bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA Interference Inhibition of Matrix Metalloproteinase-1 Prevents Melanoma Metastasis by Reducing Tumor Collagenase Activity and Angiogenesis
Authors: Blackburn Jessica S. , Rhodes C. Harker , Coon Charles I. , Brinckerhoff Constance E. 
Published: November 2007

Abstract
Melanoma incidence is increasing worldwide, and metastatic melanoma is almost completely resistant to every known therapy. New approaches to treating melanoma are urgently needed, and a greater understanding of the biology of melanoma invasion and metastasis will aid in their creation. A high proportion of invasive melanomas have a constitutively active Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascade; however, the downstream effectors of ERK signaling that contribute to melanoma invasion and metastasis are unknown. ERK signaling drives the production of the interstitial collagenase matrix metalloproteinase-1 (MMP-1), which is expressed specifically by invasive melanomas. Using short hairpin RNAs (shRNA) to knock down MMP-1 expression in a human melanoma cell line, we investigated the role of MMP-1 in melanoma metastasis in a xenograft model. Knockdown of MMP-1 had no effect on primary tumor growth, but reduction of MMP-1 expression significantly decreased the ability of the melanoma to metastasize from the orthotopic site in the dermis to the lung. Mechanistically, tumor cells expressing MMP-1 shRNAs had diminished collagenase activity, which is required for tumor cell invasion. Additionally, attenuation of MMP-1 expression reduced angiogenesis. These results show, for the first time, that targeted inhibition of MMP-1, a single effector of the Raf/MEK/ERK signaling cascade, prevents the progression of melanoma from a primary to metastatic tumor and, as such, may represent a useful therapeutic tool in controlling this disease. [Cancer Res 2007;67(22):10849–58]
Role of GLI2 Transcription Factor in Growth and Tumorigenicity of Prostate Cells
Authors: Thiyagarajan Saravanan , Bhatia Neehar , Reagan-Shaw Shannon , Cozma Diana , Thomas-Tikhonenko Andrei , Ahmad Nihal , Spiegelman Vladimir S. 
Published: November 2007

Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway has been reported in various cancer types including prostate cancer. The GLI2 transcription factor is a primary mediator of Hh signaling. However, its relative contribution to development of prostate tumors is poorly understood. To establish the role of GLI2 in maintaining the tumorigenic properties of prostate cancer cells, we developed GLI2-specific small hairpin RNA. Knockdown of GLI2 in these cells resulted in significant down-regulation of the Hh signaling pathway, followed by inhibition of colony formation, anchorage-independent growth, and growth of xenografts in vivo. Conversely, ectopic expression of Gli2 in nontumorigenic prostate epithelial cells resulted in accelerated cell cycle progression, especially transition through G2-M, and augmented proliferation. Altogether, our findings suggest that GLI2 plays a critical role in the malignant phenotype of prostate cancer cells, and GLI2 may potentially become an attractive therapeutic target for the treatment of prostate cancer. [Cancer Res 2007;67(22):10642–6]
Treatment of Invasive Retinoblastoma in a Murine Model Using an Oncolytic Picornavirus
Authors: Wadhwa Lalita , Hurwitz Mary Y. , Chévez-Barrios Patricia , Hurwitz Richard L. 
Published: November 2007

Abstract
Retinoblastoma, the most common intraocular malignancy of childhood, metastasizes by initial invasion of the choroid and the optic nerve. There is no effective treatment for metastatic retinoblastoma, especially when the central nervous system (CNS) is involved, and prevention of this complication is a treatment priority. Seneca Valley Virus (SVV-001) is a conditionally replication-competent picornavirus that is not pathogenic to normal human cells but can kill human retinoblastoma cells in vitro with an IC50 of &lt;1 viral particle (vp) per cell. A xenograft murine model of metastatic retinoblastoma was used to examine the therapeutic potential of SVV-001. Histopathologic analysis of ocular and brain tissues after a single tail vein injection of SVV-001 (1 × 1013 vp/kg) showed effective treatment of choroid and ocular nerve tumor invasion (1 of 20 animals with invasive disease in the treated group versus 7 of 20 animals with invasive disease in the control group; P = 0.017) and prevention of CNS metastasis (0 of 20 animals with CNS metastatic disease in the treated group versus 4 of 20 animals with CNS disease in the control group; P = 0.036). There were no observed adverse events due to the virus in any of the treated animals. SVV-001 may be effective as a treatment of locally invasive and metastatic retinoblastoma. [Cancer Res 2007;67(22):10653–6]
Erlotinib (Tarceva, OSI-774) Antagonizes ATP-Binding Cassette Subfamily B Member 1 and ATP-Binding Cassette Subfamily G Member 2–Mediated Drug Resistance
Authors: Shi Zhi , Peng Xing-Xiang , Kim In-Wha , Shukla Suneet , Si Qiu-Sheng , Robey Robert W. , Bates Susan E. , Shen Tong , Ashby Charles R. , Fu Li-Wu , Ambudkar Suresh V. , Chen Zhe-Sheng 
Published: November 2007

Abstract
It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)– and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)–mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E217βG and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [125I]iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic. [Cancer Res 2007;67(22):11012–20]
Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of INK4a/ARF
Authors: Bean Gregory R. , Bryson Andrew D. , Pilie Patrick G. , Goldenberg Vanessa , Baker Joseph C. , Ibarra Catherine , Brander Danielle M.U. , Paisie Carolyn , Case Natalie R. , Gauthier Mona , Reynolds Paul A. , Dietze Eric , Ostrander Julie , Scott Victoria , Wilke Lee G. , Yee Lisa , Kimler Bruce F. , Fabian Carol J. , Zalles Carola M. , Broadwater Gloria , Tlsty Thea D. , Seewaldt Victoria L. 
Published: November 2007

Abstract
Purpose: p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation. These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer.
Experimental Design: To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index.
Results: INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-β2, estrogen receptor-α, and breast cancer-associated 1 genes (P = 0.001).
Conclusions: Because INK4a/ARF promoter hypermethylation does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation.
Distribution Patterns of Dendritic Cells and T Cells in Diffuse Large B-Cell Lymphomas Correlate with Prognoses
Authors: Chang Kung-Chao , Huang Guan-Cheng , Jones Dan , Lin Ya-Hui 
Published: November 2007

AbstractPurpose: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphomas, accounts for 30% to 40% of all lymphoma cases. However, long-term survival by current chemotherapy was achieved in only 40% of patients, warranting the development of novel therapeutic strategies including T-cell immunotherapy. However, the level of baseline immune activation in DLBCL is unclear.Experimental Design: The density and distribution of dendritic cells and T cells in 48 cases of primary DLBCL was evaluated by immunohistochemistry.Results: Increased numbers of intratumoral CD1a+ dendritic cells and increased S100+ cells and CD45RO+ T cells around the edges of the tumors were seen in 10 of 48 (21%), 9 of 48 (19%), and 10 of 48 (21%) cases and these were correlated with a favorable prognosis (P = 0.015; P = 0.070, and P = 0.017, respectively), along with increased granzyme B+ T cells in tumor beds (P = 0.013). Increased peritumoral T cells were correlated with tumor expression of HLA-DR (r = 0.446; P = 0.002). Extranodal lymphomas showed fewer tumor-associated CD45RO+ T cells (r = −0.407; P = 0.001) and less conspicuous dendritic cell infiltrates.Conclusions: In DLBCL, the presence of baseline antitumor immune response is associated with favorable clinical outcome, and thus adjuvant T-cell immunotherapy may further boost treatment responses.
Response to [90Yttrium-DOTA]-TOC Treatment is Associated with Long-term Survival Benefit in Metastasized Medullary Thyroid Cancer: A Phase II Clinical Trial
Authors: Iten Fabienne , Müller Beat , Schindler Christian , Rochlitz Christoph , Oertli Daniel , Mäcke Helmut R. , Müller-Brand Jan , Walter Martin A. 
Published: November 2007

Abstract
Purpose: We aimed to explore the efficacy of 90Yttrium–1,4,7,10-tetra-azacyclododecane N,N′,N″,N-‴-tetraacetic acid (90Y-DOTA)–Tyr3-octreotide (TOC) therapy in advanced medullary thyroid cancer.
Experimental Design: In a phase II trial, we investigated the response, survival, and long-term safety profile of systemic [90Y-DOTA]-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models.
Results: Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of [90Y-DOTA]-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidence interval, 0.05-0.81; P = 0.02) and from time of first [90Y-DOTA]-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009). The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival.
Conclusions: Response to [90Y-DOTA]-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.
Phase I Trial of Single-Dose Temozolomide and Continuous Administration of O6-Benzylguanine in Children with Brain Tumors: a Pediatric Brain Tumor Consortium Report
Authors: Broniscer Alberto , Gururangan Sridharan , MacDonald Tobey J. , Goldman Stewart , Packer Roger J. , Stewart Clinton F. , Wallace Dana , Danks Mary K. , Friedman Henry S. , Poussaint Tina Y. , Kun Larry E. , Boyett James M. , Gajjar Amar ,   for the Pediatric Brain Tumor Consortium
Published: November 2007

Abstract
Purpose: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O6-benzylguanine in patients ≤21 years with recurrent brain tumors.
Experimental Design: Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.v. administration of O6-benzylguanine at 120 mg/m2 was followed by 48-h continuous infusion at 30 mg/m2/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628, and 835 mg/m2) was given at least 6 h after completion of O6-benzylguanine bolus. Treatment was repeated after recovery from toxicities at least 4 weeks apart for a maximum of 12 courses. Dose escalation followed the modified continual reassessment method. Pharmacokinetic analyses of temozolomide and 5-triazeno imidazole carboxamide (MTIC) were done in 28 patients.
Results: A total of 44 and 26 eligible patients were enrolled on Str1 and Str2, respectively. Median age at study entry in each stratum was 8.6 and 11.3 years, respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and Str2 were 562 and 407 mg/m2, respectively, the doses recommended for phase II investigations are 472 and 355 mg/m2, respectively. DLTs were predominantly neutropenia and thrombocytopenia. Three patients with gliomas experienced centrally confirmed partial responses to therapy. Four patients completed all planned therapy. Temozolomide and MTIC exposures were statistically associated with temozolomide dosage.
Conclusions: The current schedule of temozolomide and O6-benzylguanine is safe and showed modest activity against recurrent brain tumors in children.
Biological Therapy and Other Novel Therapies in Early-Stage Disease: Are They Appropriate?
Authors: Grothey Axel 
Published: November 2007

Abstract
For nearly two decades, adjuvant chemotherapy has been the standard of care in patients with early-stage colon cancer at high risk of recurrence. Until now, treatment has been based on the use of cytotoxic drugs that have well-demonstrated efficacy in advanced colorectal cancer. Most recently, targeted biological agents [i.e., antibodies against the epidermal growth factor receptor and vascular endothelial growth factor] have become essential components of the palliative medical treatment of colorectal cancer. Proof of efficacy of these agents in advanced disease has led to the initiation of several trials testing epidermal growth factor receptor and vascular endothelial growth factor antibodies in the adjuvant setting. Although definitive results of ongoing adjuvant studies will not be available for 2 to 3 years, some oncologists might already inappropriately consider the use of these targeted agents as a component of adjuvant therapy in selected patients. Whether the results obtained in advanced colorectal cancer can be readily translated into a projected efficacy in early-stage colon cancer, however, is unclear. In addition, the long-term safety of biological agents in potentially surgically cured patients has not yet been established. This review discusses the potential caveats and concerns associated with the uncritical use of targeted agents as adjuvant therapy before their safety and efficacy in this setting has been indisputably established in definitive phase III trials.
Management of Early Rectal T1 and T2 Cancers
Authors: Stamos Michael J. , Murrell Zuri 
Published: November 2007

Abstract
The treatment of rectal cancer has undergone a tremendous surgical evolution over the past century. Initially, in the 19th century, the only possible safe treatment was a diverting colostomy, which then evolved first to local treatment, primarily via the Lisfranc and Kraske procedures (posterior approach), and later, in the 20th century, to the abdominal-perineal resection popularized by Miles. Subsequently, anterior resection and low anterior resection gained a solid foothold as the most efficacious ways to treat most cancers of the rectum. In the past 3 decades, transanal excision has reemerged as a popular treatment option for T1 and selected T2 rectal adenocarcinomas, allowing less morbidity for early cancers. The selection criteria for this treatment have often included mobile tumor, size &lt;4 cm, favorable histology without lymphovascular invasion, and anatomic accessibility with the ability to achieve 1-cm circumferential margins. Although the use of transanal excision for T1 rectal cancer increased from 26% to ∼44% between 1989 and 2003, multiple recent retrospective studies have suggested that locoregional recurrence after this procedure is as high as 18% for T1 cancers and 47% for T2 cancers. Of interest, limited available prospective data reveal much better results (4-5% locoregional recurrence rate for T1 and 14-16% for T2). Much of the apparent discrepancy is due to patient selection, which is far more rigid in prospective trials. Conflicting data also exist as to how this outcome affects overall survival, although surgical salvage averages ∼50% with close follow-up. The following topics will be discussed in this article: the surgical evolution of rectal cancer, best patient selection criteria for transanal excision versus more radical operation, utility and effect of adjuvant therapy in early-stage rectal cancer, current trends in the treatment of early-stage rectal cancer, and current early-stage rectal cancer trials.
Normal Brain Cells Contribute to the Bystander Effect in Suicide Gene Therapy of Malignant Glioma
Authors: Miletic Hrvoje , Fischer Yvonne Heidemarie , Giroglou Tsanan , Rueger Maria Adele , Winkeler Alexandra , Li Huongfeng , Himmelreich Uwe , Stenzel Werner , Jacobs Andreas H. , von Laer Dorothee 
Published: November 2007

Abstract
Purpose: Lentiviral vectors pseudotyped with glycoproteins of the lymphocytic choriomeningitis virus (LCMV-GP) are promising candidates for gene therapy of malignant glioma, as they specifically and efficiently transduce glioma cells in vitro and in vivo. Here, we evaluated the therapeutic efficacy of LCMV-GP and vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors.
Experimental Design: Therapeutic efficacy was tested for unmodified (9L) and DsRed-modified (9LDsRed) gliomas using the suicide gene thymidine kinase of the herpes simplex virus type 1 (HSV-1-tk). Positron emission tomography (PET) and magnetic resonance imaging were done to analyze transduction of tumors and monitor therapeutic outcome.
Results: LCMV-GP pseudotypes mediated a successful eradication of 9LDsRed tumors with 100% of long-term survivors. Before initiation of ganciclovir treatment, a strong HSV-1-tk expression within the tumor was detected by noninvasive PET using the tracer 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine. Therapeutic outcome was successfully monitored by magnetic resonance imaging and PET imaging and correlated with the histopathologic data. In the 9L model, LCMV-GP and VSV-G pseudotyped lentiviral vectors displayed similar therapeutic efficacy. Further studies revealed that normal brain cells transduced with VSV-G pseudotypes were not eliminated by ganciclovir treatment and contributed significantly to the bystander killing of tumor cells.
Conclusions: Suicide gene transfer using pseudotyped lentiviral vectors was very effective in the treatment of rat glioma and therefore is an attractive therapeutic strategy also in human glioblastoma especially in conjunction with an imaging-guided approach. In addition, high selectivity of gene transfer to tumor cells may not always be desirable for therapeutic genes that exert a clear bystander effect.
Randomised comparison of G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow-mononuclear cells for the treatment of patients with lower limb arteriosclerosis obliterans
Authors: Huang Ping Ping , Yang Xiao Feng , Li Shan Zhu , Wen Jin Chao , Zhang Yan , Han Zhong Chao 
Published: November 2007

SummaryPrevious studies have suggested that the lower limb arteriosclerosis obliterans (LASO) could be improved by autologous transplantation of either bone marrow mononuclear cells (BMMNC) or G-CSF-mobilized peripheral blood mononuclear cells (M-PBMNC). However, the number of patients observed was very limited, and little information is available regarding comparison. The present randomised trial was designed to assess which is the better option. One hundred fifty patients with LASO were randomised to either group A (76 cases implanted with M-PBMNC) or group B (74 cases implanted with BMMNC), and followed up for 12 weeks. Primary outcomes were safety and efficacy of treatment, based on ankle-brachial index (ABI) and rest pain, and analysis was per protocol. Significant improvement of the main clinical index was observed in both groups after transplantation. No transplantation-related complication was observed in either group. Comparative analysis revealed that at 12 weeks after cell implantation, improvement of ABI (difference 0.06 ± 0.01; p<0.0001), skin temperature (difference 0.55 ± 0.25; p=0.028), and rest pain (difference –0.57 ± –0.15;p<0.0001) was significantly better in groupA patients than group B patients. However, there was no significant difference between two groups for pain-free walking distance, transcutaneous oxygen pressure, ulcers, and rate of lower limb amputation. Autologous transplantation of either M-PBMNC or BMMNC significantly promotes improvement of limb ischaemia in patients with LASO. Comparative analysis indicated that M-PBMNC should be more practical in comparison with BMMNC in the treatment of LASO.