tbuckley/cabot-search huggingface dataset:
Abstract IA14: Exploiting the translational and functional opportunities for homologous recombination deficiency
Authors: Richard John Edmondson
Journal: Clinical Cancer Research (2013)

Abstract Cancer is a disease of DNA, and the processes by which cells repair DNA damage are critical, not only in causing the disease but also in determining how the cancer cell will respond to treatment. Of the six major pathways by which DNA damage is repaired, homologous recombination (HR) is perhaps the best studied in ovarian cancer. This pathway is responsible for repairing double strand breaks and uses at least forty proteins, including both BRCA1 and BRCA2. We have shown that 50% of high grade serous cancers are defective in homologous recombination and this group are more likely to be sensitive to platinum chemotherapy and have a better prognosis than tumours which are competent for the pathway. As may be expected, this group also includes all the tumours occurring in women with germline mutations of BRCA1 and BRCA2. HR status has also been suggested to be predictive of response to PARP inhibitors and it is proposed that this is an example of synthetic lethality in which inactivation of one pathway is not harmful to a cell but inhibition of two (one by the PARP inhibitor and the other the underlying HR defectiveness) will render the cell non viable. We have confirmed in a large panel of ovarian cancer primary cultures and cell lines that HR defectiveness is indeed a very strong predictor of ex vivo drug sensitivity with positive and negative predictive values close to 100%. These data provide the basis for developing biomarker directed therapy for PARP inhibitors and provide a rationale for increasing the indication for these drugs to tumours other than those caused by germline mutations. Challenges still exist however and current work is seeking to investigate the interplay of the different DNA damage repair pathways and how these may be used to further refine the biomarkers currently available. Citation Format: Richard John Edmondson. Exploiting the translational and functional opportunities for homologous recombination deficiency. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA14.
Destruction of Bystander Cells by Tumor Cells Transfected With Inducible Nitric Oxide (NO) Synthase Gene
Authors: K. Xie, S. Huang, Z. Dong, S.-H. Juang, Y. Wang, I. J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The activation of an enzyme, inducible nitric oxide synthase (iNOS), catalyzes the production of endogenous nitric oxide (NO). NO, in turn, is associated with cell death, suppression of tumor development, and inhibition of metastasis of murine melanoma cells. Moreover, the in vivo induction of iNOS is associated with regression of established hepatic metastases. Whether this regression required the activation of the iNOS gene in every tumor cell or whether NO-producing tumor cells can also kill bystander (neighboring) cells has been previously unknown. Purpose: The goal of this study was to determine whether cells producing NO and then undergoing autolysis can also kill bystander cells in vitro and in vivo. Methods: Murine K-1735 C4.parental (C4.P) melanoma cells were transfected with the functional iNOS gene (transfectant denoted as C4.L8) or with a control truncated-nonfunctional iNOS gene (transfectant denoted as C4.S2). NO-mediated cytolysis and bystander cell killing were determined in vitro and in vivo. Results: Only the functional iNOS-transfected C4.L8 cells produced NO and underwent autolysis. C4.L8 cells also produced statistically significant lysis of iNOS-negative C4.P cells. This lysis was suppressed by the specific iNOS inhibitor NG -methyl-L-arginine. NO-producing C4.L8 cells and control C4.P or C4.S2 cells were injected subcutaneously into syngeneic C3H/HeN mice. Control C4.P and C4.S2 cells produced rapidly growing subcutaneous tumors, whereas C4.L8 cells did not. The mixture of C4.P and C4.S2 cells (1:5 ratio) produced rapidly growing subcutaneous tumors, whereas the mixture of C4.P and C4.L8.5 cells (1:5 ratio) produced slow-growing tumors. The subcutaneous growth of C4.P cells was not affected by C4.L8.5 cells injected subcutaneously at a distant site. Mixtures of C4.P cells labeled with [ 125 I]iododeoxyuridine and C4.L8 cells (NO producing) or C4.S2 cells (control) were injected subcutaneously. The survival rate of the radiolabeled cells indicated that the NOproducing C4.L8.5 cells lysed the bystander C4.P cells. Conclusion: The production of high-level endogenous NO causes autolysis in tumor cells and lysis of bystander cells under in vitro and in vivo conditions. Implications: NO-mediated cell killing does not require transfection of genes into every cell in a neoplasm.
Inhibiting Fatty Acid Synthase for Chemoprevention of Chemically Induced Lung Tumors
Authors: Hajime Orita, Jonathan Coulter, Ellen Tully, Francis P. Kuhajda, Edward Gabrielson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Fatty acid synthase (FAS) is overexpressed in lung cancer, and we have investigated the potential use of FAS inhibitors for chemoprevention of lung cancer. Experimental Design: Expression of FAS was evaluated in preinvasive human lung lesions (bronchial squamous dysplasia and atypical adenomatous hyperplasia) and in murine models of lung tumorigenesis [4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone–induced and urethane-induced lung tumors in A/J mice]. Then, the ability of pharmacologic inhibitors of FAS to prevent development of the murine tumors was investigated. Finally, the effect of the FAS inhibitor treatment of levels of phosphorylated Akt in the murine tumors was evaluated by immunohistochemistry. Results: Immunohistochemical studies show that human bronchial dysplasia and atypical adenomatous hyperplasia express high levels of FAS compared with normal lung tissues, suggesting that FAS might be a target for intervention in lung carcinogenesis. FAS is also expressed at high levels in chemically induced murine lung tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with pharmacologic inhibitors of FAS, C75 and C93. C93 treatment is associated with reduced levels of phosphorylated Akt in tumor tissues, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventative activity of this compound. Conclusions: We conclude that increased levels of FAS are common in human preinvasive neoplasia of the lung. Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of lung tumors that have high expression of this enzyme.
Estrogen Receptor Status in <b> <i>BRCA1</i> </b>- and <b> <i>BRCA2</i> </b>-Related Breast Cancer
Authors: William D. Foulkes, Kelly Metcalfe, Ping Sun, Wedad M. Hanna, Henry T. Lynch, Parviz Ghadirian, Nadine Tung, Olufunmilayo I. Olopade, Barbara L. Weber, Jane McLennan, Ivo A. Olivotto, Louis R. Bégin, Steven A. Narod
Journal: Clinical Cancer Research (2004)

Abstract Purpose: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. Experimental Design: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. Results: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P &amp;lt; 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (Pintercept = 0.0002, Pslope = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (Pslope = 0.98). Conclusions: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.
THE CATALYTIC EFFECT OF METHYLENE BLUE ON THE OXYGEN CONSUMPTION OF TUMORS AND NORMAL TISSUES
Authors: E. S. Guzman Barron
Journal: The Journal of Experimental Medicine (1930)

1. Methylene blue has no catalytic effect on the oxygen consumption of those normal adult tissues which do not possess aerobic glycolysis. The dye increases the oxygen consumption of these tissues when their respiration has been inhibited by the addition of KCN and their fermentative power thus brought into action. 2. Methylene blue increases the oxygen consumption of normal tissues having aerobic glycolysis, and of tumors. 3. The effect of methylene blue is roughly proportional to the fermentative power of tissues.
Virological and biochemical long-term follow-up of patients with chronic hepatitis c treated with interferon
Authors: Inmaculada Castillo, Javier Bartolomé, Sonia Navas, Sara Gonzalez, Montserrat Herrero, Vicente Carreño
Journal: Hepatology (1994)

We studied the long-term outcomes of 43 patients with chronic hepatitis C treated with one or two interferon cycles, in relation to hepatitis C virus RNA in serum and peripheral-blood mononuclear cells. After the first interferon cycle, 15 (35%) patients had normal transaminase levels, although only five of them had normal levels throughout follow-up (complete responders). After treatment, hepatitis C virus RNA was detected in serum and peripheral-blood mononuclear cells with a similar frequency among the five complete responders (60% and 40%, respectively) and the 10 responders with relapse (50% and 20%, respectively). During the follow-up of the complete responders (up to 27 mo), fluctuating viremia levels were found, as demonstrated by the intermittent serum hepatitis C virus RNA positivity. In responders with relapse serum hepatitis C virus RNA reappeared concurrent with the relapse, without changes in peripheral-blood mononuclear cells. A second interferon cycle was performed in 23 nonresponders. Six of them had normalized transaminase levels but four had relapses. After retreatment, hepatitis C virus RNA was detected in peripheral-blood mononuclear cells with the same frequency (50%) in complete responders and in responders with relapse. Loss of serum hepatitis C virus RNA was only achieved in responders with relapse. During the follow-up, half of the complete responders lost serum hepatitis C virus RNA. This marker reappeared in responders with relapse, and hepatitis C virus RNA was found de novo in PBMCs of one responder with relapse. None of the 17 nonresponders to retreatment lost hepatitis C virus RNA in serum or PBMCs during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Dosing of a Phase I Study of KW-0761, an Anti-CCR4 Antibody, for Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma
Authors: Ritsuro Suzuki
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: We read with great interest the article regarding a phase I study of KW-0761, an anti-CCR4 antibody, for adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. A dose escalation of KW-0761 was conducted from 0.01 to 1.0 mg/kg, but the maximum-tolerated dose (MTD) was not reached. On the basis of the results, the authors conclude that 1.0 mg/kg is the recommended dose for further phase II study. However, the final dose is much lower than other antibodies used for lymphoma treatment, and therefore, the dose escalation seems to be incomplete. Indeed, as mentioned by the authors, the trough concentration level of 10 g/mL, which was the in vitro efficacy dose, was only achieved after the fourth (final) dose of infusion. In the phase I study of other antibodies for malignant lymphoma, the final dose has ranged from 240 to 1,500 mg/m (CD20, CD22, CD23, CD52, or CD80 antibody) or from 8 to 15 mg/kg (CD30 or CD40 antibody), as shown in Table 1. CD20 (ofatumumab) antibody was given at a fixed dose of 1,000 mg/wk. In all trials, the maximum-tolerated dose was not reached. Although lower doses were determined as recommended doses for subsequent studies in CD22 and CD52 antibodies, the sufficient design of the phase I studies well illuminated the safety and efficacy profiles. Although the maximum dose of phase I study is unknown, a fixed dose of 980 mg is used for CD4 antibody (zanolimumab) in phase II studies. Because the molecular weights of antibodies are similar, a concern is raised about whether the tumor cells can be successfully saturated by the antiCCR4 antibody with such a lower dose. In fact, the functional concentration of antibody-dependent cellular cytotoxicity was only achieved after the fourth (final) dose of the maximum level in this study. There still remains a possibility that the appropriate dose level of anti-CCR4 antibody with tolerable toxicity and greater efficacy is much higher than 1 mg/kg. If the maximum dose in a phase I study is low, the manufacturer may be benefited by reducing the time and cost for drug development and can avoid a risk of excessive toxicity. However, the unexpected severe adverse events caused by antibody drugs are not always associated with excessive dose, and an incomplete dosing of a phase I study may produce a significant delay in or even termination of the quest for appropriate use of the agent. Retrial of a phase I study after a failure of phase II or III studies as a result of inappropriate dose requires much more time and human and financial resources. I believe that the founder of novel agents should be more responsible for a long-term view of the treatment of patients with malignant disorders.
Mycophenolate mofetil prevents a clinical relapse in patients with systemic lupus erythematosus at risk
Authors: M Bijl, G Horst, H Bootsma, P C Limburg, C G M Kallenberg
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Systemic lupus erythematosus (SLE) is characterised by the presence of antibodies to double stranded DNA (dsDNA), which are involved in the pathogenesis of SLE. Previous studies showed that at least two thirds of patients develop a clinical relapse within six months after a significant rise in the anti-dsDNA level, and most relapses were prevented by the administration of corticosteroids at the time of the rise. <b>Objective:</b> To determine whether mofetil mycophenolate (MMF) can prevent a clinical relapse without the side effects associated with corticosteroids. <b>Methods:</b> 36 patients with SLE were examined monthly to determine whether a rise in anti-dsDNA level had occurred. A rise was defined as an increase of 25% of the level of the previous sample of at least 15 IU/ml within a four month period. After a rise patients were treated with MMF 2000 mg daily for six months. Patients were monitored monthly for the occurrence of a clinical relapse and to assess the serological activity and state of activation of CD4+, CD8+, and CD19+ lymphocyte subsets. <b>Results:</b> Anti-dsDNA rose in 10 patients. Treatment with MMF was started in all these patients, and after six months no clinical relapse had occurred. Side effects were minimal. Antibodies to dsDNA decreased during the treatment (p&lt;0.001), associated with a decrease in the state of activation of CD19+ lymphocytes. No changes were found in the state of activation of CD4+ or CD8+ lymphocyte subsets. <b>Conclusion:</b> Administration of MMF after a rise in antibodies to dsDNA is well tolerated, decreases anti-dsDNA and B cell activation, and seems to prevent the occurrence of a clinical relapse in patients with SLE.
Evaluation of the <i>In vitro</i> and <i>In vivo</i> Antitumor Activity of Histone Deacetylase Inhibitors for the Therapy of Retinoblastoma
Authors: Clifton Lee Dalgard, Kurtis R. Van Quill, Joan M. O'Brien
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB). Experimental Design: Growth-inhibitory effects of HDACi [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), or MS-275] were assessed in human and transgenic murine RB cells. Effects of TSA and MS-275 were also assessed in combination with standard therapeutic agents for RB. Proapoptotic effects of MS-275 and TSA were evaluated by caspase-3/7 activity, Annexin V translocation, and/or Bim expression analyses. Effects of MS-275 on cell cycle distribution and reactive oxygen species levels were determined by flow cytometry. Retinal tissue morphology was evaluated in mice after local administration of MS-275. Analysis of retinal acetyl-histone levels was used to assess MS-275 delivery after systemic administration. Therapeutic effects of MS-275 were determined in transgenic mouse and rat ocular xenograft models of RB after i.p. injection of 20 mg/kg every other day for 21 or 13 days, respectively. Results: TSA, SAHA, and MS-275 dose dependently reduced RB cell survival. TSA and MS-275 showed additive growth-inhibitory effects in combination with carboplatin, etoposide, or vincristine. TSA and MS-275 increased caspase-3/7 activity. MS-275 increased Annexin V membrane translocation and induced G1 arrest. Cytotoxicity of MS-275 was dependent on increased reactive oxygen species levels and was reversed by antioxidant pretreatment. Intraocular administration of 1 μL of 10 μmol/L MS-275 did not alter ocular tissue morphology. Increased acetyl-histone levels confirmed MS-275 delivery to retinal tissue after systemic administration. MS-275 significantly reduced tumor burden in both mouse and rat models of RB. Conclusions: HDACi should be considered for clinical trials in children with RB.
Increased number of mature dendritic cells in Crohn's disease: evidence for a chemokine mediated retention mechanism
Authors: P Middel
Journal: Gut (2005)

Activation of T cells by dendritic cells (DC) is thought to play a pivotal role in induction and maintenance of Crohn's disease. Detailed analyses however concerning the phenotype and maturation of DC as well as the mechanisms underlying their recruitment are still lacking for Crohn's disease.Different myeloid and plasmacytoid DC subsets were characterised by immunohistochemistry. Expression of the so-called "lymphoid" chemokines CCL19, CCL20, and CCL21 was determined by real time reverse transcription-polymerase chain reaction in Crohn's disease and normal controls. Furthermore, expression of CCL19, CCL20, and CCL21 as well as their receptors CCR6 (for CCL20) and CCR7 (for CCL19 and CCL21) was characterised by immunohistochemistry and, in addition, their cellular localisation was determined by double immunofluorescence investigations.Colonic tissue affected by Crohn's disease was characterised by an increased number of mature myeloid DC forming clusters with proliferating T cells. In keeping with their advanced maturation, DC possess the chemokine receptor CCR7. Increased expression of the CCR7 ligands CCL19 by DC themselves as well as CCL21 by reticular cells and lymphatic vessels was observed in Crohn's disease, thereby causing the matured DC to be trapped at the site of inflammation.Our results demonstrate that autocrine and paracrine actions of lymphoid chemokines in Crohn's disease may lead to increased numbers of mature DC away from their usual migration to lymphoid organs and result in the development of a tertiary lymphatic tissue within the bowel wall maintaining the autoimmune inflammation in Crohn's disease.
Farletuzumab, a Humanized Monoclonal Antibody against Folate Receptor α, in Epithelial Ovarian Cancer: a Phase I Study
Authors: Jason A. Konner, Katherine M. Bell-McGuinn, Paul Sabbatini, Martee L. Hensley, William P. Tew, Neeta Pandit-Taskar, Nicholas Vander Els, Martin D. Phillips, Charles Schweizer, Susan C. Weil, Steven M. Larson, Lloyd J. Old
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Folate receptor α expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. Farletuzumab, a humanized monoclonal antibody against folate receptor α, has shown antitumor activity and favorable toxicity in preclinical evaluation. This phase I, dose-escalation study was conducted to determine the safety of weekly i.v. farletuzumab and establish the maximum tolerated dose (MTD). Experimental Design: Patients with platinum-refractory or platinum-resistant epithelial ovarian cancer received farletuzumab (12.5-400 mg/m2) on days 1, 8, 15, and 22 of a 5-week cycle. Intrapatient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related adverse event of grade 3 or higher, and the MTD was the highest dose at which one or none of six patients experienced a DLT. Disease progression was recorded using Response Evaluation Criteria in Solid Tumors criteria and serum CA-125. Results: Twenty-five heavily pretreated patients were included in the safety, efficacy, and pharmacokinetic analyses. No DLTs or MTDs were encountered, and dose escalation was continued to farletuzumab 400 mg/m2. Cmax and AUC0-24 (area under the serum concentration-time curve) increased in an approximately dose-proportional manner, and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. Stable disease by Response Evaluation Criteria in Solid Tumors was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles. Conclusions: In this phase I study, farletuzumab administered as an i.v. infusion at doses of 12.5 to 400 mg/m2 was generally safe and well tolerated in the management of heavily pretreated patients with epithelial ovarian cancer. Clin Cancer Res; 16(21); 5288–95. ©2010 AACR.