bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma CellsIn vitroandIn vivo
Authors: Ikeda Hiroshi , Hideshima Teru , Fulciniti Mariateresa , Lutz Robert J. , Yasui Hiroshi , Okawa Yutaka , Kiziltepe Tanyel , Vallet Sonia , Pozzi Samantha , Santo Loredana , Perrone Giulia , Tai Yu-Tzu , Cirstea Diana , Raje Noopur S. , Uherek Christoph , Dälken Benjamin , Aigner Silke , Osterroth Frank , Munshi Nikhil , Richardson Paul , Anderson Kenneth C. 
Published: June 2009

AbstractPurpose: We investigated the antitumor effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo.Experimental Design: We examined the growth inhibitory effect of BT062-SPDB-DM4, BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells from MM patients. We also examined in vivo activity of these agents in murine MM cell xenograft model of human and severe combined immunodeficient (SCID) mice bearing implant bone chips injected with human MM cells (SCID-hu model).Results: Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines and primary tumor cells from MM patients without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2-M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The coculture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity of immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model.Conclusion: These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.
Mixed Tocopherols Prevent Mammary Tumorigenesis by Inhibiting Estrogen Action and Activating PPAR-γ
Authors: Lee Hong Jin , Ju Jihyeung , Paul Shiby , So Jae-Young , DeCastro Andrew , Smolarek Amanda , Lee Mao-Jung , Yang Chung S. , Newmark Harold L. , Suh Nanjoo 
Published: June 2009

AbstractPurpose: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the α, β, γ, and δ variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis.Experimental Design: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells.Results: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-γ, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated peroxisome proliferator activated receptor-γ and antagonized estrogen action in breast cancer.Conclusion: The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer.
MiR-21 Indicates Poor Prognosis in Tongue Squamous Cell Carcinomas as an Apoptosis Inhibitor
Authors: Li Jinsong , Huang Hongzhang , Sun Lijuan , Yang Mei , Pan Chaobin , Chen Weiliang , Wu Donghui , Lin Zhaoyu , Zeng Chunxian , Yao Yandan , Zhang Peter , Song Erwei 
Published: June 2009

Abstract
Purpose: We aim to examine miR-21 expression in tongue squamous cell carcinomas (TSCC) and correlate it with patient clinical status, and to investigate its contribution to TSCC cell growth, apoptosis, and tumorigenesis.
Experimental Design: MicroRNA profiling was done in 10 cases of TSCC with microarray. MiR-21 overexpression was quantitated with quantitative reverse transcription-PCR in 103 patients, and correlated to the pathoclinical status of the patients. Immunohistochemistry was used to examine the expression of TPM1 and PTEN, and terminal deoxynucleotidyl transferase–mediated dUTP labeling to evaluate apoptosis. Moreover, miR-21 antisense oligonucleotide (ASO) was transfected in SCC-15 and CAL27 cell lines, and tumor cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, adherent colony formation, and soft agar assay, whereas apoptosis was determined by Annexin V assay, cytochrome c release, and caspase 3 assay. Tumorigenesis was evaluated by xenografting SCC-15 cells in nude mice.
Results: MiR-21 is overexpressed in TSCC relative to adjacent normal tissues. The level of miR-21 is reversely correlated with TPM1 and PTEN expression and apoptosis of cancer cells. Multivariate analysis showed that miR-21 expression is an independent prognostic factor indicating poor survival. Inhibiting miR-21 with ASO in TSCC cell lines reduces survival and anchorage-independent growth, and induces apoptosis in TSCC cell lines. Simultaneous silencing of TPM1 with siRNA only partially recapitulates the effect of miR-21 ASO. Furthermore, repeated injection of miR-21 ASO suppresses tumor formation in nude mice by reducing cell proliferation and inducing apoptosis.
Conclusions: miR-21 is an independent prognostic indicator for TSCC, and may play a role in TSCC development by inhibiting cancer cell apoptosis partly via TPM1 silencing.
MMP11: A Novel Target Antigen for Cancer Immunotherapy
Authors: Peruzzi Daniela , Mori Federica , Conforti Antonella , Lazzaro Domenico , De Rinaldis Emanuele , Ciliberto Gennaro , La Monica Nicola , Aurisicchio Luigi 
Published: June 2009

Abstract
Purpose: Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases that mediate numerous physiologic and pathologic processes, including matrix degradation, tissue remodeling, inflammation, and tumor metastasis. To develop a vaccine targeting stromal antigens expressed by cancer-associated fibroblasts, we focused on MMP11 (or stromelysin 3). MMP11 expression correlates with aggressive profile and invasiveness of different types of carcinoma.
Experimental Design: To show the efficacy of a vaccine targeting MMP11, we constructed a series of plasmid DNA vectors expressing murine MMP11. Mice were vaccinated by i.m. injection followed by in vivo DNA electroporation. A chemically induced, MMP11-overexpressing colon cancer model was established and characterized. Antibody and T-cell responses were determined, and immunoreactive epitopes were characterized. To analyze the possible use of MMP11 as tumor-associated antigen in cancer patients, HLA-A2.1 transgenic mice (HHD) were used to identify reactive epitopes as tools to assess immunogenicity in humans.
Results: Using microarray, we confirmed the overexpression of MMP11 mRNA in a large panel of human tumor samples. MMP11 vaccine induced cell mediated and antibody immune response and exerted significant antitumoral protection in mice with colon cancer in prophylactic and therapeutic settings. HHD transgenic mice were vaccinated with a plasmid encoding human MMP11, and a HLA-A2.1–restricted epitope (hMMP237) was identified. hMMP237 was shown to be immunogenic in human peripheral blood mononuclear cells (PBMC) by in vitro priming.
Conclusion: Our study describes the identification of MMP11 as a novel broadly expressed tumor associated antigen as target candidate for cancer immunotherapy.
Locked Nucleic Acid In situ Hybridization Analysis of miR-21 Expression during Colorectal Cancer Development
Authors: Yamamichi Nobutake , Shimomura Ryoichi , Inada Ken-ichi , Sakurai Kouhei , Haraguchi Takeshi , Ozaki Yuka , Fujita Shuji , Mizutani Taketoshi , Furukawa Chihiro , Fujishiro Mitsuhiro , Ichinose Masao , Shiogama Kazuya , Tsutsumi Yutaka , Omata Masao , Iba Hideo 
Published: June 2009

Abstract
Purpose: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH).
Experimental Design: Locked nucleic acid (LNA)/DNA probes and a biotin-free tyramide signal amplification system were used in ISH analyses of miRNA expression. Conditions for specific detection of miR-21 were determined using human cell lines and miR-21–expressing lentiviral vectors. Expression was determined in 39 surgically excised colorectal tumors and 34 endoscopically resected colorectal polyps.
Results: In the surgical samples, miR-21 expression was much higher in colorectal cancers than in normal mucosa. Strong miR-21 expression was also observed in cancer-associated stromal fibroblasts, suggesting miR-21 induction by cancer-secreted cytokines. Protein expression of PDCD4, a miR-21 target, was inversely correlated with miR-21 expression, confirming that miR-21 is indeed a negative regulator of PDCD4 in vivo. In the endoscopic samples, miR-21 expression was very high in malignant adenocarcinomas but was not elevated in nontumorigenic polyps. Precancerous adenomas also frequently showed miR-21 up-regulation.
Conclusion: Using the LNA-ISH system for miRNA detection, miR-21 was detectable in precancerous adenomas. The frequency and extent of miR-21 expression increased during the transition from precancerous colorectal adenoma to advanced carcinoma. Expression patterns of miR-21 RNA and its target, tumor suppressor protein PDCD4, were mutually exclusive. This pattern may have clinical application as a biomarker for colorectal cancer development and might be emphasized by self-reinforcing regulatory systems integrated with the miR-21 gene, which has been previously shown in cell culture.
Impaired STAT Phosphorylation in T Cells from Melanoma Patients in Response to IL-2: Association with Clinical Stage
Authors: Mortarini Roberta , Vegetti Claudia , Molla Alessandra , Arienti Flavio , Ravagnani Fernando , Maurichi Andrea , Patuzzo Roberto , Santinami Mario , Anichini Andrea 
Published: June 2009

AbstractPurpose: To assess the extent of signal transducer and activator of transcription (STAT) activation in response to interleukin 2 (IL-2) in melanoma patients' T cells, along with clinical stage of tumor progression.Experimental Design: T lymphocytes from peripheral blood of healthy donors and of American Joint Committee on Cancer stage I to IV melanoma patients, as well as from metastatic lymph nodes of patients, were evaluated for responsiveness to IL-2. CFSE assays and single-cell phospho-STAT–specific flow cytometry screening were used.Results. T cells from advanced melanoma patients, in comparison with healthy donors, showed reduced proliferation to IL-2 and IL-15, but not to anti-CD3 monoclonal antibody. Impaired response occurred in CCR7+ and CCR7− T-cell subsets, but not in CD3− CD8+ natural killer (NK) cells, and was not explained by induction of apoptosis, increased cytokine consumption, or altered IL-2R subunit expression in patients' T lymphocytes. By phospho-specific flow cytometry, defective STAT1 and STAT5 activation in response to IL-2 was found mainly in T lymphocytes from peripheral blood and/or tumor site of American Joint Committee on Cancer stage III and IV patients, compared with stage I and II patients and to donors, and in melanoma antigen-specific T cells isolated from metastatic lymph nodes. At tumor site, impaired STAT activation in T cells did not correlate with frequency of CD4+ CD25+ Foxp3+ T cells. Serum from advanced melanoma patients inhibited IL-2–dependent STAT activation in donors' T cells and a neutralizing monoclonal antibody to transforming growth factor β1 counteracted such inhibition.Conclusions: These results provide evidence for development of impaired STAT signaling in response to IL-2, along with clinical evolution of the disease, in melanoma patients' T cells.
CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy
Authors: Bao Rudi , Lai Cheng-Jung , Qu Hui , Wang Dagong , Yin Ling , Zifcak Brian , Atoyan Ruzanna , Wang Jing , Samson Maria , Forrester Jeffrey , DellaRocca Steven , Xu Guang-Xin , Tao Xu , Zhai Hai-Xiao , Cai Xiong , Qian Changgeng 
Published: June 2009

Abstract
Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types.
Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.
Results: CUDC-305 shows high affinity for HSP90α/β (IC50, ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non–small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models.
Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.
Anti-EMMPRIN Monoclonal Antibody as a Novel Agent for Therapy of Head and Neck Cancer
Authors: Dean Nichole R. , Newman J. Robert , Helman Emily E. , Zhang Wenyue , Safavy Seena , Weeks D.M. , Cunningham Mark , Snyder Linda A. , Tang Yi , Yan Li , McNally Lacey R. , Buchsbaum Donald J. , Rosenthal Eben L. 
Published: June 2009

Abstract
Purpose: Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer. These features make it a potential therapeutic target for monoclonal antibody (mAb)–based therapy. Because molecular therapy is considered more effective when delivered with conventional cytotoxic agents, anti-EMMPRIN therapy was assessed alone and in combination with external beam radiation.
Experimental Design: Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells.
Results: Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN–expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb–treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1β (IL-1β), IL-6, and IL-8 cytokine production, in vitro and in vivo.
Conclusions: These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.
Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer
Authors: Soucy Teresa A. , Smith Peter G. , Rolfe Mark 
Published: June 2009

Abstract
E3 ubiquitin ligases regulate many dynamic cellular processes important for cancer cell survival. Together with ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzymes (E2s), E3s catalyze the ubiquitination of numerous protein substrates that are subsequently targeted to the 26S proteasome for degradation. The clinical success of the proteasome inhibitor bortezomib has encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention. Targeting specific E3s is particularly attractive because there is the potential to selectively block the degradation of certain cellular proteins and possibly avoid unwanted effects on other proteins. The cullin-RING ubiquitin E3 ligases (CRLs) represent the largest subfamily of E3s. The requirement that CRLs be activated by NEDD8 modification on the cullin protein offers an “achilles heel” for modulating this entire subfamily. NEDD8-activating enzyme (NAE) catalyzes the first step in the NEDD8 pathway and as such controls the activity of CRLs. In this article, we describe the role of the NEDD8 pathway in activating CRLs and discuss the preclinical findings with a first-in-class NAE inhibitor that is currently in phase I clinical trials for both solid tumor and hematological malignancies. In addition, we speculate where NAE inhibitors may find clinical utility.
Phase I Study of Eribulin Mesylate Administered Once Every 21 Days in Patients with Advanced Solid Tumors
Authors: Tan Antoinette R. , Rubin Eric H. , Walton Diana C. , Shuster Dale E. , Wong Y. Nancy , Fang Fang , Ashworth Simon , Rosen Lee S. 
Published: June 2009

Abstract
Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21 days in patients with advanced solid tumors.
Experimental Design: Eribulin mesylate was given as a 1-hour infusion every 21 days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m2. The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose.
Results: Twenty-one patients were enrolled. At 4 mg/m2, three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m2 where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m2 (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m2. Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasma-concentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non–small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease.
Conclusions: Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m2, with further dose escalation limited by neutropenia.
Toward an Effective Targeted Chemotherapy for Multiple Myeloma
Authors: Polson Andrew G. , Sliwkowski Mark X. 
Published: June 2009

Abstract
Antibody-drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells. Anti-CD138 ADCs show promising preclinical efficacy for the treatment of multiple myeloma; however, the safety aspects of targeting CD138 have yet to be explored.
Lipid-lowering therapy in type 2 diabetes: a review of the evidence
Authors: Steinmetz Armin 
Published: June 2009

Current treatment guidelines highlight the importance of lipid-lowering therapy in reducing cardiovascular risk in patients with type 2 diabetes. Statins have been shown to be effective in reducing cardiovascular risk in patients with diabetes, but they fail to address adequately the coronary risk associated with low plasma levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides, commonly reported in these patients. Fibrates are effective against all three components of the atherogenic dyslipidaemic profile that characterises type 2 diabetes. Clinical studies such as the Veterans Affairs HDL Intervention Trial (VA-HIT), which showed a marked and statistically significant reduction in coronary heart disease death and stroke, as well as the Diabetes Atherosclerosis Intervention Study (DAIS), which showed that treatment with fenofibrate produced significantly less progression in markers of focal coronary artery disease, support a role for fibrate therapy in cardiovascular risk reduction in type 2 diabetes. Together, these data provided the rationale for the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, the largest study to date in patients with type 2 diabetes.
Reducing vascular risk in the diabetic patient: implications from the FIELD study
Authors: Zambon Alberto 
Published: June 2009

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, involving 9, 795 patients with type 2 diabetes, is the largest study to date investigating the role of a lipid-modifying therapy in reducing cardiovascular risk in type 2 diabetes. Although the reduction in the primary end point (non-fatal myocar-dial infarction [MI] and coronary heart disease [CHD] death) did not reach statistical significance, fenofibrate treatment was associated with a significant reduction in total cardiovascular events, largely driven by reductions in non-fatal MI and revascularisation procedures. Subgroup analyses demonstrated greater treatment effect in patients without prior cardiovascular disease than in those with established cardiovascular disease (relative risk reduction for CHD events of 25%, p=0.014 vs. a non-significant 8% increase, respectively; and for total cardiovascular events of 19%, p=0.004 vs. no effect). Differences in the magnitude of the reduction in cardiovascular risk between studies emphasise the importance of considering patient characteristics, such as duration of diabetes, concomitant lipid-modifying therapy, glycaemic control and prior cardiovascular disease, which may all influence treatment response. Taking these factors into account, as well as the promising effects on microangiopathy observed in FIELD, suggests that fenofibrate may have a role as a well-tolerated treatment (most likely in combination with a statin) in patients with early stage type 2 diabetes without evidence of macrovascular disease.