tbuckley/cabot-search huggingface dataset:
Abstract 2696: Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells
Authors: Tianjiao Wang, Yuhui Yuan
Journal: Cancer Research (2015)

Abstract Pancreatic carcinoma (PC) is a deadly form of cancer with poor overall survival. Currently, chemotherapeutic such as gemcitabine and 5-fluorouracil (5-FU) are the most popular medication that can slightly improve survival, but rapid drug-resistance makes it urgent to search for more effective drugs. In hunting for natural components that cure PC, we found that arenobufagin, a cardiac glycosides-like compound, showed significant effects on the gemcitabine-resistant cell line Panc-1, the gemcitabine-sensitive cell line ASPC-1 and K-Ras activating HPNE cells at nanomolar concentrations. We used MTT and clonogenic survival assays to examine survival and proliferation and western blotting to assess changes of K-Ras downstream and apoptosis related proteins. We also detected the cell cycle and migration by flow cytometry and wound healing assay. Arenobufagin inhibited cellular survival and proliferation, decreased the phosphorylation of key proteins of K-Ras downstream such as Akt, Erk and nuclear factor kappa B (NF-κB), induced cell cycle G2/M arrest and apoptosis, and downregulated the level of phosphorylated epidermal growth factor receptor (EGFR). Most importantly, our data showed that arenobufagin can enhance the sensitivity of PC cells to gemcitabine and 5-fluorouracil (5-FU). Arenobufagin could enhance the effect of gemcitabine and 5-FU on PC cells through targeting multiple key proteins. All above makes arenobufagin a novel agent for combination therapy of pancreatic carcinoma. Citation Format: Tianjiao Wang, Yuhui Yuan. Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells. [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 2696. doi:10.1158/1538-7445.AM2015-2696
Abstract 3149: Is Plasma B-type Natriuretic Peptide Measurement Valid for Prediction of Cardiovascular Events in Chronic Kidney Disease? A Community-Based Longitudinal Study
Authors: Masafumi Sakuma, Motoyuki Nakamura, Fumitaka Tanaka, Toshiyuki Onoda, Shinji Makita, Kazuko Kawamura, Kazuyoshi Itai, Yuuki Yoshida, Tomohiro Takahashi, Kiyomi Sakata, Akira Okayama
Journal: Circulation (2008)

Elevated plasma B-type natriuretic peptide (BNP) levels have been reported to be a marker for risk of cardiovascular events (CVE) including heart failure, coronary artery disease and stroke in the general population. However, plasma BNP is increased by renal dysfunction, and it is therefore not known whether plasma BNP might be a reliable biomarker for predicting onset of CVE in the cohort with impaired renal function as represented by chronic kidney disease (CKD). Baseline data including plasma BNP, serum creatinine, and urine protein were determined in 14265 participants from a community-based population. Estimated glomerular filtration rate (eGFR) was calculated using a modified MDRD equation, and CKD was defined by the following two methods (Def 1 = eGFR&lt;60 ml/min/1.73m 2 and/or proteinuria; Def 2 = eGFR&lt;60 ml/min/1.73m 2 ). Numbers of CKD subjects were 1927 according to Def 1 and 1604 according to Def 2. CVE endpoint was surveyed prospectively. The mean follow-up duration was 2.9 years. After adjustment for traditional cardiovascular risk factors and atrial fibrillation, relative risk (RR) for CVE was significantly higher in the highest BNP quartile compared to the lowest BNP quartile according to both definitions (Def 1, RR=3.51, p&lt;0.01: Def 2, RR=4.67, p&lt;0.01) (Figure ). Furthermore, the RR for a composite endpoint of CVE and death was also significantly higher in the highest BNP quartile, again by both definitions (Def1, RR=2.71, p&lt;0.01: Def 2, RR=3.09, p&lt;0.02). Measurement of plasma BNP levels provides strong predictive information about future onset of CVE and death, even in CKD subjects selected from the general population.
Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation.
Authors: S I Bearman, G L Anderson, M Mori, M S Hinds, H M Shulman, G B McDonald
Journal: Journal of Clinical Oncology (1993)

PURPOSE Hepatic venoocclusive disease (VOD) is a common complication of cytoreductive therapy for marrow transplantation. Only 25% of patients who develop VOD have severe disease. We tested the hypothesis that early clinical signs of VOD would predict which patients would recover and which would die. PATIENTS AND METHODS We evaluated 355 consecutive patients who had transplants between August 6, 1987 and July 21, 1988 for occurrence of VOD and whether it was reversible within 100 days of transplant. Total serum bilirubin and weight gain from day -7 through day +16 posttransplant were compared among patients with no, severe, or nonsevere VOD. Logistic regression models were developed to estimate probabilities of severe VOD at each of six time intervals. The accuracy of these models was tested by applying them to 392 consecutive patients who underwent transplantation between July 22, 1988 and July 20, 1989. RESULTS As early as day -1, bilirubin and weight gain were significantly different between patients whose VOD proved to be severe and patients with reversible VOD or no disease. Regression models were used to generate coefficients (beta 0, beta 1, beta 2) for the equation P = 1/(1 + e-z), where P is the probability of severe VOD and z = beta 0 + beta 1 (In total serum bilirubin [mg/dL]) + beta 2 (percent weight gain). Application of this equation to the next 392 patients allowed us to calculate sensitivity, specificity, and positive predictive value for a range of probabilities. CONCLUSION The course of VOD after cytoreductive therapy can be predicted by knowing the serum bilirubin and weight gained within 1 to 2 weeks of transplantation. Probability estimates derived from patient data are highly specific and moderately sensitive. Such probability estimates may be useful when considering potentially risky interventions to treat VOD, such as recombinant human tissue plasminogen activator.
Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case–control–control study
Authors: D.R. Giacobbe, V. Del Bono, E.M. Trecarichi, F.G. De Rosa, M. Giannella, M. Bassetti, A. Bartoloni, A.R. Losito, S. Corcione, M. Bartoletti, E. Mantengoli, C. Saffioti, N. Pagani, S. Tedeschi, T. Spanu, G.M. Rossolini, A. Marchese, S. Ambretti, R. Cauda, P. Viale, C. Viscoli, M. Tumbarello
Journal: Clinical Microbiology and Infection (2015)
Abstract 18113: High Exercise-Induced Platelet Reactivity in Patients with Fabry Disease
Authors: Maurizio Pieroni, Costantino Smaldone, Antonia Camporeale, Giancarla Scalone, Andrea Macchione, Claudio Feliciani, Fulvio Bellocci, Gaetano A Lanza, Filippo Crea
Journal: Circulation (2011)

Background: Cerebrovascular events represent a major cause of disability in young patients with Fabry disease (FD). However the pathogenesis of cerebrovascular events in these patients is not fully understood and prevention, besides enzyme replacement therapy (ERT), is empirically based on antiplatelet drugs. We evaluated platelet function in patients with FD without evidence of coronary or carotid atherosclerosis. Methods: Fifteen patients with genetically confirmed FD (mean age 42, 6 F) underwent treadmill exercise stress test (EST). Platelet reactivity was assessed by flow cytometry at baseline and at peak EST, with and without ADP stimulation, by measuring monocyte-platelet aggregate (MPA) formation (expressed as percentage of monocyte binding platelets) and CD41 expression (assessed as mean fluorescence intensity). All patients underwent carotid ultrasound and coronary angiography to rule out carotid or coronary artery disease. Patients on ERT were submitted to EST the day before drug infusion. Thirty healthy sex- and age-matched subjects were studied as controls. Results: Coronary angiography and carotid ultrasound showed no evidence of atherosclerosis in all FD patients; EST showed signs of ischemia in 3 patients with FD cardiomyopathy. Thirteen patients were on ERT at the time of the study. Compared to resting values, MPA and CD41 expression,with and without ADP stimulation, significantly increased after exercise in the FD group but not in controls. Exercise-induced values of MPA (20.1vs18.7, p=0.001 - with ADP:25.2vs22.0, p&lt;0.0001) and CD41 expression (20.3vs19.4 p=0.006 - with ADP:26.1vs21.9, p&lt;0.0001) were higher in FD patients than in controls, while resting values didn't significantly differ. Conclusions: High exercise-induced platelet reactivity has been reported in patients at high risk for thrombotic events, like those with coronary or peripheral atherosclerosis. In this study we found high exercise-induced platelet reactivity in patients with FD, suggesting that enhanced platelet reactivity may contribute to the pathogenesis of cerebrovascular events in these patients. Our data support the inclusion of antiplatelet drugs in conventional therapy for FD. The effect of ERT on platelet function remains to be clarified.
Abstract 4010: Soluble TRAIL in Peripheral Blood is a Novel Marker for Acute Coronary Syndromes
Authors: Kayoko Sato, Keiko Gomita, Kazutaka Kitamura, Nobuhisa Hagiwara
Journal: Circulation (2008)

Background: Apoptosis of vascular smooth muscle cells and endothelial cells in the fibrous cap is prone to plaque vulnerability. Recently, we found that CD4 T cells trigger the TRAIL/TRAIL receptor 2 (DR5) pathway and cause VSMC apoptosis in acute coronary syndrome (ACS). We also showed that activated plasmacytoid dendritic cells (pDC) produce INFα through TRL9 and amplify cytotoxic CD4 T cell functions by enhancing TRAIL expression. In this study, we examined whether soluble TRAIL (sTRAIL) in peripheral blood shows changes in ACS that may serve as predictive marker of vulnerable patients. Methods and Results: The sTRAIL levels were measured by ELISA in 110 patients undergoing coronary angiography, including 90 ACS patients and 20 chest pain syndrome patients without apparent coronary atherosclerosis. Fresh CD4 T cells were isolated from the peripheral blood of patients. The sTRAIL levels were lower in ACS than in controls (P&lt;0.001). CD4 T cells capable of inducing HUVEC apoptosis expressed high levels of TRAIL in ACS patients (P&lt;0.03), and negatively correlated with the sTRAIL levels (R=0.372, P&lt;0.02). To examine whether sTRAIL levels could be used as marker of vulnerable patients with ACS, we measured sTRAIL levels in the time course and compared them with CPK and TnT after onset of ACS. While CPK and TnT of acute myocardial infarction elevated in the acute phase and recovered after 3days, sTRAIL showed negative parallel changes. Meanwhile, sTRAIL showed the same changes in unstable angina without CPK and TnT elevation. The levels of sTRAIL more decreased in patients with multiple coronary artery stenosis than in that without coronary artery stenosis while the levels of hsCRP did not. Furthermore, given a cutoff value of 48.6pg/ml, sTRAIL was able to discriminate ACS from control groups with sensitivity of 62.4%, specificity of 85.0%, and area under the receiver-operating characteristic curve (AUC) of 0.736. In contrast, an hsCRP cutoff value of 1.25mg/l showed lower sensitivity (47.3%), specificity (77.8%), and AUC (0.597) for the diagnosis of ACS. Conclusions: Monitoring of TRAIL levels in ACS patients with both acute myocardial infarction and unstable angina was found useful in predicting vulnerability in patients with vulnerable plaques.
Novel beta-catenin inhibiting teterahydropyrano-indoles retard the growth of HT-29 colon tumor xenografts in mice
Authors: Sarath Kanekal, Brian Crain, Qi Chao, Mimi Philips, Gary Elliott
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5892 

SDX-101, a teterahydropyrano-indole, is an anti-neoplastic drug in Phase II clinical trials in chronic lymphocytic leukemia. SDX-101 inhibits β-catenin-mediated gene transcription via its interaction with the PPAR-RXR-β-catenin nuclear complex. We have synthesized several substituted teterahydropyrano-indoles and have reported that some of these are more potent in vitro than SDX-101 and inhibit growth of Daudi tumor xenografts in vivo following oral administration (Kanekal et al, 2004 NCI/EORTC). This study explores the activity of these compounds in the HT-29 colon tumor xenograft model. HT-29 cells (2 X 106 cells) in suspension of Matrigel were inoculated subcutaneously in the dorsal area of athymic nude mice. After the tumors reached approximately 100 mm3, the mice were administered compounds SDX-308, SDX-309 or SDX-328 for two weeks via oral gavage (250 mg/kg/d M-F). Mice treated with the above compounds showed delayed tumor growth compared to the untreated control: tumor volumes for compound #s 308, 309 and 328 were 804+/−169, 1230+/−377 and 1188+/−250 mm3 respectively on day 23. The control tumors grew faster: tumor volumes were 1839+/−372 mm3 on day 23. Tumor volume of SDX-308-group was significantly different (ANOVA/Dunnet p<0.05) from the control animals. There was a mild transient loss of body weight in the mice treated with these compounds on day 3, recovery was apparent by day 7 and mice continued to gain weight thereafter. No treatment-related mortalities occurred in any groups. The tumor growth inhibitory effect of these compounds observed in this study is consistent with our previous observation in the Daudi model, and these data provide the first in vivo evidence for activity in a solid tumor model.
cAMP-dependent protein kinase activity in major depression
Authors: R C Shelton, D H Mainer, F Sulser
Journal: American Journal of Psychiatry (1996)

The author's intent was to evaluate the activity of the beta-adrenoceptor-linked, cAMP-dependent protein kinase (protein kinase A) in patients with major depression compared with a group of nondepressed volunteer subjects.Skin fibroblast samples were obtained by 2-mm punch biopsy from 12 patients (11 were women) who had major depression diagnosed according to the Structured Clinical Interview for DSM-III-R and from 10 nondepressed volunteers (seven were women). Fibroblasts were cultured in Dulbecco's modified Eagle medium. Baseline and cAMP-stimulated activities of protein kinase A were determined in both particulate and supernatant fractions (900g). Linkage of the finding to beta adrenergic receptor function was evaluated by determination of protein kinase A activity after incubation of the confluent cultures for 30 minutes with 10 microM isoproterenol.There were significant differences between groups in the baseline and cAMP-stimulated phosphorylation in the supernatant fraction. Moreover, the attenuated protein kinase A response was accompanied by a blunted isoproterenol response.Patients with depression exhibit significantly less activity of beta-adrenoceptor-linked protein kinase A than do normal subjects. The reductions in protein kinase A activity support the significance of beta-receptor-mediated events in depression.
Inflammatory regulation of steroid sulfatase: A novel mechanism to control estrogen homeostasis and inflammation in chronic liver disease
Authors: Mengxi Jiang, Marcus Klein, Ulrich M. Zanger, Mohammad K. Mohammad, Matthew C. Cave, Nilesh W. Gaikwad, Natasha J. Dias, Kyle W. Selcer, Yan Guo, Jinhan He, Xiuhui Zhang, Qiujin Shen, Wenxin Qin, Jiang Li, Song Li, Wen Xie
Journal: Journal of Hepatology (2015)
Screening for modulators of androgen receptor transcriptional activity using a high-throughput, flow-cytometry system
Authors: Megan Dennis, Harmony Bowles, Larry Sklar, Eric Prossnitz, Todd Thompson
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

LB-150 

Small molecules modulators of androgen receptor (AR) activity may serve as therapeutic agents against prostate cancer. The most effective screens for identification of novel chemotherapeutic agents are likely to be based on the measurement of specific biologic activity. As interest in screens to identify active chemicals in cancer research grows, we have developed a novel, high-throughput assay to screen for small-molecules that modulate AR activity to aid in the identification of new agents against prostate cancer. This assay, designated the Multifunctional Androgen Receptor Screening (MARS) assay, can efficiently screen for both AR agonists and antagonists in a rapid, high-throughput format. Androgen-independent human prostate adenocarcinoma-derived PC3 cells were transfected to co-express the wild-type human AR and an androgen-sensitive promoter regulating the expression of destabilized enhanced GFP. The sensitivity and dynamic range of androgenic stimulation was established using a dose-response of the stable, synthetic androgen R1881. Identification of novel antagonists of AR transcription was achieved via co-administration of R1881 at its EC50 (i.e., 1 pM) with potential AR antagonists. The assay was formatted for high-throughput screening using the HyperCyt autosampling system and flow cytometry. A library of endocrine active chemicals developed by NICETAM/ICCVAM, which includes steroidal compounds with known agonist and antagonist activity and compounds with putative endocrine modulatory activity, was used to validate the utility of the MARS assay. High-throughput screening of 118 chemicals from the library using the MARS assay resulted in the identification of compounds with a range of activities on AR transcription. The endogenous AR ligand dihydrotestosterone, and the therapeutic AR antagonists bicalutamide and cyproterone acetate, compounds with known AR-mediated activity, performed as expected, verifying the accuracy of the assay. Surprisingly, because the MARS assay uniquely measures AR activity, agonist activity of both bicalutamide and cyproterone acetate was observed at higher concentrations of these agents, which may have important implications for screening AR antagonists. Analysis of screening results from the NICETAM/ICCVAM library indicated that 19 compounds exhibited agonist activities, 37 were antagonists, and 16 compounds displayed partial agonist characteristics. The remaining compounds were not active. Dose-response assays were completed to determine the potency of compounds with novel activities and to help elucidate novel mechanisms of action (e.g., competitive binding versus allosteric activity). MARS analyses of additional chemical libraries are in progress to identify chemical classes modulating AR activity to further guide the development of therapeutic agents against prostate cancer.
Abstract 16436: Low Stroke Volume Index is Associated With a Low Transvalvular Gradient and Predicts Survival in Patients With Severe Aortic Stenosis
Authors: Brian R Lindman, Suzanne V Arnold, Jose A Madrazo, Stephanie N Johnson, Eric Novak, Mark R Holland, Tara A Hohn, Alan Zajarias, James G Miller, Julio E Perez
Journal: Circulation (2011)

Background: A low transvalvular mean gradient (MG) is associated with worse outcomes in patients with severe aortic stenosis (AS) (AVA <1.0cm2), but the factors that impact the MG remain incomplete...
Protective Effect of Traumatic Lesions on Rheumatoid Arthritis
Authors: J. S. Kamermann
Journal: Annals of the Rheumatic Diseases (1966)

Jacqueline (1953) reported the case of a man who had developed a paresis of the right arm and leg when 2 years old; at the age of 41, he developed articular disorders which developed into a severe rheumatoid arthritis, but only on the side not affected by the hemiplegia.Thompson and Bywaters (1962) reported four patients with hemiplegia due to meningioma, cerebral thrombosis, syphilis, and cerebrovascular disease respectively.Later in life, these patients developed rheumatoid arthritis on the non-hemi- plegic side of the body, and in the second and fourth of these cases, a few joints on the hemiplegic side which had retained some locomotor and weight- bearing function were also affected.The sparing mechanism in the other cases was therefore con- sidered to reside in the non-use of the joints on the hemiplegic side.No other explanation (of a vasomotor or neurological nature) could be found.The same protective effect has also been observed in arthrosis, with lesions of the higher as well as of the lower motor neuron.The protective effect of lesions of the lower motor neuron in rheumatoid arthritis has not hitherto been described, and we believe that the case reported below is an example of this phenomenon.
Breast feeding: the baby friendly initiative
Authors: A. Radford, C. Rickitt, A. Williams, J. Burgess, O O Ejidokun, J Norton, S. Ramaiah, D P Gunasekera, P C Gunasekera
Journal: BMJ (1998)

Editor—We share Malik and Cutting’s enthusiasm for Unicef’s baby friendly initiative in the United Kingdom but were disappointed that they did not acknowledge the great progress made over the past year.1 It is pessimistic to state that hospitals have been slow to work with the initiative. In fact, almost all units are working towards baby friendly accreditation; 11 British maternity units have achieved the required standard and another 40 have a certificate of commitment. Although Malik and Cutting suggest that hospitals might be demoralised by unachievable targets (such as the 75% breastfeeding rate required for the global baby friendly award), we removed this requirement for the United Kingdom’s standard award in order to focus on the support and encouragement of best clinical practice.

It is also unfair to suggest that the baby friendly initiative is confined to hospitals. On 15 May we launched best practice standards for community healthcare settings, with the support of the minister for public health. This is the first step in introducing the initiative into the community and provides a framework around which clinical accreditation will be developed. The United Kingdom will probably be unique in having a primary care baby friendly award. As with the existing awards, particular emphasis is placed on support for mothers to make informed decisions about feeding their babies.

Malik and Cutting call for better coordination with existing groups that support mothers; in fact, all four national groups are fully involved with the baby friendly initiative. We were also puzzled by the statement that “government and NHS managers should recognise and encourage [the baby friendly initiative’s] development.” The Department of Health has worked in partnership with the initiative since its inception in the United Kingdom,2,3 while an increasing proportion of NHS managers see the initiative as a cost effective quality framework to achieve a high standard of care, which can be independently accredited.

We agree that much more could be done to support mothers in their choice to breast feed. Nevertheless, the healthcare system has a crucial role; it was particularly pleasing to note that the 1995 infant feeding statistics4 documented progress on relevant hospital practices.5 We are optimistic that the progress of Unicef’s baby friendly initiative in the United Kingdom can strengthen this trend.
Abstract 3489: Axon Guidance of Sympathetic Neurons to Native and Induced Pluripotent Stem (iPS) Cell-Derived Cardiomyocytes Using Glial Cell Line-Derived Neurotrophic Factor (GDNF)
Authors: Keiko Miwa, Jong-Kook Lee, Yoshiko Takagishi, Yasuhiko Jimbo, Tobias Opthof, Itsuo Kodama
Journal: Circulation (2009)

[Aim] Appropriate autonomic innervation is crucial to engineer functional cardiac tissues. The present study is to explore a novel technology for sympathetic axon guidance to iPS cell-derived and n...