tbuckley/cabot-search huggingface dataset:
Camptothecin binding to topoisomerase I-DNA complexes impedes DNA uncoiling and induces the accumulation of positive supercoils
Authors: Komaraiah Palle, Daniel Koster, Nynke Dekker, Mary-Ann Bjornsti
Journal: Cancer Research (2007)

5735   DNA topoisomerase I (Top1) catalyzes the relaxation of positively or negatively supercoiled DNA via the formation of a transient Top1-DNA covalent intermediate, which acts as a swivel to allows DNA uncoiling or rewinding, respectively. Camptothecin targets Top1 by reversibly stabilizing this covalent complex. During S-phase, the collision of advancing replication forks with Top1-DNA-drug complexes are thought to induce the formation of potentially lethal DNA lesions that cause cell death. Several camptothecin analogs, including irinotecan and topotecan have significant activity against adult and pediatric solid tumors. A detailed understanding of Top1-drug interactions is critical for the optimal clinical development of these chemotherapeutics; however, the dynamic interactions underlying Top1 poisoning by camptothecins and their biological ramifications remain largely unknown. Employing a single-molecule technique allowed us to monitor the binding and unbinding of an individual topotecan molecule in real-time and quantify the drug-induced trapping of Top1 on DNA. In these experiments, a single double-stranded DNA molecule is anchored between a glass surface and a paramagnetic bead. A pair of magnets generates an upward stretching force, while rotating the magnets about their axis mechanically injects positive or negative supercoils. By continuously monitoring bead height (DNA extension), the degree of DNA supercoiling is determined in real-time. Our studies show that a bound topotecan molecule alters the Top1 swivel in two ways. First, we conclude that an individual topotecan traps Top1 for at least 2 minutes, an increase of roughly a factor of 100 in comparison to when topotecan is absent. Second, our findings also show that topotecan significantly hinders DNA rotation within the covalent complex. Unexpectedly, however, this effect was more pronounced on the removal of positive (overwound) rather than negative supercoils. These single-molecule observations led us to posit that this bias towards negative supercoil removal would also be induced by camptothecin in vivo, during cellular processes such as transcription and replication that induce DNA supercoiling. Indeed, yeast as a model system, we show that camptothecin poisoning of Top1 induces the accumulation of positive supercoils in G1 and S-phases of the cell cycle, independent of Topoisomerase II. These findings suggest a novel mechanism for drug-induced cell death. Instead of the covalent complex presenting a physical barrier to the advancing fork, the local domain of positive supercoils generated ahead of the fork, which is not efficiently removed by the drug-bound Top1, may itself hamper fork progression. The resultant stalling of the replication machinery would result in fork collapse and the formation of potentially lethal DNA lesions that ultimately induce cell death.
Abstract 1789: Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion
Authors: Linda Sleire, Bente Sandvei Skeie, Inger Anne Netland, Hilde Elise Førde, Ernest Dodoo, Frode Selheim, Lina Leiss, Jian Wang, Jan Heggdal, Paal-Henning Pedersen, Per Øyvind Enger
Journal: Cancer Research (2015)

Abstract Glioblastomas (GBMs) are lethal cancers and inherently resistant to radiotherapy. Established treatments including surgery, radio- and chemotherapy have a limited efficacy, and the median survival is approximately 14.6 months. Thus, treatment resistance represents a major challenge in the clinical management of these patients, and new therapies are urgently needed. We hypothesized that the Xc−-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Expression of the catalytic subunit of system Xc−, xCT, was found in a panel of 30 human GBM biopsies. Sections from normal brain tissue displayed only weak immunopositivity, thus our findings therefore suggest that xCT expression is common to most GBMs, which together with its low expression in normal brain tissue could provide a therapeutic window. SAS treatment dramatically reduced cysteine-uptake and glutathione (GSH) levels in glioma cells in vitro and markedly increased the levels of reactive oxygen species (ROS). Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared to controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients. We are currently preparing a clinical trial for patients with GBM recurrences combining pre-treatment with SAS and GKRS. Citation Format: Linda Sleire, Bente Sandvei Skeie, Inger Anne Netland, Hilde Elise Førde, Ernest Dodoo, Frode Selheim, Lina Leiss, Jian Wang, Jan Heggdal, Paal-Henning Pedersen, Per Øyvind Enger. Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1789. doi:10.1158/1538-7445.AM2015-1789
Abstract 3000: Blood Pressure Imposes Different Cardiovascular Morbidity On Renal Transplant Candidates Depending On The Presence Of Concomitant Cardiovascular Disease Regardless Of Left Ventricular Function
Authors: Luis Henrique W Gowdak, Flavio J de Paula, Luiz Antonio M Cesar, Eduardo M Krieger, Jose Jayme G De Lima
Journal: Circulation (2008)

Background: Renal transplant candidates (RTC) are at risk of cardiovascular disease (CVD) and events (MACE). We compared the impact of blood pressure on the incidence of MACE in RTC according to left ventricular (LV) function and the presence of CVD. Methods: 956 RTC (62% men, 53 ± 11 years) were divided according to the presence of CVD (CAD, heart failure, peripheral arterial disease, and/or stroke). LV ejection fraction (EF) was obtained by echo and the mean arterial pressure (MAP) calculated during the baseline visit. The composite incidence of fatal/non-fatal MACE was determined during a median follow-up of 24 months and its rate plotted for each MAP level for RTC with and without CVD; the best curve to fit the regression model was determined by the regression coefficient (R 2 ). Results: The incidence of MACE was 18.4% in the overall population. RTC with concomitant CVD had a 3-fold increase in the endpoint (31.9%) compared with RTC without CVD (11.3%) (P &lt; 0.0001). As shown by the dark lines, in RTC with ( “J-shape” curve; R 2 = 0.91; P &lt; 0.0001) or without CVD (linear; R 2 = 0.88; P &lt; 0.0001), the MAP was associated with MACE. In the graph, the mean LVEF for each MAP level is represented by the bars (CVD[−]= white; CVD[+]= gray). There was no difference in the mean LVEF in RTC without CVD (P = 0.57), whereas in the group with CVD, the mean LVEF was lower in those with lower MAP (P = 0.014). Even so, in RTC with CVD and similar LVEF, those with a MAP between 101–120mmHg had the lowest rate of events. Conclusions: In RTC, blood pressure has a different impact on the occurrence of MACE depending on the presence of CVD. In RTC with CVD, this effect seems to be stronger at extreme levels of MAP, regardless of the LV function.
Abstract 4878: Role of Mitochondrial Superoxide in Endothelial Dysfunction and Hypertension
Authors: Anna E Dikalova, Alfiya T Bikineyeva, Klaudia Budzyn, Rafal R Nazarewicz, William Lewis, David G Harrison, Sergey Dikalov
Journal: Circulation (2009)

Background. Superoxide (O 2 − • ) production by vascular NADPH oxidase is strongly implicated in the pathogenesis of hypertension; however, the role of mitochondrial O 2 − • is not clear. In this work we have investigated the role of mitochondrial O 2 − • in endothelial dysfunction and hypertension in cultured human aortic endothelial cells and in hypertensive mice using mitochondria-targeted superoxide dismutase mimetic mitoTEMPO, depletion or overexpression of mitochondrial superoxide dismutase (SOD2). Results. We found that supplementation of AngII-stimulated endothelial cells with mitoTEMPO decreased AngII-stimulated mitochondrial O 2 − • , inhibited production of cellular O 2 − • , restored nitric oxide (NO), attenuated c-Src activity and inhibited NADPH oxidase. SOD2 plasmid increased SOD activity in mitochondria but not in the cytoplasm, however, it inhibited cytoplasm NADPH oxidase and blocked AngII-induced cellular O 2 − • . SOD2 depletion with siRNA increased both basal and AngII-stimulated cellular O 2 − • due to higher NADPH oxidase activity while mitoTEMPO treatment mimicked SOD2 overexpression. Infusion of mitoTEMPO to AngII-treated mice attenuated AngII-induced hypertension. mito-TEMPO treatment after the onset of hypertension decreased blood pressure by 30 mm Hg both in AngII-infused and DOCA-salt mice (Table 1 ). The antihypertensive effect of mitoTEMPO was accompanied by decreased vascular O 2 − • , increased vascular NO production and recovery of endothelial-dependent relaxation. Interestingly, mice transgenic for mitochondrial SOD2 demonstrated attenuated AngII-induced hypertension and vascular oxidative stress similar to mitoTEMPO supplementation (Table 1 ). Conclusion. Our data show that mitochondrial O 2 − • is important for regulation of vascular NADPH oxidase and it represents a novel therapeutic target to treat endothelial dysfunction and hypertension. Table 1. Antihypertensive effect of mitoTEMPO (mT) and SOD2 overexpression (mm Hg) This research has received full or partial funding support from the American Heart Association, National Center.
In vitro and ex vivo activity of SDX-105 (bendamustine) in drug-resistant lymphoma cells
Authors: Lorenzo M. Leoni, Brandi Bailey, Christina C. Niemeyer, Jack Reifert, Heather Bendall, Lisa Dauffenbach, Christopher Kerfoot
Journal: Cancer Research (2004)

1215  SDX-105 (bendamustine), currently in Phase II clinical trials in the US for the treatment of rituximab relapsed/resistant Non-Hodgkin’s Lymphoma (NHL), has been shown to have clinical activity in patients refractory to conventional alkylator chemotherapy. To better define the activity and mechanism of action of SDX-105, we generated resistant lymphoma cells and assayed ex vivo NHL specimens from patients previously shown to be resistant to cyclophosphamide, doxorubicin, and etoposide. Two SDX-105 resistant cell lines were generated by continuous exposure to increasing concentrations of the drug for over a year. SU-DHL-1 cells, an anaplastic large cell lymphoma cell line, demonstrate an IC50 of approximately 20 μM. SDX-105-resistant SU-DHL-1 cells displays an IC50 of approximately 150 μM. SU-DHL-9 cells, EBV-negative diffuse large B-cell lymphoma, have an IC50 of approximately 20 μM while the SDX-105-resistant SU-DHL-9 cells have an IC50 of approximately 80 μM. Initial experiments show no cross-resistance of both of these resistant cell sublines to chlorambucil, phosphoramide mustard (a cyclophosphamide metabolite), fludarabine, cisplatinum, and doxorubicin. An initial analysis of the effect of SDX-105 on the SU-DHL-1 gene expression profile using the Affymetrix genechip has been performed. A comparison between the parental and SDX-105-resistant cells will allow the identification of genes potentially important for the resistant phenotype. Activity of SDX-105 was also evaluated using the DiSC® assay, a clinically validated assay with the potential to predict patient treatment response to traditional chemotherapeutic agents. Twenty primary NHL specimens obtained from patients who failed prior chemotherapy were tested with SDX-105 and an active metabolite of cyclophosphamide (4-HC). At equipotent concentrations, SDX-105 was cytotoxic to NHL specimens defined as 4-HC resistant (P = 0.0004). In addition, SDX-105 showed a statistically significant increase in cytotoxic activity in the samples that were previously analyzed and defined as doxorubicin-resistant (P = 0.000098) and etoposide-resistant (P = 0.00038). These data suggest that SDX-105 is a novel chemotherapeutic agent with a mechanism of action and drug resistance potentially distinct from other DNA-damaging agents. In addition, the activity in multidrug resistant NHL tumors suggest that SDX-105 is a promising agent for the treatment of patients refractory to conventional cytotoxic therapy.
Sumoylation-associated sensitization of drug responses through the apoptosis pathways
Authors: Fangting Wu, Susanna Chiocca, Yin-Yuan Mo
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1261 

SUMO (small ubiquitin-related modifier) conjugation or sumoylation has been implicated in regulating a wide variety of cellular processes. Sumoylation is a multi-step process involving several enzymes, including the activating enzyme E1 (SAE1/SAE2), conjugating enzyme E2 (Ubc9), and E3 ligases. Blockade of sumoylation by inactivating these enzymes provides a useful means to unveil the biological function of SUMO. An early gene product Gam1 encoded by the avian adenovirus CELO has been recently shown to strongly inhibit the SUMO pathway by interfering with the activity of E1 and causing depletion of E1 and E2. In this study, we found that Gam1 suppressed both constitutive and inducible sumoylation. More importantly cell growth inhibition assays indicated that Gam1-transfected cells grew significantly slowly than the vector control. To determine the underlying mechanism of this inhibition, we treated the cells with caspase inhibitors and found that the growth inhibition was delayed by caspase inhibitors. Furthermore, caspases such as caspase 3 were induced in the Gam1-treated cells, suggesting a role of apoptosis in the Gam1-mediated growth inhibition. Recently, several groups have reported that sumoylation regulates DNA repair pathways, which might account for the increased sensitivity to genotoxic agents by suppression of sumoylation. However, it is not clear whether suppression of sumoylation also increases the sensitivity to non-DNA damaging agents. Thus, we tested vincritine and paclitaxel, which are known to target tubulin or microtubule. MTT assays revealed that the cells expressing Gam1 were more sensitive to both of the agents, in addition to DNA damaging agents. In consistent with this finding, we found that a dominant negative mutant Ubc9 (Ubc9-DN) also sensitized cells to these agents. Finally, the caspase inhibitors were able to reverse the increased cytotoxicity associated with suppression of sumoylation. Taken together, these results suggest a role for sumoylation in regulating cellular apoptosis. (Supported in part by CA102630 from NIH).
Characterization Of Bone Marrow Derived CD34+ Cells With Different Mobility Potentials By Micro RNA Fingerprinting
Authors: Blake Warbington, Daniel Weinstein, David Mallinson, Daria Olijnyk, Sarah Paterson, Susan Ridha, Vincent O'Brien, Marvin Lin, Courtney LeBlon, Timothy C. Fong, Wai Shun Chan
Journal: Blood (2013)
Abstract 9168: Echocardiography-Based Screening for Rheumatic Heart Disease: A Sensitive and Cost-effective Way to Reduce Disease Burden in the Developing World
Authors: Andrea Beaton, Emmy Okello, Winston Batambuze, Peter Lwabi, Charles Mondo, Robert McCarter, Craig Sable
Journal: Circulation (2011)

Introduction: Early detection and prophylaxis of rheumatic heart disease (RHD) can prevent devastating sequlae. Echocardiography (echo)-based screening improves detection of RHD in endemic regions, but the best protocol to maximize case detection and minimize over-diagnosis is unclear. The recent WHO/NIH 2006 guidelines have yet to be assessed in a large-scale prevalence study. We used these guidelines and identified risk factors for occult RHD in a large cohort of Ugandan school children. We tested two hypotheses: echo screening for RHD is inexpensive and more sensitive than auscultation and laboratory testing; and RHD is more prevalent in lower socioeconomic groups. Methods: Auscultation and portable ultrasound were used to screen students, ages 5 to 16, from randomly selected schools in Kampala, Uganda. Positive cases followed up at Kampala's main referral hospital. Studies were blindly reviewed by three independent cardiologists. Categories for disease likelihood - definite, probable, and possible - were assigned based on the 2006 guidelines. Detection rates by auscultation and echo imaging were compared. ASO titers and markers of inflammation (ESR/CRP) were obtained on follow-up cases. The impact of socioeconomic status was examined. Results: Screening of 4869 of 5006 (97%) eligible students occurred in 6 schools over a 4-month period. Screening was abnormal in 130 children. On follow-up, 18 had congenital heart disease, 40 were normal, and 72 had possible, probable, or definite RHD. Echo detected 3 times as many cases of RHD than auscultation alone: 72 (1.5%) vs.23 (0.5%), p&lt;0.001. Children with RHD were older (10.1 yr vs. 9.3 yr, p=0.002). Most cases (98%) involved only the mitral valve. Children from lower socioeconomic schools had RHD more frequently (2.7% vs. 1.4%, p=0.036) and had more advanced disease (64% vs. 26%, p&lt;0.001). Labs had no significance. Each study cost $0.18 (echo machine, nursing, and transportation). Conclusions: This is the largest single-country childhood RHD prevalence study to date. Our data support the inclusion of echo in screening protocols and identify lower socioeconomic groups as the most vulnerable. Efforts should be made to promote more widespread use of echo screening, which can be done for only pennies a student.
Abstract 16393: Causes and Timing of Death in Patients With NSTE ACS: An Analysis of the TIMI Trials
Authors: David D Berg, Stephen D Wiviott, Sarah Sloan, Amir Kashani, C. Michael Gibson, Christopher P Cannon, David Morrow, Charles F Contant, Marc S Sabatine, Eugene Braunwald, Robert P Giugliano
Journal: Circulation (2011)

Background: Although early sequelae of non-ST elevation acute coronary syndromes (NSTE ACS) are well described, less is known about the longer-term risks and causes of death following NSTE ACS. Met...
Noninvasive Electrocardiographic Mapping to Improve Patient Selection for Cardiac Resynchronization Therapy
Authors: Sylvain Ploux, Joost Lumens, Zachary Whinnett, Michel Montaudon, Maria Strom, Charu Ramanathan, Nicolas Derval, Adlane Zemmoura, Arnaud Denis, Maxime De Guillebon, Ashok Shah, Mélèze Hocini, Pierre Jaïs, Philippe Ritter, Michel Haïssaguerre, Bruce L. Wilkoff, Pierre Bordachar
Journal: Journal of the American College of Cardiology (2013)
Prenatal Phthalate Exposures and Childhood Fat Mass in a New York City Cohort
Authors: Jessie P. Buckley, Stephanie M. Engel, Michelle A. Mendez, David B. Richardson, Julie L. Daniels, Antonia M. Calafat, Mary S. Wolff, Amy H. Herring
Journal: Environmental Health Perspectives (2015)

Experimental animal studies and limited epidemiologic evidence suggest that prenatal exposure to phthalates may be obesogenic, with potential sex-specific effects of phthalates having anti-androgenic activity.We aimed to assess associations between prenatal phthalate exposures and childhood fat mass in a prospective cohort study.We measured phthalate metabolite concentrations in third-trimester maternal urine in a cohort of women enrolled in New York City between 1998 and 2002 (n = 404). Among 180 children (82 girls and 98 boys), we evaluated body composition using a Tanita scale at multiple follow-up visits between ages 4 and 9 years (363 total visits). We estimated associations of standard deviation differences or tertiles of natural log phthalate metabolite concentrations with percent fat mass using linear mixed-effects regression models with random intercepts for repeated outcome measurements. We assessed associations in multiple metabolite models and adjusted for covariates including prepregnancy body mass index, gestational weight gain, maternal smoking during pregnancy, and breastfeeding.We did not observe associations between maternal urinary phthalate concentrations and percent body fat in models examining continuous exposures. Fat mass was 3.06% (95% CI: -5.99, -0.09%) lower among children in the highest tertile of maternal urinary concentrations of summed di(2-ethylhexyl) phthalate (ΣDEHP) metabolites than in children in the lowest tertile. Though estimates were imprecise, there was little evidence that associations between maternal urinary phthalate concentrations and percent fat mass were modified by child's sex.Prenatal phthalate exposures were not associated with increased body fat among children 4-9 years of age, though high prenatal DEHP exposure may be associated with lower fat mass in childhood.Buckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, Wolff MS, Herring AH. 2016. Prenatal phthalate exposures and childhood fat mass in a New York City cohort. Environ Health Perspect 124:507-513; http://dx.doi.org/10.1289/ehp.1509788.
A ten-year follow-up of alcoholic Native Americans in Minnesota
Authors: Joseph Westermeyer, Emily Peake
Journal: American Journal of Psychiatry (1983)

In a 10-year follow-up of 45 alcoholic American Indians, 42 (93%) were located. Seven had been abstinent for 2 or more years, 26 still had drinking problems despite repeated treatment, and 9 had died. The authors hypothesize that the absence of stable employment and a stable marriage or family environment reduced the efficacy of treatment efforts in this population. Those who achieved 2 years of abstinence were characterized by stable employment and/or marriage, as well as by stronger interpersonal relationships and less depression than the others. The recovered subjects provided considerable help to other alcoholic persons in addition to serving as positive role models.
Abstract 12358: Anti-Atherogenic Effect of Novel Peroxisome Proliferator-Activated Receptor {delta} Agonist RSC-451061 Hydrochloride Accompanied by Anti-Inflammatory Effects in LDL Receptor Knockout Mice
Authors: Keita Fukao, Noriyuki Naya, Akemi Nakamura, Naoko Higuchi, Minoru Ikeda, Tadateru Hamada, Masayuki Sugimoto, Kohji Nomura, Seijiro Hara, Toru Nakano, Toshihiro Shinosaki, Kohji Hanasaki
Journal: Circulation (2011)
Psychotherapy: historical roots, universal elements, and cultural variations
Authors: W S Tseng, J F Mcdermott
Journal: American Journal of Psychiatry (1975)

The authors review various forms of traditional psychotherapeutic interventions to trace the historical development of psychotherapy, which demonstrates a shift in focus from the supernatural world, to the natural world, to the physical person, then to the psychological person. The basic processes of identifying problems, providing explanations, and prescribing for change are observed among various kinds of treatment systems. Universal elements fundamental to successful treatment can be identified in each of these processes, and each is strongly modified by cultural factors. The authors conclude that the special cultural dimension of psychotherapy consists of defining cultural norms, reinforcing culturally sanctioned coping mechanisms, and providing "time out" from usual cultural expectations.