bluuebunny/crossref_metadata_2025_split huggingface dataset:
A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.
Authors: Body Jean-Jacques , Facon Thierry , Coleman Robert E , Lipton Allan , Geurs Filip , Fan Michelle , Holloway Donna , Peterson Mark C , Bekker Pirow J 
Published: March 2006

Abstract
PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent
Authors: McKeage Mark J. , Fong Peter , Jeffery Mark , Baguley Bruce C. , Kestell Phil , Ravic Miroslav , Jameson Michael B. 
Published: March 2006

Abstract
This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m−2), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate–corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in Ktrans and kep were observed but Ve, a secondary dynamic contrast–enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m−2, the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 ± 25.8 μg/mL, 29 ± 6.4 μg/mL·d, 8.0 ± 1.77 μg/mL, and 0.43 ± 0.07 μg/mL·d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m−2, with a plateau thereafter. Doses in the range of 1,200 mg m−2 have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate–corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.
Biological Significance of Isolated Tumor Cells and Micrometastasis in Lymph Nodes Evaluated Using a Green Fluorescent Protein–Tagged Human Gastric Cancer Cell Line
Authors: Yokoyama Hiroyuki , Nakanishi Hayao , Kodera Yasuhiro , Ikehara Yuzuru , Ohashi Norifumi , Ito Yuichi , Koike Masahiko , Fujiwara Michitaka , Tatematsu Masae , Nakao Akimasa 
Published: March 2006

AbstractPurpose: The biological significance of isolated tumor cells and micrometastasis in lymph node defined by the International Union against Cancer remains essentially unknown because of the lack of appropriate animal models. In the present study, we developed a lymph node micrometastasis model featuring a human gastric cancer cell line tagged with green fluorescent protein gene (GCIY-EGFP), which allows visualization of even isolated tumor cells in the development of metastasis without histologic procedure. Using this model, we investigated the effect of surgery and chemotherapy on the growth of early-phase metastasis formation in the lymph nodes.Experimental Design: The time course of spontaneous inguinal lymph node metastasis after s.c. inoculation of GCIY-EGFP cells into nude mice was examined with fluorescence dissecting microscopy. Then, the effects of surgical removal of the primary tumor with or without anti-asialo GM1 treatment or postoperative chemotherapy on the growth of isolated tumor cells and micrometastasis in the lymph nodes were examined.Results: GCIY-EGFP cells were found to metastasize spontaneously to the inguinal lymph nodes to form isolated tumor cells, micrometastasis, and, finally, develop macroscopic metastasis at 1 to 2, 3 to 5, and 5 weeks postinjection, respectively. When the primary tumors were removed within 2 weeks of inoculation, isolated tumor cells, but not micrometastasis, in the lymph nodes regressed by 4 weeks after surgery in all the mice examined (five of five). This spontaneous regression of isolated tumor cells was completely reversed by anti-asialo GM1 treatment, which could deplete natural killer cells effectively in nude mice. Chemotherapy following resection of the primary tumor at an early stage partially eliminated the remaining micrometastasis in the lymph nodes.Conclusions: These results suggest that isolated tumor cells in the regional lymph nodes regressed by removal of the primary tumor mainly via natural killer cell–mediated antitumor activity and that micrometastasis in the lymph nodes could be effectively eliminated by the postoperative chemotherapy.
Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.
Authors: Brandacher Gerald , Perathoner Alexander , Ladurner Ruth , Schneeberger Stefan , Obrist Peter , Winkler Christiana , Werner Ernst R , Werner-Felmayer Gabriele , Weiss Helmut G , G√∂bel Georg , Margreiter Raimund , K√∂nigsrainer Alfred , Fuchs Dietmar , Amberger Albert 
Published: March 2006

Abstract
PURPOSE: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive network that promotes tumor growth and protects the tumor from immune attack. In this study, we examined the contribution of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon. EXPERIMENTAL DESIGN: Expression of IDO was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of 143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical variables. RESULTS: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly dependent on IFN-gamma stimulation. Immunohistochemical scores revealed IDO-high expression in 56 of 143 (39.2%) tumor specimens, whereas 87 of 143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction of CD3+ infiltrating T cells (46.02 +/- 7.25) as compared with tissue samples expressing low IDO (19.42 +/- 2.50; P = 0.0003). Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged as an independent prognostic variable (&lt;45 months, P = 0.006; &gt;45 months, P = 0.04). CONCLUSION: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression and overall survival in patients with colorectal cancer.
Computer-Assisted Analysis of Biopsy Specimen Microvessels Predicts the Outcome of Esophageal Cancers Treated with Chemoradiotherapy
Authors: Zhang Shi-chuan , Hironaka Shuichi , Ohtsu Atsushi , Yoshida Shigeaki , Hasebe Takahiro , Fukayama Masashi , Ochiai Atsushi 
Published: March 2006

Abstract
Purpose: A computer-assisted microvessel analysis system was developed to evaluate correlations between the architecture of biopsy specimen microvessels and the outcome for patients with esophageal cancer treated with chemoradiotherapy.
Experimental Design: Biopsy specimens from 51 patients with esophageal cancer (T2-3, any N, M0) treated with chemoradiotherapy were immunostained with an anti-CD31 antibody and quantified using computerized image analysis. We evaluated the association of several microvessel factors with overall survival, including the ratio of total microvessel perimeter to total tumor area (TP/TA), the tumor hypoxic ratio, and the ratio of total microvessel number to total tumor area (TN/TA). Results from traditional manual microvessel density (MVD) hotspot count and computerized hotspot count were compared and the relation between hotspot MVD count and survival rate was evaluated.
Results: The median follow-up time was 32 months. Both univariate and multivariate analyses revealed that computer-counted hotspot MVD and TN/TA and TP/TA ratios correlated significantly with the outcome of chemoradiotherapy. Kaplan-Meier survival curves showed that patients with high computer-counted hotspot MVDs and high TN/TA and TP/TA ratios had better overall survival rate than patients with low MVDs or ratios (P = 0.025, 0.008, and 0.031, respectively). Combining computer-counted MVD or TN/TA ratio with TP/TA ratio proved more predictive than any single factor. Two researcher-counted hotspot MVDs had no significant relation with outcome.
Conclusion: Computer-assisted tumor microvessel analysis is a powerful tool in predicting the outcome for patients with esophageal cancer treated with chemoradiotherapy because intraobserver and interobserver variability is minimized.
Oncogenic Property of Acrogranin in Human Uterine Leiomyosarcoma: Direct Evidence of Genetic Contribution in In vivo Tumorigenesis
Authors: Matsumura Noriomi , Mandai Masaki , Miyanishi Masanori , Fukuhara Ken , Baba Tsukasa , Higuchi Toshihiro , Kariya Masatoshi , Takakura Kenji , Fujii Shingo 
Published: March 2006

Abstract
To identify potential oncogenes that contribute to the development of uterine leiomyosarcoma, we conducted a cDNA microarray analysis between normal uterine smooth muscle and uterine leiomyosarcoma. We found that acrogranin (also named PCDGF or progranulin) is overexpressed in uterine leiomyosarcoma. With immunohistochemical staining of 12 leiomyosarcoma cases, we verified acrogranin expression in tumor cells. Furthermore, the intensity of acrogranin expression correlated with high histologic grade and poor prognosis. To directly analyze the oncogenic properties of acrogranin, we established an immortalized uterine smooth muscle cell line by transfection of human telomerase reverse transcriptase into primary culture. This cell line retained the original characteristics of uterine smooth muscle cells, including spindle-shaped extension as well as expression of vimentin, estrogen receptor α, progesterone receptor, and α smooth muscle actin. Transfection of acrogranin into the immortalized uterine smooth muscle cells resulted in colony formation in soft agar, but the diameter of the colonies did not exceed 100 μm. Transfection of both acrogranin and SV40 early region (SV40ER) into the immortalized uterine smooth muscle cells resulted in an increased number of colonies and increased colony size in soft agar versus transfection of SV40ER alone. We show that only immortalized uterine smooth muscle cells expressing both acrogranin and SV40ER are capable of tumor formation in nude mice. Thus, acrogranin is overexpressed in uterine leiomyosarcoma cells, particularly in high-grade cases, and forced expression of acrogranin in immortalized uterine smooth muscle cells contributes to malignant transformation, which suggest that acrogranin plays an important role in the pathogenesis of uterine leiomyosarcoma.
A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors.
Authors: Fakih Marwan G , Pendyala Lakshmi , Smith Patrick F , Creaven Patrick J , Reid Mary E , Badmaev Vladimir , Azrak Rami G , Prey Joshua D , Lawrence David , Rustum Youcef M 
Published: March 2006

Abstract
PURPOSE: We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecan with fixed, nontoxic high dose of selenomethionine. EXPERIMENTAL DESIGN: Selenomethionine was given orally as a single daily dose containing 2,200 mug of elemental selenium (Se) starting 1 week before the first dose of irinotecan. Irinotecan was given i.v. once weekly x 4 every 6 weeks (one cycle). The starting dose of irinotecan was 125 mg/m(2)/wk. Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites. RESULTS: Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m(2)/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m(2)/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response. The long half-life of selenium resulted in a prolonged accumulation towards steady-state concentrations. No significant changes in the pharmacokinetics of CPT-11, SN-38, or SN-38G were identified; however, the coadministration of selenomethionine significantly reduced the irinotecan biliary index, which has been associated with gastrointestinal toxicity. CONCLUSIONS: Selenomethionine at 2,200 mug/d did not allow the safe escalation of irinotecan beyond the previously defined MTD of 125 mg/m(2). None of the patients receiving 125 mg/m(2) of irinotecan had grade &gt;2 diarrhea. Unexpected responses and disease stabilizations were noted in a highly refractory population. Further escalation of selenomethionine is recommended in future trials to achieve defined protective serum concentrations of selenium.
Human T Cells Armed with Her2/neu Bispecific Antibodies Divide, Are Cytotoxic, and Secrete Cytokines with Repeated Stimulation
Authors: Grabert Ryan C. , Cousens Leslie P. , Smith Janelle A. , Olson Sarah , Gall Jonathan , Young Wendy B. , Davol Pamela A. , Lum Lawrence G. 
Published: March 2006

AbstractPurpose: Cancer immunotherapy has been limited by anergy of patient T cells, inadequate numbers of precursor tumor-specific CTL, and difficulty in producing therapeutic doses of CTL. To overcome these limitations, bispecific antibodies have been used to create artificial antibody receptors that direct polyclonal activated T cells (ATC) to target tumor antigens. Studies reported herein were designed to characterize bispecific antibody–armed ATC functions during multiple rounds of targeted cell stimulation.Experimental Design: ATCs were generated from human peripheral blood mononuclear cells (PBMC) by culture with anti-CD3 and interleukin 2 for 14 days and armed with anti-CD3 × anti-Her2 bispecific antibody (Her2Bi). In vitro, Her2Bi-armed ATC were examined for a range of functions after repeated stimulation with the Her2/neu-expressing breast cancer cell line SK-BR-3. PBMC isolated from cancer patients treated with Her2Bi-armed ATC were tested ex vivo for cytotoxicity against SK-BR-3.Results: In vitro, armed ATC divided, maintained surface Her2Bi, and expressed a range of activities for extended periods of time. Perforin-mediated cytotoxic activity by armed ATC continued for at least 336 hours, and cytokines and chemokines (i.e., IFN-γ and regulated on activation, normal T-cell expressed and secreted protein [RANTES]) were secreted during successive rounds of stimulation. Furthermore, PBMC isolated from patients over their courses of immunotherapy exhibited significant cytolytic activity against SK-BR-3 as a function of Her2Bi-armed ATC infusions.Conclusions: These studies show that armed ATC are specific, durable, and highly functional T-cell populations in vitro. These previously unappreciated broad and long-term functions of armed ATC are encouraging for their therapeutic use in treating cancer.
Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma
Authors: Slebos Robbert J.C. , Yi Yajun , Ely Kim , Carter Jesse , Evjen Amy , Zhang Xueqiong , Shyr Yu , Murphy Barbara M. , Cmelak Anthony J. , Burkey Brian B. , Netterville James L. , Levy Shawn , Yarbrough Wendell G. , Chung Christine H. 
Published: March 2006

Abstract
Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC). Between 15% and 35% of HNSCCs harbor HPV DNA. Demographic and exposure differences between HPV-positive (HPV+) and negative (HPV−) HNSCCs suggest that HPV+ tumors may constitute a subclass with different biology, whereas clinical differences have also been observed. Gene expression profiles of HPV+ and HPV− tumors were compared with further exploration of the biological effect of HPV in HNSCC. Thirty-six HNSCC tumors were analyzed using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV by PCR and real-time PCR. Eight of 36 (22%) tumors were positive for HPV subtype 16. Statistical analysis using Significance Analysis of Microarrays based on HPV status as a supervising variable resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a subset of these genes were verified by real-time PCR. Genes highly expressed in HPV+ samples included cell cycle regulators (p16INK4A, p18, and CDC7) and transcription factors (TAF7L, RFC4, RPA2, and TFDP2). The microarray data were also investigated by mapping genes by chromosomal location (DIGMAP). A large number of genes on chromosome 3q24-qter had high levels of expression in HPV+ tumors. Further investigation of differentially expressed genes may reveal the unique pathways in HPV+ tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment.
CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.
Authors: Tse Kam Fai , Jeffers Michael , Pollack Vincent A , McCabe Denise A , Shadish Melanie L , Khramtsov Nikolai V , Hackett Craig S , Shenoy Suresh G , Kuang Bing , Boldog Ferenc L , MacDougall John R , Rastelli Luca , Herrmann John , Gallo Michael , Gazit-Bornstein Gadi , Senter Peter D , Meyer Damon L , Lichenstein Henri S , LaRochelle William J 
Published: March 2006

Abstract
PURPOSE: Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets. EXPERIMENTAL DESIGN AND RESULTS: By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011 monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011 alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cells in vitro. Ectopic overexpression and small interfering RNA transfection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. In a melanoma xenograft model, CR011-vcMMAE induced significant dose-proportional antitumor effects, including complete regressions, at doses as low as 1.25 mg/kg. CONCLUSION: These preclinical results support the continued evaluation of CR011-vcMMAE for the treatment of melanoma.
A Synthetic Triterpenoid, CDDO-Me, Inhibits IκBα Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents through Down-Regulation of Expression of Nuclear Factor κB–Regulated Gene Products in Human Leukemic Cells
Authors: Shishodia Shishir , Sethi Gautam , Konopleva Marina , Andreeff Michael , Aggarwal Bharat B. 
Published: March 2006

AbstractThe C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), a synthetic triterpenoid based on naturally occurring ursolic and oleanolic acids, induces apoptosis in tumor cells, induces differentiation, and inhibits inflammatory response through a poorly understood mechanism. Because the nuclear transcription factor nuclear factor κB (NF-κB) has been shown to suppress apoptosis and promote proliferation and is linked with inflammation and differentiation, we postulated that CDDO-Me modulates NF-κB activity and NF-κB-regulated gene expression. Using human leukemia cell lines and patient samples, we show that CDDO-Me potently inhibits both constitutive and inducible NF-κB activated by tumor necrosis factor (TNF), interleukin (IL)-1β, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. CDDO-Me was more potent than CDDO and its imidazole derivative. NF-κB suppression occurred through inhibition of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-mediated reporter gene transcription. This inhibition correlated with suppression of NF-κB-dependent genes involved in antiapoptosis (IAP2, cFLIP, TRAF1, survivin, and bcl-2), proliferation (cyclin d1 and c-myc), and angiogenesis (VEGF, cox-2, and mmp-9). CDDO-Me also potentiated the cytotoxic effects of TNF and chemotherapeutic agents. Overall, our results suggest that CDDO-Me inhibits NF-κB through inhibition of IκBα kinase, leading to the suppression of expression of NF-κB-regulated gene products and enhancement of apoptosis induced by TNF and chemotherapeutic agents.