bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Efficacy of Dose-Intensive Oral Vitamin A in Subjects with Sun-Damaged Skin
Authors: Alberts David , Ranger-Moore James , Einspahr Janine , Saboda Kathylynn , Bozzo Paul , Liu Yun , Xu Xiao-chun , Lotan Reuben , Warneke James , Salasche Stuart , Stratton Suzanne , Levine Norman , Goldman Rayna , Islas Marcy , Duckett Laura , Thompson Deborah , Bartels Peter 
Published: September 2005

Abstract
Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU/day would be both safe and more efficacious in skin cancer chemoprevention.
Experimental Design: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25,000, 50,000, or 75,000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sun-damaged skin.
Results: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25,000 IU/day, 50,000 IU/day, and 75,000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22,600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25,000 and 50,000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor α, retinoic acid receptor β, and retinoid X receptor α at the 50,000 IU/day vitamin A dose.
Conclusions: The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.
The Stable Nitroxide Tempol Facilitates Salivary Gland Protection during Head and Neck Irradiation in a Mouse Model
Authors: Vitolo Joseph M. , Cotrim Ana P. , Sowers Anastasia L. , Russo Angelo , Wellner Robert B. , Pillemer Stanley R. , Mitchell James B. , Baum Bruce J. 
Published: September 2005

Abstract
Purpose: Radiotherapy is commonly used to treat a majority of patients with head and neck cancers. The long-term radiation-induced reduction of saliva output significantly contributes to the posttreatment morbidity experienced by these patients. The purpose of this study was to test the ability of the stable-free radical Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), an established radioprotector, to prevent radiation-induced salivary hypofunction in mice.
Experimental Design: The heads of C3H mice were exposed to a range of single radiation doses with or without an i.p. injection of 275 mg/kg Tempol 10 min before treatment. Salivary gland output was assessed 8 weeks postirradiation.
Results: Radiation caused a dose-dependent reduction in salivary flow in this model. Tempol treatment alone significantly reduced radiation-induced salivary hypofunction. The combination of Tempol with mouth/nose shielding showed essentially complete radiation protection at 15 Gy and ∼75% protection at 17.5 Gy.
Conclusions: This study demonstrates for the first time that significant radioprotection of the salivary glands is possible with Tempol in C3H mice.
Genetic and Plasma Markers of Venous Thromboembolism in Patients with High Grade Glioma
Authors: Sciacca Francesca L. , Ciusani Emilio , Silvani Antonio , Corsini Elena , Frigerio Simona , Pogliani Simona , Parati Eugenio , Croci Danilo , Boiardi Amerigo , Salmaggi Andrea 
Published: September 2005

Abstract
Purpose: Deep venous thrombosis/pulmonary embolism (DVT/PE) is a frequent complication in the course of cancer, particularly in brain tumors. We investigated genetic and plasma factors possibly associated with risk of DVT/PE in patients with high-grade glioma.
Experimental Design: In a case-control study, we studied polymorphisms of the genes coding for factor II (G20210A), factor V (G1691A), methylenetetrahydrofolate-reductase (C677T), tissue-type plasminogen activator (tPA; insertion/deletion), plasminogen activator inhibitor-1 (PAI-1; 4G/5G), and vascular endothelial growth factor (VEGF; C936T). We also measured plasma levels of d-dimer, lipoprotein (lp) (a), homocysteine, VEGF, tPA, and PAI-1, comparing healthy control patients with patients with glioma or with patients with neurological nonneoplastic disease (multiple sclerosis).
Results: Genotype frequencies of polymorphisms analyzed were similar in patients with glioma and in healthy matched population. d-dimer, lp (a), homocysteine, VEGF, tPA, and PAI-1 plasma levels were significantly higher in patients with glioma than in healthy controls, whereas patients having neurological nonneoplastic disease had plasma values of these molecules not significantly different from healthy controls. VEGF, tPA, and PAI-1 were also found at high-plasma levels in patients carrying genotypes that, in healthy controls, were associated with “low-producing” phenotypes.
Conclusions: Genetic risk factors alone did not explain the high incidence of DVT/PE observed in patients with glioma. Higher plasma levels of molecules influencing the coagulation pathways indicate that the tumor itself might confer an increased risk of DVT/PE; thus, d-dimer, homocysteine, lp (a), VEGF, tPA, and PAI-1 look like good candidates to be evaluated as DVT/PE prognostic factors.
The Expression of ERβcx in Human Breast Cancer and the Relationship to Endocrine Therapy and Survival
Authors: Palmieri Carlo , Lam Eric W.-F. , Mansi Janine , MacDonald Claire , Shousha Sami , Madden Peter , Omoto Yoko , Sunters Andrew , Warner Margaret , Gustafsson Jan-Åke , Coombes R. Charles 
Published: September 2005

Abstract
Purpose: Estrogen receptor (ER) α-positive breast cancer is often treated with endocrine therapy using either antiestrogens or aromatase inhibitors. However, 30% of patients who receive endocrine therapy will derive no benefit from such treatments and may indeed suffer adverse effects. Currently, there are no ways to predict response to such treatments. ERβcx, a variant of ERβ, has a dominant-negative effect over ERα, and its expression thought to modulate response to endocrine treatment may represent a predictor of response to endocrine therapy.
Experimental Design: We investigated the expression of the ERβcx in 82 frozen breast samples (8 benign, 1 ductal carcinoma in situ, and 73 malignant) by Western blot analysis. The relationship between the expression of ERβcx variants with prognosis and outcome of endocrine therapy was examined.
Results: There was a statistically significant association between the presence of ERβcx and the response to endocrine therapy (Fisher’s exact test, P = 0.04). We also examined the influence of the ERβcx status of a tumor on time to progression and death. There was a relationship between the presence of ERβcx and survival, with patients whose tumors express ERβcx having a longer survival rate (P = 0.05). Cell-type specificity of expression was assessed by immunohistochemistry on a selection of histological samples.
Conclusions: On the basis of this small group of patients, we conclude that the expression of ERβcx correlated with favorable response to endocrine therapy. A larger study involving the staining of archival material is currently underway to confirm these preliminary results.
High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas
Authors: Selvakumar Ponniah , Lakshmikuttyamma Ashakumary , Kanthan Rani , Kanthan Selliah Chandra , Dimmock Jonathan R. , Sharma Rajendra K. 
Published: September 2005

Abstract
Purpose: Several viral and eukaryotic proteins required for signal transduction and regulatory functions undergo lipophilic modification by the enzyme N-myristoyltransferase. Previously we reported that N-myristoyltransferase activity is higher in colon and gallbladder carcinoma than in the corresponding normal tissues. Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. To investigate whether MetAP2 contributes to the pathogenesis of colon carcinoma, we investigated the expression of MetAP2 in both normal and invasive tumor components of human samples.
Experimental Design: We evaluated 50 cases of colon carcinoma for this study. In this report we analyzed 15 cases for MetAP2 activity and 13 cases for the expression of MetAP2 by Western blot in both the normal and in invasive tumor components of human samples. In addition, immunohistochemistry analysis was also carried out on samples from all patients.
Results: MetAP activity was elevated in all cancerous tissues compared with normal tissues. Western blot analysis also showed the higher expression of MetAP2 in all cases of cancerous tissues. In addition, immunohistochemistry analysis revealed that all cases of colorectal adenocarcinoma showed moderate to strong cytoplasmic positivity for MetAP2 with increased intensity in the invasive component.
Conclusions: Elevated MetAP protein expression is associated with metastatic tumor progression and appears to be a strong molecular marker for clinical prognosis. MetAP2 inhibition may represent a potential target for therapeutic intervention in colorectal carcinoma.
Plasma Etoposide Catechol Increases in Pediatric Patients Undergoing Multiple-Day Chemotherapy with Etoposide
Authors: Zheng Naiyu , Felix Carolyn A. , Pang Shaokun , Boston Ray , Moate Peter , Scavuzzo Jennifer , Blair Ian A. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to determine inter- and intrapatient differences in the pharmacokinetic profiles of etoposide and its genotoxic catechol metabolite during conventional multiple-day dosing of etoposide in pediatric patients.
Experimental Design: Seven pediatric patients with various malignancies received etoposide at a dose of 100 mg/m2 i.v. over 1 h daily for 5 days. Blood samples were taken at selected time points on days 1 and 5. Plasma and protein-free plasma concentrations of etoposide and etoposide catechol were determined using a validated liquid chromatography/tandem mass spectrometry assay. Pharmacokinetic parameters of both etoposide and etoposide catechol were calculated using the WinSAAM modeling program developed at NIH.
Results: The mean maximum concentration (Cmax) for total (0.262 ± 0.107 μg/ml) and free catechol (0.0186 ± 0.0082 μg/ml) on day 5 were higher than the mean Cmax for total (0.114 ± 0.028 μg/ml) and free catechol (0.0120 ± 0.0091 μg/ml) on day 1. The mean area under the plasma concentration-time curve (AUC)24h for total (105.4 ± 49.1 μg.min/ml) and free catechol (4.89 ± 2.23 μg.min/ml) on day 5 were much greater (P &lt; 0.05) than those for total (55.9 ± 16.1 μg.min/ml) and free catechol (3.04 ± 1.04 μg.min/ml) on day 1. In contrast, the AUC24h for etoposide was slightly lower on day 5 than on day 1.
Conclusions: The Cmax and AUC24h for etoposide catechol were significantly higher on day 5 than on day 1. This suggests that metabolism of etoposide to its catechol metabolite increases in pediatric patients receiving multiple-day bolus etoposide infusions. These findings may be relevant to future reduction of the risk of leukemia as a treatment complication, because etoposide and etoposide catechol are both genotoxins.
Mouse Mammary Tumor-Like Virus Is Associated with p53 Nuclear Accumulation and Progesterone Receptor Positivity but not Estrogen Positivity in Human Female Breast Cancer
Authors: Faedo Margaret , Ford Caroline E. , Mehta Reena , Blazek Katrina , Rawlinson William D. 
Published: September 2005

Abstract
Purpose: The purpose is to compare the presence of proteins with known associations with breast cancer—progesterone receptor (PgR), estrogen receptor, and p53, with the prevalence of mouse mammary tumor virus (MMTV)-like DNA sequences in human female breast cancers.
Experimental Design: A cohort of 128 Australian female breast cancers were screened for MMTV-like DNA sequences using PCR. The presence of PgR, estrogen receptor, and nuclear accumulation of p53 protein was assessed in the same samples using immunohistochemical staining.
Results: Nuclear accumulation of p53 was significantly more prevalent (P = 0.05) in archival human breast cancers containing MMTV-like DNA sequences. The presence of progesterone receptor was significantly higher in MMTV-positive than MMTV-negative breast cancers (P = 0.01). No correlation between estrogen receptor and MMTV-like DNA sequences was found.
Conclusions: MMTV causes breast cancer in mice, and hormones up-regulate expression of virus in mice mammary tissue. It is unknown if this is the case in human breast cancers shown to contain DNA of MMTV-like viruses. The positive association between MMTV-like DNA sequences and PgR indicates hormones and MMTV may play a role in human breast cancer. Mutations of the tumor suppressor gene p53 are common in human breast cancer and are associated with higher grades of cancer. The association of MMTV-like DNA sequences with higher grades of cancer, and the positive association between p53 and MMTV-like DNA sequences clearly warrant additional investigation.
Aberrant Promoter Methylation in Human DAB2 Interactive Protein (
hDAB2IP
) Gene in Breast Cancer
Authors: Dote Hideaki , Toyooka Shinichi , Tsukuda Kazunori , Yano Masaaki , Ouchida Mamoru , Doihara Hiroyoshi , Suzuki Makoto , Chen Hong , Hsieh Jer-Tsong , Gazdar Adi F. , Shimizu Nobuyoshi 
Published: September 2005

Abstract
Purpose: Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumor suppressor gene inactivated by methylation in prostate cancer. We analyzed methylation and expression status of hDAB2IP in breast cancer.
Experimental Design: The promoter region of hDAB2IP was divided into two regions (m2a and m2b) following our previous report on prostate cancer, and methylation status was determined in breast cancer cell lines with bisulfited DNA sequencing. Expression was semiquantified with real-time reverse transcription-PCR to find that aberrant methylation showed the inverse relationship with expression. On the basis of sequence data, we developed methylation-specific PCR for m2a and m2b regions and applied to samples.
Results: Aberrant methylation was detected in 11 of 25 breast cancer cell lines (44%) and 15 of 39 primary tumors (38%) at the m2a region and in 12 of 25 cell lines (48%) and 13 of 39 tumors (33%) at the m2b region. In addition, gene expression was restored in methylated cell lines with 5-aza-2′-deoxycytidine, confirming that methylation caused gene down-regulation. We also examined the relationship between hDAB2IP methylation and clinicopathologic features in primary tumors and found that methylation in the m2b region was associated with progressive nodal status of tumors.
Conclusions: We developed methylation-specific PCR for hDAB2IP and examined its methylation status in breast cancer. Our results demonstrate that hDAB2IP methylation frequently is present in breast cancer and plays a key role in hDAB2IP inactivation, suggesting the relationship between hDAB2IP methylation and lymph node metastasis of breast cancer.
Human Kallikrein Gene 11 (
KLK11
) mRNA Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer
Authors: Shigemasa Kazushi , Gu Lijun , Tanimoto Hirotoshi , O’Brien Timothy J. , Ohama Koso 
Published: September 2005

Abstract
Purpose: The purpose of this study was to examine expression levels of the human tissue kallikrein 11 gene (KLK11) in epithelial ovarian tumors and to identify the relationship between KLK11 expression and patient survival.
Experimental Design: KLK11 mRNA expression was examined by semiquantitative PCR in 64 epithelial ovarian tumors (7 adenomas, 6 low malignant potential tumors, and 51 adenocarcinomas) and in 10 normal ovaries. Semiquantitative PCR results were correlated with clinicopathologic variables and overall survival. cDNA from human normal tissues and tumor tissues was also analyzed.
Results: KLK11 mRNA expression was detected in various human cancer tissues including breast, lung, colon, prostate, pancreas, and ovarian carcinoma. The mean value of relative KLK11 expression ratio was significantly higher in ovarian tumor samples than in normal ovary samples (compared with normal samples: adenoma, P = 0.0006; low malignant potential tumor, P = 0.0049; and carcinoma, P &lt; 0.0001). No statistically significant associations between KLK11 mRNA expression level and clinical stage, histological type, or histological grade were observed. The log-rank test showed that high KLK11 mRNA expression and advanced clinical stage significantly correlated with poor patient survival (P = 0.0185 and P = 0.0043, respectively). High KLK11 mRNA expression and clinical stage remained significantly associated with overall survival (P = 0.0225 and P = 0.0202, respectively) after multivariate analysis.
Conclusions: KLK11 expression may play an important role in ovarian cancer development and act as an independent prognostic marker in ovarian cancer patients.
A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice
Authors: Ikoma Tetsuro , Takahashi Tomoyuki , Nagano Satoshi , Li Yun-Mo , Ohno Yasushi , Ando Kazuki , Fujiwara Takako , Fujiwara Hisayoshi , Kosai Ken-ichiro 
Published: September 2005

Abstract
Purpose: Lung cancer is a major cause of cancer death, and its incidence is increasing in the world. Conventional therapies remain less effective for metastases of lung cancer, leading to poor prognosis of this disorder. The present study investigates pathological roles of RhoC in metastasis of lung cancer using a clinically relevant mouse model of lung cancer.
Experimental Design: RhoA, RhoC, dominant-negative Rho (dnRho) or green fluorescent protein gene was retrovirally transduced to murine lung cancer cells. For in vivo study, these transduced cells were intrapulmonary inoculated in syngeneic mice, and subsequently, growth and metastasis were analyzed. Migration and invasion activities were further investigated by in vitro chemotaxic chamber assays. Expression levels and activities of certain matrix metalloproteinases (MMPs) were explored by reverse transcription-PCR and gelatin zymography.
Results: Metastasis of lung cancer in the animal model, as well as in vitro migration and invasion, were significantly enhanced or inhibited by overexpression of RhoC or dnRho, respectively, without affecting the growth of primary tumors. Expression levels of certain MMPs and the activity of MMP-2 were significantly enhanced or suppressed by overexpression of RhoC or dnRho, respectively.
Conclusion: RhoC plays a crucial role in metastasis of lung cancer. RhoC does not affect tumor growth but enhances the metastatic nature of lung cancer by not only stimulating cell motility but also up-regulating certain MMPs. Attenuation of RhoC activity may be a potential target in the development of a novel strategy for treating metastasis of lung cancer.
Single Ascending Dose Tolerability, Pharmacokinetic–Pharmacodynamic Study of Dihydropyrimidine Dehydrogenase Inhibitor Ro 09-4889
Authors: Bellibas S. Eralp , Patel Indra , Chamorey Emmanuel , Brivet Bettyna , Bush Ernest D. , Kircher Catherine , Nave Stephane , Banken Ludger , Renée Nicole , Milano Gérard 
Published: September 2005

Abstract
Purpose: Ro 09-4889 was designed to enhance the anticancer efficacy of capecitabine (Xeloda) by generating a dihydropyrimidine dehydrogenase inhibitor (DPDi) 5-vinyluracil (5-VU) preferentially in tumor tissues. This study assessed the tolerance to Ro 09-4889 treatment, and related pharmacokinetic and pharmacodynamic data such as inhibition of DPD activity in peripheral blood mononuclear cells (PBMCs) and plasma uracil levels.
Experimental design: This was a single-center, double-blind, placebo-controlled, single-dose escalation study in 64 healthy male volunteers at 1-, 5-, 20-, 50-, 75-, 100-, and 200-mg oral dose of Ro 09-4889. Also, food effect was assessed separately in a group dosed with 20 mg of the compound.
Results: No serious adverse effects or significant laboratory and electrocardiogram abnormalities were observed during the study. Ro 09-4889 has a short elimination half-life (t1/2) of 0.5 h, followed by metabolites 5′-deoxy-5-vinyluridine (5′-DVUR), 5′-deoxy-5-vinylcytidine (5′-DVCR), and 5-VU with t1/2 of 1.3, 1.2, and 2 h, respectively. The major metabolite excreted in urine was 5-DVCR (45% of dose). The inhibition of PBMC DPD activity and the increase in plasma uracil were related to Ro 09-4889 dose. DPD inhibition versus dose and uracil AUC (area under the curve) versus dose were modeled using the Emax model with a baseline effect. The model-predicted ED50 value was 100 mg.
Conclusion: Single oral doses of Ro 09-4889 ranging from 1 to 200 mg were well tolerated. On the basis of these findings, a 10-to-30-mg dose range of Ro 09-4889 combined with capecitabine could be appropriate for further evaluation in cancer patients.
A Multicenter Phase I Gene Therapy Clinical Trial Involving Intraperitoneal Administration of E1A-Lipid Complex in Patients with Recurrent Epithelial Ovarian Cancer Overexpressing HER-2/
neu
Oncogene
Authors: Madhusudan Srinivasan , Tamir Ayala , Bates Nicholas , Flanagan Elizabeth , Gore Martin E. , Barton Desmond P. J. , Harper Peter , Seckl Michael , Thomas Hilary , Lemoine Nicholas R. , Charnock Mark , Habib Nagy A. , Lechler Robert , Nicholls Joanna , Pignatelli Massimo , Ganesan Trivadi S. 
Published: September 2005

Abstract
Purpose: HER-2/neu oncogene is overexpressed in 10–30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients.
Experimental Design: A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m2, given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity
Results: Fifteen patients, with a median age of 57 years (range, 43–81) were recruited. Three (1.8 mg DNA/m2), 4 (3.6 mg DNA/m2), and 8 patients (7.2 mg DNA/m2) received i.p. E1A. A total of 91 infusions (range, 1–18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m2. E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity.
Conclusions: I.P. EIA-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.