bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiangiogenic Properties of Gold Nanoparticles
Authors: Mukherjee Priyabrata , Bhattacharya Resham , Wang Ping , Wang Ling , Basu Sujit , Nagy Janice A. , Atala Anthony , Mukhopadhyay Debabrata , Soker Shay 
Published: September 2005

Abstract
Here, we report an intrinsic property of gold nanoparticles (nanogold): they can interact selectively with heparin-binding glycoproteins and inhibit their activity. Gold nanoparticles specifically bound vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-165 and basic fibroblast growth factor, two endothelial cell mitogens and mediators of angiogenesis resulting in inhibition of endothelial/fibroblast cell proliferation in vitro and VEGF-induced permeability as well as angiogenesis in vivo. In contrast, nanogold did not inhibit VEGF-121 or epidermal growth factor, two non–heparin-binding growth factors, mediated cell proliferation. Gold nanoparticles significantly inhibited VEGF receptor-2 phosphorylation, intracellular calcium release, and migration and RhoA activation in vitro. These results report for the first time a novel property of gold nanoparticles to bind heparin-binding proteins and thereby inhibit their subsequent signaling events.
Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids
Authors: Richard Christina , Matthews Donald , Duivenvoorden Wilhelmina , Yau Jonathan , Wright Paul S. , Th'ng John P.H. 
Published: September 2005

Abstract
Purpose: We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.
Experimental Design: Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.
Results: The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.
Conclusion: Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.
Expression of Cell Cycle–Regulated Proteins pRB2/p130, p107, E2F4, p27, and pCNA in Salivary Gland Tumors: Prognostic and Diagnostic Implications
Authors: Russo Giuseppe , Zamparelli Alessandra , Howard Candace M. , Minimo Corrado , Bellan Cristiana , Carillo Giovanna , Califano Luigi , Leoncini Lorenzo , Giordano Antonio , Claudio Pier Paolo 
Published: September 2005

Abstract
The retinoblastoma family consists of the tumor suppressor nuclear phosphoprotein pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in lung and endometrial cancer and choroidal melanomas show a tight inverse correlation between the histologic grading in the most aggressive tumor types and pRb2/p130 expression. This led us to investigate the role of pRb2/p130 in salivary tumors. We studied the expression of pRb2/p130, p107, E2F4, p27, and PcNA by immunohistochemistry in a panel of 44 salivary gland tumors. We found a direct correlation between the cytoplasmic expression of pRb2/p130 and tumor grading and the presence of metastasis that was highly statistically significant (P &lt; 0.001). Additionally, increased cytoplasmic pRb2/p130 expression was significantly correlated with a decreased probability of survival (P &lt; 0.001). Interestingly, p107 nuclear expression showed a strong direct correlation when compared with the same variables. pRb2/p130 showed the highest percentage of undetectable nuclear levels in the specimens examined and the tightest inverse correlation (P &lt; 0.0001) with both the histologic grading and pCNA expression in malignant salivary tumors. Additionally, E2F4 showed an identical localization pattern as to that of pRb2/p130. These data suggests an important role for pRb2/p130 in the pathogenesis and progression of certain salivary gland cancers.
Low-Molecular Weight Caldesmon as a Potential Serum Marker for Glioma
Authors: Zheng Ping-Pin , Hop Wim C. , Sillevis Smitt Peter A.E. , van den Bent Martin J. , Avezaat Cees J.J. , Luider Theodorus M. , Kros Johan M. 
Published: September 2005

Abstract
Purpose: Testing the feasibility of using the serum low-molecular weight caldesmon (l-CaD) level as a serum marker for the presence of glioma.
Experimental Design: Within a total of 230 serum samples, the l-CaD level was measured in healthy volunteers (30), patients with gliomas (57), nonglial intracranial tumors (107), and nontumor neurologic diseases (36) by ELISA. The specificity of the assay was monitored by combination of immunoprecipitation and immunoblotting.
Results: The serum level of l-CaD is significantly higher in the group of glioma patients as compared with any of the other groups (P &lt; 0.001). The cutoff value of 45 yields optimal sensitivity and specificity of the assay (91% and 84%, respectively; area under the curve score = 0.91). The specificity of ELISA was confirmed by the immunoprecipitation/immunoblotting control experiments. There were no significant differences in serum l-CaD levels between patients with low- or high-grade gliomas.
Conclusions: The serum l-CaD level as determined by ELISA is a good discriminator between glioma patients versus patients with other intracranial tumors, other neurologic diseases, and healthy people. Prospective studies are required to test the contribution of the assay in making the diagnosis of glioma, or its feasibility for monitoring the tumor during treatment.
Analysis of KIT Mutations in Sporadic and Familial Gastrointestinal Stromal Tumors: Therapeutic Implications through Protein Modeling
Authors: Tarn Chi , Merkel Erin , Canutescu Adrian A. , Shen Wei , Skorobogatko Yuliya , Heslin Martin J. , Eisenberg Burton , Birbe Ruth , Patchefsky Arthur , Dunbrack Roland , Arnoletti J. Pablo , von Mehren Margaret , Godwin Andrew K. 
Published: September 2005

Abstract
Purpose: Gastrointestinal stromal tumors (GIST) are characterized by expressing a gain-of-function mutation in KIT, and to a lesser extent, PDGFR. Imatinib mesylate, a tyrosine kinase inhibitor, has activity against GISTs that contain oncogenic mutations of KIT. In this study, KIT and PDGFRα mutation status was analyzed and protein modeling approaches were used to assess the potential effect of KIT mutations in response to imatinib therapy.
Experimental Design: Genomic DNA was isolated from GIST tumors. Exons 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRα were evaluated for oncogenic mutations. Protein modeling was used to assess mutations within the juxtamembrane region and the kinase domain of KIT.
Results: Mutations in KIT exons 9, 11, and 13 were identified in GISTs with the majority of changes involving the juxtamembrane region of KIT. Molecular modeling indicates that mutations in this region result in disruption of the KIT autoinhibited conformation, and lead to gain-of-function activation of the kinase. Furthermore, a novel germ-line mutation in KIT was identified that is associated with an autosomal dominant predisposition to the development of GIST.
Conclusions: We have used protein modeling and structural analyses to elucidate why patients with GIST tumors containing exon 11 mutations are the most responsive to imatinib mesylate treatment. Importantly, mutations detected in this exon and others displayed constitutive activation of KIT. Furthermore, we have found tumors that are both KIT and PDGFRα mutation negative, suggesting that additional, yet unidentified, abnormalities may contribute to GIST tumorigenesis.
Correlation between DNA Repair Capacity in Lymphocytes and Acute Side Effects to Skin during Radiotherapy in Nasopharyngeal Cancer Patients
Authors: Wang Wei-dong , Chen Zheng-tang , Li De-zhi , Cao Zheng-huai , Sun Shi-liang , Pu Ping , Chen Xiao-pin 
Published: September 2005

Abstract
Purpose: Repair of radiation-induced DNA damage plays a critical role for both the susceptibility of patients to side effects after radiotherapy and their subsequent cancer risk. The study objective was to evaluate whether DNA repair data determined in vitro are correlated with the occurrence of acute side effects during radiotherapy.
Experimental Design: Nasopharyngeal cancer patients receiving radiation therapy were recruited in a prospective epidemiologic study. As an indicator for clinical radiosensitivity, adverse reactions of the skin were recorded. Cryopreserved lymphocytes from 100 study participants were γ-irradiated with 5 Gy in vitro and analyzed using the alkaline comet assay. Reproducibility of the assay was determined by repeated analysis (n = 22) of cells from a healthy donor. A coefficient of variation of 0.24 was calculated.
Results: The various parameters determined to characterize the individual DNA repair capacity showed large differences between patients. Twenty-one patients were identified with considerably enhanced DNA damage induction, and 19 patients exhibited severely reduced DNA repair capacity after 15 and 30 minutes. Eight patients were considered as clinically radiosensitive, indicated by moist desquamation of the skin after a total radiation dose of 70 Gy.
Conclusions: Using the alkaline comet assay as described here, nasopharyngeal cancer patients were identified showing abnormal cellular radiation effects, but this repair deficiency corresponded only at a very limited extent to the acute radiation sensitivity of the skin.
Blockade of Transforming Growth Factor-β Signaling Suppresses Progression of Androgen-Independent Human Prostate Cancer in Nude Mice
Authors: Zhang Fahao , Lee Juwon , Lu Shan , Pettaway Curtis A. , Dong Zhongyun 
Published: September 2005

AbstractWe investigated the role of transforming growth factor-β (TGF-β) signaling in the growth and metastasis of PC-3MM2 human prostate cancer cells. Highly metastatic PC-3MM2 human prostate cancer cells were engineered to constitutively overexpress a dominant-negative type II TGF-β receptor (DNR). Transfection of DNR had minimal direct effects on cell growth and attenuated TGF-β-induced cell growth inhibition and TGF-β1 production. There were no discernable differences in tumorigenicity (tumor incidence) among PC-3MM2 variants when the cells were implanted into the prostates of nude mice. Growth rate and metastatic incidence of DNR-engineered PC-3MM2 cells, however, were significantly reduced. Most cells in the control tumors were positively stained by an antibody to proliferation cell nuclear antigen and very few cells were stained by terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL). In sharp contrast, tumors formed by PC-3MM2-DNR cells contained fewer proliferation cell nuclear antigen–positive cells and many more TUNEL-positive cells. Staining with antibody against CD31 showed that control tumors contained more blood vessels than PC-3MM2-DNR tumors. Expression of interleukin-8 (IL-8) in tumors formed by PC-3MM2 cells was significantly reduced as revealed by both Northern blotting and ELISA. Finally, transfection of antisense IL-8 cDNA significantly reduced IL-8 production by PC-3MM2 cells and antisense IL-8-transfected PC-3MM2 cells grew slower in comparison with parental and control vector-transfected cells. Taken together, our data suggest that TGF-β signaling, by regulating IL-8 expression in tumor cells and hence tumor angiogenesis, is critical for progressive growth of PC-3MM2 cells in the prostate of nude mice.
Noninvasive Monitoring of Murine Tumor Blood Flow During and After Photodynamic Therapy Provides Early Assessment of Therapeutic Efficacy
Authors: Yu Guoqiang , Durduran Turgut , Zhou Chao , Wang Hsing-Wen , Putt Mary E. , Saunders H. Mark , Sehgal Chandra M. , Glatstein Eli , Yodh Arjun G. , Busch Theresa M. 
Published: September 2005

Abstract
Purpose: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy.
Experimental Design: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2).
Results: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average ± SE: 168.1 ± 39.5%) and subsequent decrease (59.2 ± 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute−1) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2 = 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2 = 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P ≤ 0.015) of treatment durability.
Conclusion: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.
Spontaneous Regression of High-Grade Cervical Dysplasia: Effects of Human Papillomavirus Type and HLA Phenotype
Authors: Trimble Cornelia L. , Piantadosi Steven , Gravitt Patti , Ronnett Brigitte , Pizer Ellen , Elko Andrea , Wilgus Barbara , Yutzy William , Daniel Richard , Shah Keerti , Peng Shiwen , Hung Chienfu , Roden Richard , Wu Tzyy Choou , Pardoll Drew ,   The Johns Hopkins Medical Institutions, Baltimore, MD
Published: September 2005

Abstract
Purpose: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions.
Experimental Design: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy. We prospectively followed 100 women over 15 weeks before standard resection. HPV typing was done using PCR and a reverse line blot detection method.
Results: The rate of spontaneous histologic regression, defined as (CIN1 or less at resection) was 28%. The overall rate of HPV infection was 100%. HPV16 was identified in 68% of the lesions. Women with HPV16 only were significantly less likely to regress, compared with women with HPV types other than HPV16 (odds ratio, 0.342; 95% confidence interval, 0.117-0.997; P = 0.049). In the cohort with HPV16 only, patients who had an HLA*A201 allele had similar outcomes to those who did not carry A201. However, among patients with HPV types other than HPV16, the HLA*A201 allele interaction was significant; patients with HLA*A201 were the least likely to resolve.
Conclusions: CIN2/3 lesions associated with HPV16 alone are significantly less likely to resolve spontaneously than those caused by other types. Interactions among HPV type, HLA type, and regression rate support a role for HLA-restricted HPV-specific immune responses in determining disease outcome.
Cyr61 Induces Gastric Cancer Cell Motility/Invasion via Activation of the Integrin/Nuclear Factor-κB/Cyclooxygenase-2 Signaling Pathway
Authors: Lin Ming-Tsai , Zuon Chung-Yaou , Chang Cheng-Chi , Chen Szu-Ta , Chen Chih-Ping , Lin Been-Ren , Wang Ming-Yang , Jeng Yung-Ming , Chang King-Jen , Lee Po-Huang , Chen Wei-Jao , Kuo Min-Liang 
Published: September 2005

Abstract
Purpose: Cysteine-rich 61 (Cyr61/CCN1) is involved in many different types of tumor development and progression. Nonetheless, the role of Cyr61 in human gastric cancer has not yet been fully characterized.
Experimental design: We addressed the issue by immunohistochemical staining of 81 gastric adenocarcinoma specimens. Liposome-mediated transfection was used to introduce a Cyr61 expression vector into gastric cancer AGS cell lines. Transfectants were tested in invasion assay by a Boyden chamber. Furthermore, a cyclooxygenase-2 (COX-2) reporter assay and gel mobility shift assay were done to investigate the potential signal pathway of Cyr61.
Results: Patients with gastric adenocarcinoma whose tumor displayed high expression of Cyr61 correlated well with aggressive lymph node metastasis, more advanced tumor stage, histologic diffuse type, and early recurrence. Stable transfection of Cyr61 into the AGS cell line strongly enhanced its invasive activity. The overexpression of Cyr61 into AGS cells significantly increased the expression of COX-2 mRNA, protein, and enzymatic activity. Gel mobility shift assays further showed that the nuclear factor-κB (NF-κB) pathway was evidently activated in Cyr61-expressing AGS cells. Function-neutralizing antibody to αvβ3 but not αvβ5 effectively suppressed Cyr61-mediated NF-κB activation, COX-2 gene expression, and cell invasiveness.
Conclusions: Cyr61 may contribute to the malignant progression of gastric cancer by promoting tumor cell motility/invasion through up-regulation of the functional COX-2 via an integrin αvβ3/NF-κB-dependent pathway.
A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol
Authors: Shah Manish A. , Kortmansky Jeremy , Motwani Monica , Drobnjak Marija , Gonen Mithat , Yi Sandy , Weyerbacher Amanda , Cordon-Cardo Carlos , Lefkowitz Robert , Brenner Baruch , O'Reilly Eileen , Saltz Leonard , Tong William , Kelsen David P. , Schwartz Gary K. 
Published: September 2005

Abstract
Purpose: Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy.
Patients and Methods: Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m2) followed 7 hours later by escalating flavopiridol (10-70 mg/m2) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done.
Results: At irinotecan 100 mg/m2, dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m2. At irinotecan 125 mg/m2, we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m2. Peak flavopiridol concentrations of ≥2 μmol/L were achieved above flavopiridol 50 mg/m2. No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., &gt;6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy.
Conclusions: The recommended phase II dose with irinotecan 100 mg/m2 is flavopiridol 60 mg/m2 and with irinotecan 125 mg/m2 is flavopiridol 50 mg/m2. Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy.
Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity
Authors: Perera Rushika M. , Narita Yoshitaka , Furnari Frank B. , Gan Hui K. , Murone Carmel , Ahlkvist Marika , Luwor Rodney B. , Burgess Antony W. , Stockert Elisabeth , Jungbluth Achim A. , Old Lloyd J. , Cavenee Webster K. , Scott Andrew M. , Johns Terrance G. 
Published: September 2005

Abstract
Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27KIP1 and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.