tbuckley/cabot-search huggingface dataset:
Abstract 5387: ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma
Authors: Mala Kiran Talekar, David Dicker, Joshua Allen, Wafik El-Deiry
Journal: Cancer Research (2015)

Abstract Outcome for non-Hodgkin's lymphoma (NHL) patients using conventional treatment standards remains unsatisfactory, particularly in advanced stage/ relapsed disease creating an imminent need for investigating novel treatment strategies. ONC201/TIC10 is a small molecule (Allen et al, 2013) that induces p53-independent cell death in tumor cells while sparing normal cells through inactivation of the prosurvival kinases Akt and ERK. ONC201 is currently entering Phase I/II clinical trials as a monoagent in adult advanced cancers. We have previously shown that ONC201 induces significant cytotoxicity in preclinical models of human lymphomas (Talekar et al, ASPHO 2014). Here, we show that ONC201 is not only effective as a monoagent across several NHL cell lines, but that it also synergizes with several chemotherapeutic agents to cooperatively induce cell death in vitro. We found that ONC201 induces significant apoptosis in a diverse panel of human NHL cell lines at low micromolar concentrations (1.3 to 5.06 uM). Increased surface TRAIL and surface DR5 expression was noted in a dose-dependent manner across representative cell lines. The increase in surface TRAIL correlated with increase in sub-G1 DNA content, which suggests that TRAIL may serve as a potential biomarker of response to ONC201. ONC201-induced apoptosis was inhibited using a pan-caspase inhibitor and was blocked by an anti-TRAIL antibody RIK-2, which indicate induction of TRAIL-dependent cell death. Western blot analysis of ONC201-treated NHL cells suggests ERK inhibition and Foxo3a activation as a potential mechanism of cytotoxicity via TRAIL induction. In agreement with this notion, we also observed upregulation of PARP &amp; DR5 and caspase-3 activation in response to ONC201 treatment. We further found that ONC201 synergizes to potentiate cytotoxicity with several chemotherapeutic agents approved for NHL treatment, particularly anthracyclines (doxorubicin), nitrogen mustard (bendamustine), antimetabolite (cytarabine) and proteasome inhibitor (bortezomib) via cell viability experiments that were corroborated by apoptosis assays. Together these results suggest that ONC201 is a potent antitumor agent in NHL as monoagent and in combination with several approved therapies that may be explored in phase Ib/II trials. Citation Format: Mala Kiran Talekar, David Dicker, Joshua Allen, Wafik El-Deiry. ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma. [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 5387. doi:10.1158/1538-7445.AM2015-5387
What Makes Doctors Use Computers?: Discussion Paper
Authors: D W Young
Journal: Journal of the Royal Society of Medicine (1984)

“What is the cause of this state of under achievement [implementation of clinical computing systems] when the need is so great and the technology so powerful?” asked Barnett & Greenes in 1969. This question has continued to be asked. Of 32 systems in clinical medicine surveyed in 1977, half had been abandoned or temporarily stopped and only 19% were used routinely (Friedman & Gustafson 1977). Enormous numbers of diagnostic systems have been developed (Wardle & Wardle 1978), yet the dissemination of any single system is limited.
Diagnostic and Prognostic Stratification in the Emergency Department Using Urinary Biomarkers of Nephron Damage
Authors: Thomas L. Nickolas, Kai M. Schmidt-Ott, Pietro Canetta, Catherine Forster, Eugenia Singer, Meghan Sise, Antje Elger, Omar Maarouf, David Antonio Sola-Del Valle, Matthew O'Rourke, Evan Sherman, Peter Lee, Abdallah Geara, Philip Imus, Achuta Guddati, Allison Polland, Wasiq Rahman, Saban Elitok, Nasir Malik, James Giglio, Suzanne El-Sayegh, Prasad Devarajan, Sudarshan Hebbar, Subodh J. Saggi, Barry Hahn, Ralph Kettritz, Friedrich C. Luft, Jonathan Barasch
Journal: Journal of the American College of Cardiology (2012)
Abstract 17499: Addition of Myocardial Parameters to the Diagnosis of Stage B Heart Failure
Authors: Tom Marwick, Wojciech Kosmala, Christine Jellis
Journal: Circulation (2014)

Introduction: Stage B heart failure (BHF, asymptomatic structural heart disease) is diagnosed in the presence of myocardial scar or impaired LVEF. However, the insensitivity of LVEF may lead to under-recognition of BHF in non-ischemic heart disease. This may be important, as BHF may precede the onset of HF symptoms, and necessitates the initiation of treatment. We sought the implications of using additional LV assessment to identify BHF in pts at risk of HF (stage A HF, AHF). Methods: We studied 510 asymptomatic pts (age 58±12yrs) with AHF (diabetes, hypertension or obesity), but no history of ischemic heart disease and a normal stress echo. All pts underwent echocardiography (including assessment of strain and diastolic dysfunction) and cardiopulmonary exercise testing. Results: BHF was defined as the presence of at least one of; reduced LV longitudinal strain (&lt;18%), increased LV filling pressure (E/e’&gt;13) or moderate-to-severe LV hypertrophy (LV mass index ≥109 g/m 2 in women and 132 g/m 2 in men) in 243 patients (47%). Reduced exercise capacity (peakVO 2 and METS) was identified in BHF compared with other AHF (Table). Using this definition, BHF was associated with lower peak VO 2 (β=-0.20, p&lt;0.00001) and METS (β=-0.21, p&lt;0.0001), independent of higher BMI, insulin resistance, older patient age, male sex and treatment with beta-blockers. Conclusions: LV hypertrophy, elevated LV filling pressure elevation and abnormal myocardial deformation independently contribute to lower exercise capacity in pts at risk of HF. Given the association of exercise capacity with outcome, these factors should be considered grounds for the diagnosis of BHF.
Abstract 15176: Catheter-Directed-Trombolysis for Acute Massive Pulmonary Embolism with a Novel Modified Tissue Plasminogen Activator
Authors: Katsuhiro Kondo
Journal: Circulation (2011)

BACKGROUND: Acute massive pulmonary embolism(PE) is a life-threatening condition with high mortality. Survival depands on rapid recanalization of the pulmonary arterial occlusion and reduction of t...
Abstract 2879: Profiling of lung microbial communities in lung cancer and chronic obstructive pulmonary disease patients
Authors: Yanhong Liu, Nadim J Ajami, Matthew C Wong, Michael Scheurer, E. Susan Amirian, Joseph F Petrosino, Margaret R Spitz, Melissa L Bondy, Farrah Kheradmand
Journal: Cancer Research (2015)

Abstract Background: The composition and structure of site-specific microbiota have recently been described as a biomarker associated with a variety of high impact diseases including cancer. This study sought to identify lung microbial signatures in smokers with lung cancer (LC) and/or chronic obstructive pulmonary disease (COPD). Material and Methods: We employed 16S rRNA gene compositional analysis to compare the microbiota in Optimal Cutting Temperature (OCT) embedded biopsies of lung-tissue from 30 smokers, including 10 patients with LC only, 10 patients with COPD only, and 10 patients with both LC and COPD, selected from a longitudinal study of COPD exacerbation conducted in Houston, Texas, during 2005 to 2012. Results: Microbial signatures calculated based on the 16S rRNA gene data showed that patients with COPD only presented a very distinct microbial structure defined by a significantly lower Shannon Diversity Index compared to patients with LC only (P = 0.04), and patients with both LC and COPD (P = 0.003), suggesting lower bacterial richness and evenness. Furthermore, biopsies from patients with COPD only were characterized by an increased prevalence of Acinetobacter (P &amp;lt; 0.0001) and Acidovorax (P &amp;lt; 0.0001), and a lower prevalence of Bifidobacterium, Streptococcus, and Ruminococcus species compared to patients with LC only and those with both LC and COPD. However, patients with both COPD and LC were indistinguishable from those with LC only. Conclusions: This study is the first and largest to examine the composition of the lung microbiome in smokers with LC and/or COPD. Specific bacterial signatures were identified in patients with LC only and those with both COPD and LC demonstrating that the lung microbiome can be used as a biomarker for the two diseases. Altogether, we observed altered lung microbiota of COPD and LC, but whether this is involved in disease causation or is a consequence of host selection remains unclear. Citation Format: Yanhong Liu, Nadim J Ajami, Matthew C Wong, Michael Scheurer, E. Susan Amirian, Joseph F Petrosino, Margaret R Spitz, Melissa L Bondy, Farrah Kheradmand. Profiling of lung microbial communities in lung cancer and chronic obstructive pulmonary disease patients. [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 2879. doi:10.1158/1538-7445.AM2015-2879
Abstract 1601: Comprehensive Evaluation of the Left Ventricular Systolic and Diastolic Synchronicity in 160 “Completely” Healthy Normal Volunteers Using Tissue Doppler Echocardiography
Authors: Hyung-Kwan Kim, Keun-Ho Park, Suna-A Chang, Jin-Shik Park, Hyun-Jae Kang, Bon-Kwon Koo, Yong-Jin Kim, Sang-Hyun Kim, In-Ho Chae, Byung-Hee Oh, Young-Bae Park, Dae-Won Sohn
Journal: Circulation (2007)

Background Growing use of the left ventricular(LV) systolic(LVSIsys) and diastolic synchronicity indexes(LVSIdia) in selecting potential responders to cardiac resynchronization therapy(CRT) has created a need for normative reference values. This study was performed to determine reference ranges for tissue Doppler imaging-derived LVSIsys and LVSIdia, and to assess their relationships to age and conventional parameters reflecting LV systolic and diastolic functions. Methods and Results We recruited 160 completely healthy volunteers (45±13yrs, 104 men) free of any systemic or cardiovascular disease. Maximal difference and SD of time to peak systolic and early diastolic velocities for LVSIsys and LVSIdia were measured using 6- and 12-segment models. Table and Figure represent normal ranges. Aging was not found to significantly change LVSIsys, whereas LVSIdia progressively and consistently increased with age. Significant correlations were observed between LVSIdia and parameters representing LV diastolic function, i.e. early mitral inflow velocity and its deceleration time, and early mitral annulus velocity. A physiologic rise in LV mass/Ht 2.7 showed a weak, but significant correlation with LVSIdia( r = 0.15 to 0.22), but not with LVSIsys. On multivariate analysis, age-dependent increase in LVSIdia was confirmed. Conclusions Age-specific reference ranges for LVSIsys and LVSIdia are presented here. LVSIsys remain stable throughout age groups, whereas LVSIdia progressively increases with age. These data given here will be useful for defining abnormal LV synchronous contraction and relaxation, and help better select patients likely to respond favorably to CRT.
Glucocorticoid receptor-mediated anti-apoptotic signaling requires cross-talk with the MAPK and PI3K pathways
Authors: Wei Wu, Travis Pew, Min Zou, Diana Pang, Deanna R. Brickley, Suzanne D. Conzen
Journal: Cancer Research (2005)

6125   Glucocorticoid receptor (GR) activation has been shown to inhibit apoptosis in breast epithelial cells. We have identified a group of genes that is rapidly upregulated in these cells following dexamethasone (Dex) treatment. This group includes MAP kinase phosphatase-1 (MKP-1), a negative regulator of the MAPK pathway and serum and glucocorticoid-regulated kinase (SGK-1), a downstream target of PI3-Kinase signaling. Using a model of paclitaxel-induced cell death, we have recently found that induction of MKP-1 by Dex correlates with the inhibition of extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activity, while p38 activity was minimally affected. Blocking Dex-induced MKP-1 expression by siRNA expression increased ERK1/2 and JNK phosphorylation and decreased cell survival. To explore gene expression changes that occur downstream of Dex-induced MAPK inactivation, we used a combination of temporal gene expression data and promoter element analysis. This approach yielded several previously unrecognized putative transcriptional targets of the ERK-dependent transcription factor ELK-1 that may be involved in cell survival signaling. One of these genes is tissue plasminogen activator (tPA). We verified the predicted ELK-1-tPA trascriptional regulatory relationship using a luciferase reporter assay. In parallel experiments, we are examining gene expression changes mediated by SGK-1 phosphorylation and subsequent nuclear exclusion of FOXO3a (FKHRL-1). Interestingly, we have identified several putative FKHRL-1 targets that are up-regulated or down-regulated following GR activation. Down-regulated FKHRL-1 putative target genes include several pro-apoptotic genes, while the list of putative up-regulated FKHRL-1 target genes contains several anti-apoptotic genes. Taken together, these findings are consistent with the hypothesis that GR activation signals a coordinated anti-apoptotic response in breast epithelial cells. This response appears to be executed, at least in part, by MKP-1-mediated ELK-1 dephosphorylation and SGK-1-mediated FKHRL-1 phosphorylation, both of which result in important pro- and anti-apoptotic gene expression changes.
Abstract #5614: The AA genotype of the regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma
Authors: Hagen Bachmann, Lukas Heukam, Klaus Schmitz, Carolin Hilburn, Philip Kahl, Reinhard Buettner, Holger Nueckel, Kurt Schmid, Winfried Sieffert, Angelika Eggert, Alexander Schramm, Johannes Schulte
Journal: Cancer Research (2009)

Purpose: Molecular markers predictive of the prognosis of prostate cancer are urgently needed. Overexpression of the antiapoptotic protein Bcl-2 has been repeatedly shown to be associated with adverse outcome in this malignancy. We recently discovered a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the BCL2 gene promoter which significantly affects BCL2 promoter activities. We now ask, whether the (-938C>A) SNP could serve as a molecular marker associated with prognosis in prostate cancer and whether this SNP is of functional importance in the biology of this malignancy. Experimental Design: DNA was obtained from 143 patients with primary prostate cancer. The respective (-938C>A) genotypes were then correlated with event free survival of patients and molecular and clinical tumor features. Results were validated using a second, independent cohort of 180 patients. Reporter assays were used to analyse SNP-dependent promoter activity in prostate cancer cells and EMSA was used to evaluate differential transcription factor binding. Results: Kaplan-Meier analyses revealed a significant association of the CC genotype with increased relapse free survival (P = 0.004) in prostate cancer. 5-year survival rates were 89,3% for the CC genotype, 68,3% for the AC genotype, and 60,4% for the AA genotype. Multivariable Cox regression identified the  BCL2  (-938AA) genotype as independent adverse prognostic factor for cancer-related outcome (hazard ratio 5,271 (1,50-18,49); P = 0,009). These results were confirmed in a second, independent cohort. The (-938C) allele displayed significantly increased  BCL2  promoter activity and binding of nuclear proteins compared to the A allele in PC3 prostate carcinoma cells. Conclusions: These results suggest that the (-938C>A) polymorphism in the  BCL2  promoter predicts adverse outcome in prostate cancer. Furthermore, we could demonstrate different protein binding ability depending on the allele of this base position.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5614.
First-In-Human Study Of AMG 319, a Highly Selective, Small Molecule Inhibitor Of PI3Kδ, In Adult Patients With Relapsed Or Refractory Lymphoid Malignancies
Authors: Mark C. Lanasa, Martha Glenn, Anthony R. Mato, Sallie D. Allgood, Susan Wong, Benny Amore, Gary Means, Erin Stevens, Chris Yan, Gregory Friberg, Andre Goy
Journal: Blood (2013)
Adjuvant effects of anti-4-1BB monoclonal antibody administration in adoptive T cell therapy of cancer involve host NK cells and the Stat 4 signaling pathway
Authors: Takekazu Iuchi, Qiao Li, Alfred E. Chang
Journal: Cancer Research (2006)

634  We previously reported the polarization effects of 4-1BB during the in vitro generation of tumor-reactive T cells for cancer immunotherapy, as well as the adjuvant effects of anti-4-1BB antibody administration in dendritic cell-based vaccines. In this report, we studied the adjuvant effects of anti-4-1BB mAb administration in T cell therapy of cancer and evaluated the role of NK cells and the Stat 4 signaling pathway. In an adoptive immunotherapy model, effector cells were generated invitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells. Tumor-bearing mice with macroscopic 10-day lung metastases were treated i.v with 5 x 10^6 anti-CD3/anti-CD28 activated TDLN cells with or without i.p. anti-4-1BB mAb administration (25 or 100 micrograms). While T cells or anti-4-1BB alone showed no therapeutic efficacy in this model, T cells plus anti-4-1BB administration mediated significant regression of pulmonary metastases in an antibody dose dependent manner. As a result, T cells combined with anti-4-1BB therapy prolonged the survival of these mice. In 3-day lung tumor-bearing animals, we evaluated the role of host NK cells during the T cell plus anti-4-1BB therapy. Three-day tumor-bearing mice treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. However, NK cell depletion with anti-NK1.1 antibody injection immediately following T cell and anti-4-1BB administration partially abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Using Stat 4-deficient mice, we examined the possible signaling pathway involved in anti-4-1BB-induced immunomodulation. Although T cells remained effective in mediating 3-day tumor regression as in the wild-type hosts, the simultaneous anti-4-1BB mAb administration failed to augment the therapeutic efficacy of T cell therapy in the Stat 4-deficient mice. These results indicate that administered anti-4-1BB mAb can serve as an effective adjuvant to augment the antitumor reactivity of adoptively transferred T cells. In addition, anti-4-1BB administration-enhanced therapeutic efficacy is partially mediated by host NK cells, and involves the Stat 4 molecular signaling pathway.
Prospective Randomized Pilot Trial of Selective Biliary Cannulation Using Pancreatic Guide-Wire Placement
Authors: S. Maeda, H. Hayashi, O. Hosokawa, K. Dohden, M. Hattori, M. Morita, E. Kidani, N. Ibe, S. Tatsumi
Journal: Endoscopy (2003)

In difficult cases of selective bile duct cannulation, several expanded techniques are available which have only been partially evaluated in randomized studies. This study describes a prospective, randomized trial investigating a further technique for obtaining selective biliary access--pancreatic duct wire placement.During a six-month study period, 107 consecutive patients required deep selective biliary cannulation. Accessing the bile duct using a catheter failed within 10 min in 53 of the patients, who were randomly assigned to either pre-insertion of a guide wire into the pancreatic duct or persistence with a conventional catheter. The success rate and complication rate were compared between these two groups.In the pancreatic duct-guide wire group (n=27), the success rate was significantly greater than in the conventional group (93% vs 58%). No pancreatitis complications occurred within either group.Inserting a guide wire into the pancreatic duct to facilitate deep selective bile duct cannulation is better than persisting with a conventional catheter. Further studies will be needed to confirm these results and to compare this method with other sophisticated techniques for obtaining selective access to the bile duct.
Abstract 339: EMMPRIN is Expressed on Progenitor Cell-Derived Foam Cells and Regulates MT1-MMP and MMP-9
Authors: Peter Seizer, Karin Daub, Roland Schmidt, Harald Langer, Meinrad Gawaz, Andreas E May
Journal: Circulation (2006)

Foam cell-derived matrix metalloproteinases (MMPs) such as MMP-9 and MT1-MMP are thought to induce plaque rupture in atherosclerosis. However, the key mechanism of MMP regulation within the plaque has not been clarified, yet. We could recently identify the Extracellular MatrixMetalloProteinase Inducer “EMMPRIN” as an important modulator of MMP activity in cardiovascular cells such as monocytes and smooth muscle cells (Circulation 2006). To our knowledge, EMMPRIN has not been characterized on CD34-positive progenitor cells or foam cells, yet. Therefore, by using a novel model of foam cell formation from CD34-positive cells, we have studied EMMPRIN expression during foam cell differentiation and its functional relevance. Methods and Results: Human CD34+-progenitor cells were freshly derived from umbilical veins and were coincubated with platelets (2x108/ml) for 12 days resulting in large, lipid-loaden CD68 positive foam cells as confirmed by immunocytochemistry, flow cytometry and confocal and electron microscopy. While CD34+-cells did not express EMMPRIN or MT1-MMP, foam cells strongly expressed EMMPRIN on the cell surface [flow cytometry, immunocytochemistry]. In fact, EMMPRIN expression was associated with MT1-MMP expression [flow cytometry] and with enhanced MMP-9 secretion into the cell culture supernatant [SDS-Page gelatin zymography]. Effective gene silencing of EMMPRIN by small interfering RNA (siRNA) significantly reduced the expression of MT1-MMP and of MMP-9 indicating functional relevance of EMMPRIN in foam cells. Control-siRNA had no effect on both MT1-MMP and MMP-9. Notably, MMP-2 was not affected by EMMPRIN gene silencing. Conclusion: CD34+-progenitor cells differentiate into foam cells upon coincubation with platelets. EMMPRIN is expressed on mature foam cells (but not on CD34+-progenitor cells), effectively modulates MMP activity, and, thus represents a promising target to prevent plaque rupture.
Association of Donor Killer Immunoglobulin-like Receptor (KIR) Genotype with Outcome after HLA-Matched Related Donor Hematopoietic Cell Transplantation for AML
Authors: Ronald M. Sobecks, Dawn Thomas, Aiwen Zhang, Mostafa Mohammed Saleh, Lisa Rybicki, Melissa A Yurch, Hien K. Duong, Aaron Gerds, Betty K. Hamilton, Robert M Dean, Brian T. Hill, Rabi Hanna, Brian J. Bolwell, Matt E. Kalaycio, Navneet S. Majhail, Medhat Askar
Journal: Blood (2014)
Abstract 10781: Association Between Cardiac Rehabilitation and Mortality and Rehospitalization Following Acute Myocardial Infarction
Authors: Thomas F Boyden, Kimberly J Reid, Donna M Buchanan, Fred Masoudi, Tracy Y Wang, John Spertus, Melvyn Rubenfire, Michael Ho
Journal: Circulation (2011)

Background: Cardiac rehabilitation (CR) has previously been shown to reduce mortality and morbidity. As acute and chronic treatments for acute myocardial infarction (AMI) have improved over time, t...