoma multiforme patients, 46% (n = 91) failed to express EGFR, 54% (n = 105) had overexpression of the wild-type EGFR, and 31% (n = 61) also expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, sex, Karnofsky performance scale score, extent of tumor resection, or radiation. The median overall survival times for patients with tumors having EGFR expression absent, overexpressed only, or mutant (EGFRvIII) were 0.96, 0.98, and 1.07 years, respectively. However, for patients surviving ≥1 year, these values were 2.03, 2.02, and 1.21 years (P &lt; 0.0001; log-rank test comparing EGFRvIII with all others). This effect remained significant in the multivariate analysis after adjustment for all other cofactors including age and Karnofsky performance scale score (rate ratio 4.34; 95% confidence interval, 2.21-8.51).
Conclusions: Neither the overexpressed wild-type EGFR nor EGFRvIII was an independent predictor of median overall survival in this selected cohort of patients who underwent extensive tumor resection. However, in patients surviving ≥1 year, the expression of EGFRvIII was an independent negative prognostic indicator.
Prognostic Significance of Co-expression of RON and MET Receptors in Node-Negative Breast Cancer Patients
Authors: Lee Wen-Ying , Chen Helen H.W. , Chow Nan-Haw , Su Wu-Chou , Lin Pin-Wen , Guo How-Ran 
Published: September 2005

Abstract
Purpose: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration, cell dissociation, and matrix invasion. Cross-linking experiments show that RON and MET form a noncovalent complex on the cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression patterns in node-negative breast cancer.
Experimental Design: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T1-2N0M0 breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after at least a 10-year follow-up.
Results: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET. In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON−/MET+ tumors resulted in a large risk increase for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON−/MET− tumors, was only 11.8% in patients with RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON−/MET+ and RON+/MET− tumors.
Conclusions: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.
A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Cancer
Authors: Dy Grace K. , Bruzek Laura M. , Croghan Gary A. , Mandrekar Sumithra , Erlichman Charles , Peethambaram Prema , Pitot Henry C. , Hanson Lorelei J. , Reid Joel M. , Furth Alfred , Cheng Shinta , Martell Robert E. , Kaufmann Scott H. , Adjei Alex A. 
Published: September 2005

Abstract
Purpose: This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors.
Experimental Design: Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662.
Results: Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m2), paclitaxel (225 mg/m2) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (&gt; 4 cycles) occurred in eight other patients.
Conclusions: The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.
Systemic Delivery of Liposomal Short-Chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma
Authors: Stover Thomas C. , Sharma Arati , Robertson Gavin P. , Kester Mark 
Published: September 2005

Abstract
In vitro tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic sphingolipid, ceramide. However, although cell-permeable, short-chain ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of C6-ceramide (C6) in a pegylated liposomal formulation significantly limited the growth of solid tumors in a syngeneic BALB/c mouse tumor model of breast adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C6 elicited a &gt;6-fold reduction in tumor size compared with empty ghost liposomes. Histologic analyses of solid tumors from liposomal-C6-treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which ceramide induces selective cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C6 administration, we also shown diminution of solid tumor growth in a human xenograft model of breast cancer. Together, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility, drug delivery, and antineoplastic efficacy.
Identification of a 40S Ribosomal Protein S4–Derived H-Y Epitope Able to Elicit a Lymphoblast-Specific Cytotoxic T Lymphocyte Response
Authors: Ivanov Roman , Aarts Tineke , Hol Samantha , Doornenbal Angeline , Hagenbeek Anton , Petersen Eefke , Ebeling Saskia 
Published: September 2005

AbstractPurpose: The superior graft-versus-leukemia (GVL) effect of the female-to-male stem cell transplantation is partially independent from the concomitant graft-versus-host reactivity. However, the antigenic basis of this selective GVL response remains enigmatic, because no H-Y antigens with hematopoietic-restricted expression were identified. In this study, we report a novel H-Y epitope that is preferentially recognized on activated proliferating lymphocytes.Experimental Design: We generated a CTL clone YKIII.8 that showed reactivity toward male B*5201+ CD40-activated B cells, EBV-lymphoblastoid cell lines, and phytohemagglutinin-activated T-cell blasts but little or no reactivity toward fibroblasts, CD14+ cells, or unstimulated B and T cells. The antigen recognized by YKIII.8 was identified by screening of a cDNA expression library, and its pattern of expression was investigated.Results: cDNA of the male isoform of 40S ribosomal protein S4 was found to encode the antigenic peptide TIRYPDPVI, which was recognized by YKIII.8. Western blot analysis showed that rapidly proliferating cells overexpress the RPS4 protein in comparison with nonrecognized cell subsets. Retroviral transfer of YKIII.8 T-cell receptor resulted in preservation of the lymphoblast-specific reactivity pattern.Conclusion: Our findings suggest that CTL specific to certain epitopes of ubiquitously expressed H-Y antigens may specifically target lymphoblasts, contributing to the selective GVL effect of female-to-male stem cell transplantation.
Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis
Authors: Shinozaki Masaru , Hoon Dave S.B. , Giuliano Armando E. , Hansen Nora M. , Wang He-Jing , Turner Roderick , Taback Bret 
Published: September 2005

Abstract
Purpose: Gene promoter region hypermethylation is a significant event in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown.
Experimental Design: We conducted hypermethylation profiling of 151 primary breast tumors with association to known prognostic factors in breast cancer using methylation-specific PCR for six known tumor suppressor and related genes: RASSF1A, APC, TWIST, CDH1, GSTP1, and RAR-β2. Furthermore, correlation with sentinel lymph node (SLN) tumor status was assessed as it represents the earliest stage of metastasis that is readily detected. Hypermethylation for any one gene was identified in 147 (97%) of 151 primary breast tumors. The most frequently hypermethylated gene was RASSF1A (81%).
Results: Hypermethylation of the CDH1 was significantly associated with primary breast tumors demonstrating lymphovascular invasion (P = 0.008), infiltrating ductal histology (P = 0.03), and negative for the estrogen receptor (P = 0.005), whereas RASSF1A and RAR-β2 gene hypermethylation were significantly more common in estrogen receptor–positive (P &lt; 0.001) and human epidermal growth factor receptor 2–positive (P &lt; 0.001) tumors, respectively. In multivariate analysis, hypermethylation of GSTP1 and/or RAR-β2 was significantly associated with patients having macroscopic SLN metastasis compared with those with microscopic or no sentinel node metastasis (odds ratio, 4.59; 95% confidence interval, 2.02-10.4; P &lt; 0.001). In paired SLN metastasis, CDH1 was the most frequently methylated gene (90%) and provides evidence in patients corroborating its role in the clinical development of metastasis.
Conclusion: Hypermethylation profiling of primary breast tumors is significantly associated with known pathologic prognostic factors and may have additional clinical and pathologic utility for assessing patient prognosis and predicting early regional metastasis.
Cytochrome P450 Profile of Colorectal Cancer: Identification of Markers of Prognosis
Authors: Kumarakulasingham Meera , Rooney Patrick H. , Dundas Sinclair R. , Telfer Colin , Melvin William T. , Curran Stephanie , Murray Graeme I. 
Published: September 2005

Abstract
Purpose: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer.
Experimental Design: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91 lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy.
Results: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009).
Conclusions: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51 or CYP2S1 were associated with poor prognosis and CYP51 is an independent marker of prognosis.
Aromatase Expression in Stromal Cells of Endometrioid Endometrial Cancer Correlates with Poor Survival
Authors: Segawa Tomoya , Shozu Makio , Murakami Kouich , Kasai Tadayuki , Shinohara Kazunori , Nomura Kazuhito , Ohno Satoshi , Inoue Masaki 
Published: September 2005

Abstract
Purpose and Experimental Design: To assess the prognostic significance of intratumoral aromatase in endometrioid endometrial cancer, sections from 55 patients with endometrial cancer were evaluated for expression of aromatase using immunohistochemistry, and the correlation between aromatase expression and clinicopathologic parameters were analyzed.
Results: Immunohistochemical staining for aromatase was positive for 32 (58%), 20 (36%), and 19 (34%) patients in cancer epithelial cells, stromal cells, and myometrial cells around the flank invasion, respectively. In situ hybridization also detected aromatase mRNA in all three types of cells. RT-PCR analysis revealed that aromatase mRNA was 2.5 ± 1.0 amol/μg total RNA (mean ± SE; n = 7) in tumor tissue. Western blot analysis detected the expected aromatase protein size of 58 kDa in cancer tissues more abundantly than in cancer-free endometrium (n = 3). The immunoreactivity in stromal cells correlated positively with advanced surgical stage and poor survival. Survival analysis revealed that the immunoreactivity of stromal cells was a significant prognostic factor, independent of histologic grade, muscular invasion, and lymph node metastasis, but dependent on surgical stage. By contrast, the immunoreactivity of aromatase both in cancer epithelial cells and myometrial cells did not correlate with prognosis.
Conclusions: To the best of our knowledge, this is the first evidence associating intratumoral aromatase expression in stromal cells and poor survival in endometrioid endometrial cancer. This positive linkage indicates that local expression of aromatase plays a role in tumor progression through the formation of in situ estrogens. In situ expression of aromatase may offer a potential target for management of endometrial cancers.
Association of Visceral Fat Accumulation and Plasma Adiponectin with Colorectal Adenoma: Evidence for Participation of Insulin Resistance
Authors: Otake Sayaka , Takeda Hiroaki , Suzuki Yasukuni , Fukui Tadahisa , Watanabe Shinichiro , Ishihama Katsuyoshi , Saito Takafumi , Togashi Hitoshi , Nakamura Tadashi , Matsuzawa Yuji , Kawata Sumio 
Published: September 2005

Abstract
Purpose: Colorectal carcinogenesis is thought to be related to abdominal obesity and insulin resistance. To investigate whether visceral fat accumulation contributes to colorectal carcinogenesis, we examined its accumulation and the levels of the adipose tissue–derived hormone adiponectin in Japanese patients with colorectal adenoma.
Experimental Design: Fifty-one consecutive Japanese patients ages ≥40 years and with colorectal adenoma were subjected to measurement of visceral fat area by computed tomography scanning and plasma adiponectin concentration. The patients also underwent the 75-g oral glucose tolerance test. Insulin resistance was calculated by the homeostasis metabolic assessment (HOMA-IR) method. The controls were 52 Japanese subjects ages ≥40 years and without colorectal polyp. Cigarette smokers and subjects who consumed alcohol (≥30 g ethanol/d) were excluded.
Results: The patients with colorectal adenoma showed significantly more visceral fat area and significantly less plasma adiponectin concentration in comparison with the controls [odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.47-3.28; P &lt; 0.001 and OR, 0.24; 95% CI, 0.14-0.41; P &lt; 0.001, respectively] by logistic regression analysis. HOMA-IR index was also associated with colorectal adenoma (OR 2.60; 95% CI, 1.20-5.64; P = 0.040). Visceral fat area and adiponectin were associated with adenoma number (1, 2, ≥ 3), the size of the largest adenoma (&lt;10 and ≥10 mm), and adenoma histology (tubular and tubulovillous/villous).
Conclusions: These results suggest an association of visceral fat accumulation and decreased plasma adiponectin concentration with colorectal adenoma in Japanese patients. This study may offer a new insight to understanding the relationship of colorectal carcinogenesis with abdominal obesity and insulin resistance.
Outcome in Hodgkin's Lymphoma Can Be Predicted from the Presence of Accompanying Cytotoxic and Regulatory T Cells
Authors: Álvaro Tomás , Lejeune Marylène , Salvadó Ma Teresa , Bosch Ramón , García Juan F. , Jaén Joaquín , Banham Alison H. , Roncador Giovanna , Montalbán Carlos , Piris Miguel A. 
Published: September 2005

AbstractPurpose: Recent studies of Hodgkin's lymphoma (HL) have suggested that the presence of regulatory T cells in the reactive background may explain the inhibition of the antitumoral host immune response observed in these patients. This study aimed to assess the relevance of regulatory T cells and CTLs present in the background of HL samples in the prognosis of a series of classic HL (cHL) patients.Experimental Design: Expression of granzyme B and TIA-1 (markers for CTL) and FOXP3 (a marker for regulatory T cells) were evaluated independently by immunohistochemistry in tissue microarrays of 257 cHL patients and correlated with patient outcome.Results: The combined influence of the presence of FOXP3+ and TIA-1+ cells distinguished three risk groups of patients with 5-year overall survival of 100%, 88%, and 73%. The presence of a small number of FOXP3+ cells and a high proportion of TIA-1+ cells in the infiltrate represent an independent prognostic factor that negatively influenced event-free survival and disease-free survival in cHL. Compared with the features at diagnosis, relapsed samples tended to have more TIA-1+ cells and a lower proportion of FOXP3+ cells in the reactive background.Conclusions: These data suggest that low infiltration of FOXP3+ cells in conjunction with high infiltration of TIA-1+ cells in cHL may represent biological markers predicting an unfavorable outcome. Moreover, the variation of these markers over the course of the disease implies a possible role for them in the progression of HL cases.