tbuckley/cabot-search huggingface dataset:
Abstract 3543: Complete regression of solid B16F1 melanoma tumors obtained by intratumoral injection of LTX-315 (Oncopore®)
Authors: Ketil A. Camilio, Oystein Rekdal, Baldur Sveinbjornsson
Journal: Cancer Research (2012)

Abstract Background: Malignant melanoma is imposing an increasing threat to the world's population and new therapies are needed.Standard treatment involves surgery, chemotherapy, and radiation therapy and often leads to relapse after ended therapy. LTX-315 (Oncopore®) is a chemically modified cationic cytolytic peptide which is equally active against drug-sensitive and drug-resistant cancer cells. Earlier animal studies have demonstrated that treatment of syngeneic murine A20 B-cell lymphomas and CT26WT colon carcinomas with intratumoral (i.t.) injection with LTX-315 resulted in complete tumor regression and long-term protective effect against re-inoculated tumor cells. The present study was undertaken to investigate whether LTX-315 induced an antitumor response in vivo in a highly aggressive murine melanoma tumor model. Methods: Pre-cultured B16F1 melanoma cells (5 x 104) were subcutaneously inoculated into the abdomen of syngeneic C57BL/6N mice and established tumors treated i.t. with LTX-315. Animals were taken for analysis to elaborate the mechanism of action of LTX-315 and for potential immune modulatory effects following treatment. Blood plasma was analyzed for changes in cytokine content and tumor tissue was analyzed for infiltrating immune cells using immunohistochemistry and flow-cytometry. Results: Intratumoral treatment with LTX-315 resulted in a complete regression of tumor in the treated animals. Tumors treated with LTX-315 showed an increased infiltration of immune cells into the tumor compared to control tumors receiving vehicle. Conclusions: Our results suggest that LTX-315 treatment can induce complete regression in solid B16F1 melanoma tumors, thus leading to local tumor control. Intratumoral treatment with LTX-315 can lead to immune-modulatory effects such as an increase in the number of infiltrating immune cells, causing a shift in the balance between immune effector and immune suppressive cells in the tumor environment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3543. doi:1538-7445.AM2012-3543
Abstract 683: Biological significance of conjugated linoleic acid in ovarian carcinoma
Authors: Mian M. Shahzad, Ahmed Al-Niaimi, Mildred A. Felder, Arvinder Kapur, Nick Claussen, Fatou Jallow, Hannah R. Van Galder, Joseph P. Connor, Manish S. Patankar
Journal: Cancer Research (2011)

Abstract Background: Conjugated linoleic acid (CLA) has long been recognized to exert protective effects on carcinogenesis in breast, prostate and colon malignancies. Recent data suggests that CLA plays a key role in inhibiting several important survival pathways in breast cancer cell. However, data on effects of CLA in epithelial ovarian carcinoma are lacking and was the focus of this study. Methods: A2780 and SKOV3 ovarian cancer cell were treated with increasing concentrations of two different isomers of CLA (9:11, 10:12) and effect of CLA on cell viability was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at different time points with and without oxaliplatin. Additionally, effect of CLA isomer 10:12 were evaluated on A2780 ovarian cancer cell apoptosis by flow (Annexin V/PE). Results: CLA isomer-10:12 significantly affected the ovarian cancer cell viability in a time and dose dependent fashion. Seventy-two to 96h of CLA treatment (isomer 10:12, 7µμ) resulted in ∼50% reduction in cell viability compared to control (p&amp;lt;0.01). A 20 µM dose of the CLA isomer 10:12 resulted in &amp;gt;80% reduction in live cell compared to controls. However, CLA isomer 9:11 had no effect in all doses and time points tested (0.001 µM- 50mM). Additionally, at IC50 dose of oxaliplatin treatment, the addition of CLA, resulted in a substantial reduction (by ∼50%, p&amp;lt;0.05) in percent live cell compared to oxaliplatin monotherapy. Conclusion: Our data indicate that CLA can significantly hamper the survival of ovarian cancer cell. These findings may have therapeutic implications for ovarian cancer management and needs further exploration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 683. doi:10.1158/1538-7445.AM2011-683
Abstract 525: Toll-like receptor-4 mediated cutaneous immune responses augment ultraviolet radiation-induced DNA damage and tumor development
Authors: Israr Ahmad, Purushotham Guroji, Hugo Jimenez, Eva Simanyi, Anusuiya Nagar, Priyamvada Nagar, Nabiha Yusuf
Journal: Cancer Research (2012)

Abstract UV (ultraviolet) B induced DNA damage plays a critical role in development of skin cancer. The molecular basis for this biologic activity resides at least in part from the demonstrated ability of this form of radiant energy to damage DNA, predominantly in the form of cyclobutane pyrimidine dimers (CPD). The purpose of this study was to determine whether toll-like receptor-4 (TLR4) contributed to UV-induced DNA damage responses and cutaneous tumor development. TLR4 deficient and wild type (WT) mice were subjected to a local UVB induced DNA damage regimen consisting of 90 mJ/cm2 UVB radiation. Wild type mice exhibited significant (p&amp;lt;0.05) DNA damage in the form of cyclobutane pyrimidine dimers (CPD), whereas TLR4 deficient mice developed significantly fewer CPD (p&amp;lt;0.05) in their skin and bone marrow dendritic cells (BMDC). The expression of DNA repair gene XPA was significantly less (p&amp;lt;0.05) in skin and BMDC from WT mice than TLR4 deficient mice after UVB exposure. When cytokine levels were compared in these two strains after UVB exposure, BMDC from UV-irradiated TLR4 deficient mice produced significantly more IL-12 and IL-23 cytokines (p&amp;lt;0.05) than BMDC from WT mice. Furthermore, we found that Toll like receptor-4 (TLR4) promoted UVB induced tumor development. We observed that UVB induced skin carcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared to WT mice, whereas significantly greater (p&amp;lt;0.05) numbers of tumors occurred in WT mice. Further, we found that tumor-bearing WT mice produced more IL-17 and IL-10 (p&amp;lt;0.05), whereas TLR4 deficient mice produced more IFN-γ (p&amp;lt;0.05). CD4+CD25+ regulatory T-cells from WT mice produced more IL-10 (p&amp;lt;0.05) than regulatory T-cells from TLR4 deficient mice. There was a significant increase (p&amp;lt;0.05) in Foxp3 expression in skin of WT mice than TLR4 deficient mice. Thus, strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous DNA damage and skin cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 525. doi:1538-7445.AM2012-525
Abstract 4964: Mutations of cysteine residues in Bcl-2 suppress hydrogen peroxide-induced apoptosis of human lung cancer cells through ERK1/2 interaction
Authors: Sudjit Luanpitpong, Liying Wang, Yon Rojanasakul
Journal: Cancer Research (2012)

Abstract Bcl-2 is an essential antiapoptotic protein of the mitochondrial death pathway whose expression is highly associated with apoptosis resistance in cancer cells. Hydrogen peroxide is a signaling molecule mediating apoptosis to various stimuli, e.g. cisplatin and lipoic acid, in lung cancer cells. Direct treatment of the cells with hydrogen peroxide induced oxidative stress and a concomitant increase in apoptosis of human lung cancer H460 cells. Cysteine residues are likely targets of oxidative modifications of proteins; however, their effects on apoptosis and mechanisms of regulation are not known. To determine the role of cysteine residues, we constructed Bcl-2 mutant plasmids replacing the two cysteine residues Cys158 and Cys229 with alanines (Bcl-2-DM). Overexpression of Bcl-2-DM strongly suppressed the apoptosis induced by hydrogen peroxide in H460 cells as compared to that in control cells overexpressing wild-type Bcl-2. We further found that Bcl-2 directly interacts with MAP kinase ERK1/2 and that hydrogen peroxide disrupts such interaction. However, hydrogen peroxide treatment had a minimal effect on Bcl-2 and ERK1/2 interaction in Bcl-2-DM overexpressing cells, suggesting that Cys158 and Cys229 are required for the oxidative signaling. These findings identified a novel mechanism of oxidative regulation of apoptosis via cysteine modifications of Bcl-2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4964. doi:1538-7445.AM2012-4964
Abstract LB-442: The nuclear matrix anchor domain of the DNA replication factor Ciz1 is commonly disrupted in tumours and is a circulating biomarker for lung cancer
Authors: Gillian Higgins, Heather Cook, Katherine Roper, Jennifer Munckley, Irene Watson, Fiona Blackhall, William Rom, Harvey Pass, Justin Ainscough, Dawn A. Coverley
Journal: Cancer Research (2012)

Abstract The DNA replication protein Ciz1 promotes initiation of mammalian DNA replication in cooperation with cyclin A-dependent kinase, most likely by delivering cyclin A to sites where cyclin E-dependent pre-replication complex assembly has taken place. Normally, Ciz1 is anchored within nuclear matrix-associated foci that co-localize with sites of DNA replication, but in the absence of anchor domain Ciz1 retains the ability to promote initiation of DNA replication in isolated nuclei so attachment to the nuclear matrix is not essential for function. Expression of DNA replication and nuclear matrix anchor domains of Ciz1 are uncoupled and uneven at the transcript level in a wide range of common solid tumours, including breast and lung. In cell-based assays, recombinant anchor domain protein interferes with attachment of endogenous Ciz1 to the nuclear matrix, revealing a dominant negative effect that also impacts on nuclear matrix-recruitment of key components of the pre-replication complex. This suggests that Ciz1 normally plays a role in localizing initiation of DNA replication to the nuclear matrix. These findings implicate spatially unconstrained DNA replication as a source of nuclear disorder in cancer cells. We identified a variant Ciz1 isoform with alterations in the nuclear matrix attachment domain and tumour-restricted expression. RNAi-mediated selective inhibition of variant Ciz1 expression is sufficient to restrain the growth of tumour cells that express it, identifying variant Ciz1 as a functionally relevant driver of cell proliferation. We also present evidence that this form of Ciz1 is expressed in 34/35 lung tumours but not adjacent tissue, giving rise to stable protein quantifiable in less than a microlitre of patient plasma by western blot. Using two independent sets, with 170 and 160 samples, variant Ciz1 correctly identified stage 1 lung cancer patients with clinically useful accuracy. For set 1, mean variant Ciz1 level (+SD) in individuals without diagnosed tumours established a threshold that correctly classified 94% of small cell lung cancers (SCLC) and non-SCLC patients. Within set 2, comparison of stage 1 non-SCLC with asymptomatic age-matched smokers correctly classified 85% of patients, while comparison with individuals with benign lung nodules correctly classified 83% of patients. The data show that this cancer-specific, single marker is capable of indentifying early stage lung cancer within at-risk groups, without resort to invasive procedures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-442. doi:1538-7445.AM2012-LB-442
Abstract 4934: The role of Aurora A kinase-dependent phosphorylation of cortactin in invadopodia formation.
Authors: Varvara K. Kozyreva, Laura Kelley, Sarah L. McLaughlin, Elena N. Pugacheva
Journal: Cancer Research (2013)

Abstract Aurora A kinase (AURKA) is a serine/threonine kinase known for its critical role in regulation of cell cycle progression. Overexpression and activation of AURKA is implicated in development of multiple types of human cancer. AURKA upregulation is considered as independent prognostic marker for breast cancer patients and associated with poor survival outcome. Recent work by our laboratory and others suggests a new role for AURKA in promotion of tumor cells migration and invasion through regulation of actin dynamics. However, the specific manner in which AURKA regulates actin-based machinery of migrating cancer cells is unknown. In our current work we show that phosphorylation of cortactin (CTTN) by AURKA directly regulates actin dynamics in breast cancer cells. CTTN is known to be regulated by oncogenic Src kinase. This phosphorylation is pivotal for formation of free barbed ends and further actin polymerization. Dynamic polymerization/depolimerization is required for invasion of cancer cells. Thus inhibition of Src-dependant phosphorylation of CTTN is critical for invadopodia maturation. In our current work we identify the phosphorylation site on CTTN targeted by AURKA and show that phosphorylation of CTTN by AURKA could potentially inhibit further phosphorylation of CTTN by Src leading to stabilization of invadopodia. Inhibition of AURKA activity or depletion of AURKA in cancer cells led to decrease in invasion and invadopodia maturation. In addition, we showed that adaptor protein NEDD9 which is known to bind both AURKA and Src also binds to CTTN and therefore potentially can mediate Src-CTTN-AURKA complex formation that regulates the sequential phosphorylation events necessary for invadopodia genesis. It is our expectation that AURKA-phosphorylated CTTN will inhibit Src-driven tyrosine-phosphorylation of CTTN, regulating a mechanistic switch between complementary actin polymerization and actin stabilization programs. Citation Format: Varvara K. Kozyreva, Laura Kelley, Sarah L. McLaughlin, Elena N. Pugacheva. The role of Aurora A kinase-dependent phosphorylation of cortactin in invadopodia formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4934. doi:10.1158/1538-7445.AM2013-4934
Abstract 1285: The effects of the HK5-ferritin interaction and iron on tumor angiogenesis
Authors: Annissa J. Huhn, Derek Parsonage, Suzy V. Torti, Thomas Hollis
Journal: Cancer Research (2010)

Abstract Angiogenesis, or the development of new blood vessels from existing blood vessels, is a process essential to wound healing, reproduction, and tumor growth. Tumor angiogenesis is an important factor in the growth and spread of cancer. In order for tumors to grow beyond 2mm^3, vasculature is necessary to provide oxygen and nutrients and remove waste products. The imperfect blood vessels built within tumors also allow tumor cells to travel through the bloodstream and metastasize. Endogenous inhibitors of angiogenesis are known to form from plasma proteins. For example, angiostatin is derived from plasmin. A newly described angiogenesis inhibitor derived from high molecular weight kininogen (HK) is domain 5 of HK (HK5). HK5 has been shown to inhibit endothelial cell proliferation, migration and tube formation. HK5 binds to the endothelial cell surface receptors uPAR, cytokeratin-1, gC1qR and tropomyosin to disrupt angiogenic signaling. Our laboratory has shown that the iron storage protein ferritin binds to HK5, inhibiting its antiangiogenic effects and thereby allowing endothelial cells to migrate and proliferate. We have begun to investigate the physical interaction of ferritin with the HK5 protein with the long-term goal of developing inhibitors of the HK5-ferritin interaction. Human recombinant HK5 and ferritin H were purified and their interaction studied using fluorescence anisotropy. The two proteins were found to bind with a Kd of 1.36μM. The influence of metals on the interaction was also evaluated. We found that in the presence of iron the interaction between ferritin and HK5 was maximal, while in the presence of zinc, the interaction was minimal. EDTA pretreatment of the two proteins further improved binding. The results suggest that iron is essential to the optimal binding interaction of HK5 and ferritin. Future studies will be directed at the identification of specific amino acid residues involved in this interaction. (supported by NIH R01 DK071892) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1285.
A phase II Trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody in subjects with heavily treated and platinum-resistant advanced Müllerian malignancies
Authors: M. Seiden, H. A. Burris, U. Matulonis, J. Hall, D. Armstrong, J. Speyer, J. Tillner, D. Weber, F. Muggia
Journal: Journal of Clinical Oncology (2005)

3151 Background: A high proportion of ovarian tumors express the epidermal growth factor receptor (EGFR). Preclinical and clinical studies have demonstrated this receptor as a potential therapeutic target in a wide variety of epithelial malignancies. Matuzumab is a humanized monoclonal anti-EGFR antibody that has demonstrated anti-tumor activity against solid tumors in prior phase I clinical trials. Methods: This is a multi-center, open labeled phase II clinical trial that enrolled women with a history of platinum-resistant ovarian cancer or primary peritoneal carcinoma. Cell surface staining for EGFR was required as was prior therapy with at least one other non-platinum agent at the time of tumor relapse. Subjects received 800 mg of matuzumab weekly with reassessment every 8 weeks. Pharmacokinetic (PK) behavior of matuzumab was also evaluated throughout the treatment and in selected subjects several weeks post therapy. Results: 72 women were screened for the study and 37 were treated. Median age of treated subjects was 60 with subjects having a median of 7 lines of prior therapy. Therapy was well tolerated with the most common toxicities being a constellation of skin toxicities including rash, acne, dry skin, and paronychia, as well as headache, dizziness, fatigue, and diarrhea. Serious adverse events were very rare but did include a single episode of pancreatitis that may have been drug related. All subjects have completed therapy with subjects receiving between 1 and 30 infusions of matuzumab. There were no formal responses (RR=0%, 95% CI 0–9.5%) although 21% of subjects were on therapy for more then 6 months with stable disease. Changes in the PK behavior of matuzumab with ongoing therapy will also be presented. Conclusions: Matuzumab at the dose and schedule selected is very well tolerated. In this population of very heavily pretreated subjects there was no evidence for significant clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration EMD, Merck KGaA Aventis, CTI, EMD, GlaxoSmithKline, Novartis Aventis, Bristol-Myers Squibb, EMD, Genentech, Lilly, Roche Aventis, Bristol-Myers Squibb, CTI, EMD, Genentech, GlaxoSmithKline, Lilly Oncology Novartis, Roche
Clinical Pharmacodynamics of High-Dose Methotrexate in Acute Lymphocytic Leukemia
Authors: W E Evans, M Abromowitch, W R Crom, M V Relling, W P Bowman, C H Pui, J Ochs, R Dodge
Journal: New England Journal of Medicine (1986)

As the intensity of cancer chemotherapy has been reported to influence clinical response for several drug-sensitive cancers, we have investigated the relation between systemic exposure to high-dose methotrexate (HDMTX) and clinical response in childhood acute lymphocytic leukemia (ALL). A total of 108 consecutive, previously untreated children with "standard-intermediate risk" ALL were randomized to receive postinduction therapy with HDMTX (1000 mg/m2 iv over 24 hours weekly for 3 weeks, then every 6 weeks for 72 weeks), superimposed on conventional therapy with low-dose 6-mercaptopurine (6MP; 50 mg/m2 orally per day) and methotrexate (MTX; 25 mg/m2 orally per week). The systemic clearance of HDMTX ranged from 40 to 131 ml/minute/m2 among these patients, yielding MTX steady-state plasma concentrations (Cpss) ranging from 9.3 to 25.4 microM during the infusion. The group of patients (n = 59) with median MTX Cpss less than 16 microM during the HDMTX infusion had a higher probability of having any relapse than patients (n = 49) with MTX Cpss greater than 16 microM (P less than 0.05). In a previously reported univariate analysis, patients with MTX Cpss less than or equal to 16 microM were 3.2 times more likely to relapse on therapy (P = 0.01) and 6.9 times more likely to have a hematologic relapse on therapy (P = 0.001). Multivariate and stepwise Cox's regression analyses indicated that MTX Cpss retains its prognostic importance even when other prognostic variables (i.e., DNA Index, WBC, hemoglobin) are considered.(ABSTRACT TRUNCATED AT 250 WORDS)
Mammography Screening — Polling Results
Authors: James A. Colbert, Jonathan N. Adler
Journal: New England Journal of Medicine (2013)

Recently, we gave readers the opportunity to share their opinions on mammography screening in Clinical Decisions, an interactive feature in which experts discuss a controversial topic and readers vote and post comments. The feature coincided with the publication of an article by Bleyer and Welch,1 in which the long-term effects of mammography screening on the incidence of breast cancer in the United States between 1976 and 2008 were reported. The authors found a doubling of the incidence of early-stage breast cancers during this period but only a small decrease in the incidence of late-stage breast cancers during the same period. . . .
Effect of the Tyrosine Kinase Inhibitor STI571 in a Patient with a Metastatic Gastrointestinal Stromal Tumor
Authors: Heikki Joensuu, Peter J. Roberts, Maarit Sarlomo-Rikala, Leif C. Andersson, Pekka Tervahartiala, David Tuveson, Sandra L. Silberman, Renaud Capdeville, Sasa Dimitrijevic, Brian Druker, George D. Demetri
Journal: New England Journal of Medicine (2001)

Gastrointestinal stromal tumors are a group of mesenchymal neoplasms that arise from precursors of the connective-tissue cells of the gastrointestinal tract.1 They occur predominantly in middle-aged and older persons, and approximately 70 percent of the tumors are found in the stomach, 20 to 30 percent are found in the small intestine, and less than 10 percent are found elsewhere in the gastrointestinal tract.1 Recent studies have shown that cells in gastrointestinal stromal tumors express a growth factor receptor with tyrosine kinase activity termed c-kit. This receptor, the product of the proto-oncogene c-kit, can be detected by immunohistochemical staining for . . .