tbuckley/cabot-search huggingface dataset:
Patients involved in clinical research are more concerned about intrinsic and traditional research (“publish or perish”) conflicts of interests (COI) than potential financial conflicts: Results of interviews with advanced cancer patients enrolling in phase I trials
Authors: C. K. Daugherty, F. J. Hlubocky, S. Gray, M. J. Ratain
Journal: Journal of Clinical Oncology (2006)

6008 Background: Concerns exist about the potential for financial COI to bias the design, conduct, analysis, and reporting of clinical trials. However, information is lacking about the perceptions of these COI among actual research subjects—both in general and relative to more intrinsic and traditional research COI. Methods: Using a standardized survey, cancer patients (pts) were asked closed-ended and semi-qualitative questions regarding their concerns about extrinsic, e.g., financial, and intrinsic, e.g. career advancement, COI. Results: To date, 120 pts either enrolled, or being evaluated for participation, in phase I trials have been approached for an interview with 96 completing the interview (80% response rate). Median age of respondents is 61 y (33–82); 55% male; 83% Ca, 10% AA, 2% AsA or HA; 38% college educated. 91%, 100%, and 94% thought that the involved investigators (MDs), drug companies, and hospitals benefited from a clinical trial respectively. The benefits cited for MDs was improvement in knowledge/ability to treat pts. The benefits cited for the hospital and drug company were described as prestige and financial. 38% would be concerned if an MD involved in a clinical trial receives financial benefit from the research, e.g., being a paid consultant or owning stock in company involved in a trial, and 43% thought that they should be informed of these potential benefits. 64% thought they should be concerned if an MD receives career advancement benefits from trial participation, and 69% thought they should be informed of this benefit. 45% thought that investigators might feel institutional pressure to enroll pts. Qualitative data revealed that pts’ lack of concern about financial COI related to their assumption that MDs already receive financial benefits-believing this to be acceptable-with some even encouraging it. Conclusions: Cancer pts were more concerned about intrinsic and traditional research COI than potential financial COI. As well, many assume that MDs receive financial benefits from research. These results may be helpful when considering COI management policies. No significant financial relationships to disclose.
Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care
Authors: Safia El Messaoudi, Florent Mouliere, Stanislas Du Manoir, Caroline Bascoul-Mollevi, Brigitte Gillet, Michelle Nouaille, Catherine Fiess, Evelyne Crapez, Frederic Bibeau, Charles Theillet, Thibault Mazard, Denis Pezet, Muriel Mathonnet, Marc Ychou, Alain R. Thierry
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC). Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate). Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P = 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P = 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P = 0.0089 and P = 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/BRAF-mutant cohort of patients (P = 0.0052) and appeared as a strong independent prognostic factor (P = 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P = 0.67). Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment. Clin Cancer Res; 22(12); 3067–77. ©2016 AACR.
Sequential Histopathology and Cell Kinetic Changes in Rat Pyloric Mucosa During Gastric Carcinogenesis Induced by &lt;italic&gt;N&lt;/italic&gt;-Methyl-&lt;italic&gt;N′&lt;/italic&gt;-nitro-&lt;italic&gt;N&lt;/italic&gt;-nitrosoguanidine&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: E E Deschner, K Tamura, S P Bralow
Journal: JNCI Journal of the National Cancer Institute (1979)

The effect of administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at a dose level of 83 mg/liter in the drinking water was followed in the pyloric mucosae of male noninbred Wistar rats. Autoradiographic studies were done on animals killed after 10, 15, 26, and 36 weeks of treatment. In the normal-appearing mucosae of the rats treated with MNNG for 10 weeks, the number of epithelial cells per pit column was significantly increased over that in control rats. Simultaneously, a shift in the major zone of epithelial cell proliferation was noted in the treated rats. Along with the formation of a longer pit in MNNG-treated rats, the greatest number of DNA-synthesizing cells was displaced from the middle third of the pit in a downward direction toward the muscularis mucosa. In addition, at this early experimental time period, pits lined with more immature, cuboidal, mucus-depleted cells were recognizable. These pits not only had higher labeling indices than normal-appearing pits of the same animals but also expressed a dual nature with increased proliferative activity extending either upward to the luminal surface or further in a downward direction. Focal areas of cellular atypism were present by week 10 of treatment with a threefold to sevenfold greater DNA synthesis activity than that found in the normal-appearing mucosa of the same animal. A wide range of values in proliferative activity was found not only among invasive pyloric tumors within the same animal but also within different areas of the same tumor. The mechanism for the formation of adenomas and invasive adenocarcinomas is believed to be related to the dual character of the hyperplastic pits described.
Abstract 2620: Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1
Authors: Xuejiao Liu, Wei Cai, Mingshan Niu, Rutong Yu
Journal: Cancer Research (2015)

Abstract Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21CIP1 and p27KIP1. Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. Further investigation revealed that plumbagin inhibition of glioma cell growth was also evident in a nude mouse model. Taken together, these results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas. Citation Format: Xuejiao Liu, Wei Cai, Mingshan Niu, Rutong Yu. Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1. [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 2620. doi:10.1158/1538-7445.AM2015-2620
Aurora kinase targeting in lung cancer reduces KRAS-induced transformation
Authors: Edmilson Ozorio dos Santos, Tatiana Correa Carneiro-Lobo, Mateus Nobrega Aoki, Elena Levantini, Daniela Sanchez Bassères
Journal: Molecular Cancer (2016)

Abstract Background Activating mutations in KRAS are prevalent in lung cancer and have been causally linked to the oncogenic process. However, therapies targeted to oncogenic RAS have been ineffective to date and identification of KRAS targets that impinge on the oncogenic phenotype is warranted. Based on published studies showing that mitotic kinases Aurora A (AURKA) and B (AURKB) cooperate with oncogenic RAS to promote malignant transformation and that AURKA phosphorylates RAS effector pathway components, the aim of this study was to investigate whether AURKA and AURKB are KRAS targets in lung cancer and whether targeting these kinases might be therapeutically beneficial. Methods In order to determine whether oncogenic KRAS induces Aurora kinase expression, we used qPCR and western blotting in three different lung cell-based models of gain- or loss-of-function of KRAS. In order to determine the functional role of these kinases in KRAS-induced transformation, we generated KRAS-positive A549 and H358 cells with stable and inducible shRNA-mediated knockdown of AURKA or AURKB and evaluated transformation in vitro and tumor growth in vivo. In order to validate AURKA and/or AURKB as therapeutically relevant KRAS targets in lung cancer, we treated A549 and H358 cells, as well as two different lung cell based models of gain-of-function of KRAS with a dual Aurora kinase inhibitor and performed functional in vitro assays. Results We determined that KRAS positively regulates AURKA and AURKB expression. Furthermore, in KRAS-positive H358 and A549 cell lines, inducible knockdown of AURKA or AURKB, as well as treatment with a dual AURKA/AURKB inhibitor, decreased growth, viability, proliferation, transformation, and induced apoptosis in vitro . In addition, inducible shRNA-mediated knockdown of AURKA in A549 cells decreased tumor growth in vivo. More importantly, dual pharmacological inhibiton of AURKA and AURKB reduced growth, viability, transformation, and induced apoptosis in vitro in an oncogenic KRAS-dependent manner, indicating that Aurora kinase inhibition therapy can specifically target KRAS-transformed cells. Conclusions Our results support our hypothesis that Aurora kinases are important KRAS targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for KRAS-induced lung cancer therapy.
Pretreatment positron emission tomography (PET) scan standardized uptake value (SUV) as a prognostic variable for overall survival in limited-stage small cell lung cancer (L-SCLC).
Authors: D. R. Gomez, G. W. Gladish, X. Wei, P. Allen, J. D. Cox, M. O'Reilly, J. J. Erasmus, F. V. Fossella, R. Komaki
Journal: Journal of Clinical Oncology (2010)

7045 Background: PET imaging has been increasingly utilized in L-SCLC. However, the prognostic value of the staging SUV has not been well elucidated. Methods: From 1/2004-12/2008, 59 patients with L-SCLC were treated with definitive chemoradiation at M. D. Anderson Cancer Center and received a pretreatment staging PET scan. The median radiation therapy (RT) dose was 45 Gy in 30 fractions delivered twice daily (range 40.5-61.8 Gy). Thirty two percent of patients (n = 19) underwent induction chemotherapy, though all initial PET scans were taken prior to any treatment. The median value for the maximum SUV of the primary lesion (pSUVmax) was 12.0 (range 1.3-34.6), and for the nodal disease (nSUVmax) it was 11.5 (range 3.1-35.5). Twenty eight percent of patients had assessable follow-up PET imaging within one year of completing treatment. Overall survival (OS) was measured from the end of RT to the date of death or, if not documented, the last follow-up at our institution. Kaplan-Meier analysis was utilized to determine 1, 2, and 3-year estimates of OS. Univariate analysis was then performed to evaluate the effect of pSUVmax and nSUVmax on OS. Results: The median change in pSUVmax after treatment was -63% (range +21 to -90%). At a median follow-up of 16.4 months (range 2.9-68.5 months), 1-, 2-, and 3-year rates of OS were 74%, 60%, and 46%, respectively. On univariate analysis, a pSUVmax of > 13 was of borderline significance (p = 0.05), and a pSUVmax of >14 was statistically significant as a prognostic factor for OS (p < 0.05). A higher pSUVmax was correlated with an improved survival up to a level of 18. At pSUVmax>18, small patient numbers limited analysis. Initial nSUVmax did not correlate with OS. Conclusions: Most patients who receive definitive chemotherapy and RT for L-SCLC experience marked PET scan responses. Unexpectedly, a higher initial pSUVmax was associated with better OS. This finding could be due to improved outcomes with accelerated RT in high-SUV patients, such that there is a more beneficial fractionation for patients with low SUVmax levels in L-SCLC. Individualized treatment may be indicated based on pretreatment SUV. No significant financial relationships to disclose.
Cardiac monitoring in phase I trials of a novel histone deacetylase (HDAC) inhibitor LAQ824 in patients with advanced solid tumors and hematologic malignancies
Authors: E. K. Rowinsky, J. de Bono, D. J. Deangelo, A. van Oosterom, J. Morganroth, G. H. Laird, M. Dugan, J. W. Scott, O. G. Ottmann
Journal: Journal of Clinical Oncology (2005)

3131 Introduction: LAQ824, a novel cinnamic acid hydroxamate, inhibits HDAC activity (IC50, 0.03 μM) and the hERG channel(IC50, 10 μM). Methods: In 3 phase I studies, LAQ824 was administered as a 3-hr intravenous infusion on several dosing schedules, principally days 1–3 of a 21-day cycle, to adult pts with advanced solid (studies 2102 and 2107) or hematologic (study 2101) malignancies. Pts with impaired cardiac function were excluded; drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (4 ECGs), on days of dosing and post-dose each cycle. ECG data were processed in a core lab by manual analysis. Cardiac enzymes were assessed on days of dosing. LVEF was assessed by MUGA scan or echocardiogram each cycle. Results: 77 pts (median age: 60 yrs; 48 males, 29 females) were treated at 11 dose levels, range 6 - 200 mg/m2/day. PK analysis showed dose proportionality, T1/2of 6 - 26 hrs, and 1.5 fold accumulation at steady state. There was considerable inter-patient variability in PKs and 4 pts (5%) had exposures > 10x cohort mean. Sustained histone acetylation was noted in PBL 24 hrs post-last dose at doses ≥36 mg/m2. Central tendency analysis of 2576 post-dose ECGs showed no changes in QTcF on day 1; however, there was a dose-related increase in QTcF of < 20 msec on day 3. Frequency of outliers, % of patients with at least 1 ECG with QTcF > 60 msec change from baseline, was 10% (8 pts) and occurred over a broad dose range (36 - 200 mg/m2). Outlier ECGs occurred primarily on day 3 (6/8 pts). There were no outliers on day 1. None of the pts with high LAQ824 plasma exposures had outlier ECGs. Only 1 pt had QTc > 500 msec; in cycle 1 after dosing at 200 mg/m2, and after dose reduction to 125 mg/m2 in cycle 2, a 10 sec. run of unsustained torsades de pointes. Non-specific T wave flattening occurred frequently. Two pts had small, transient increases in troponin without increase of CK MB. There were no significant changes in LVEF.Conclusions: LAQ824, a novel HDAC inhibitor, was found to induce dose-related increases in QTcF of < 20 msec at doses up to 200 mg/m2. Cardiac repolarization changes were delayed until day 3 perhaps due to a different mechanism effecting the hERG channel. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis AstraZeneca, Boehringer Ingleheim, Celgene, Novartis, Oncolytics Biotech GlaxoSmithKline, Merck, Novartis, Roche Novartis
Microarray Analysis of Dna Copy Number Aberrations in Breast Tumor: Correlation with the Efficacy of Neoadjuvant Chemotherapy
Authors: N.V. Litviakov, N.V. Cherdyntseva, M.M. Tsyganov, P.V. Ivankovskaya, E.M. Slonimskaya
Journal: Annals of Oncology (2014)
Abstract 15651: Genetic Deletion Of MURC/cavin-4 Aggravates Abdominal Aortic Aneurysm
Authors: Kotaro Miyagawa, Takehiro Ogata, Naohiko Nakanishi, Tetsuro Hamaoka, Naoki Maruyama, Tomomi Ueyama
Journal: Circulation (2013)

Background:  Abdominal aortic aneurysm (AAA) is a relatively common disease in the elderly population. MURC (muscle-restricted coiled-coil protein)/cavin-4, a fourth member of the cavin family which regulates caveolae function, is expressed in cardiomyocytes, smooth muscle cells, and skeletal myocytes. Deficiency of caveolin-1, a critical component of caveolae, has been to be protective against atherosclerosis. Although mutations in MURC have been identified in patients with dilated cardiomyopathy, roles of MURC in vascular smooth muscle cells (VSMCs) and the development of AAA remain unknown.   Methods and Results:  To examine the role of MURC in AAA, we subjected wild-type (WT) and MURC knockout (MURC-/-) mice to a model of AAA induced by periaortic application of CaCl2. After 6 weeks of CaCl2 treatment, the internal aortic diameter assessed by ultrasonography was significantly increased in MURC-/- mice compared with WT mice. Measurement of the external aortic diameter after perfusion fixation also showed an increase in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. Fibrosis and cell infiltration of the tunica media were increased in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. The dilation of the aorta in CaCl2-treated MURC-/- mice was accompanied by disruption of the elastic lamellae. The activation of JNK was suppressed in CaCl2-treated MURC-/- mice compared with CaCl2-treated WT mice. Since MURC is expressed only VSMCs in the aorta, we then examined the role of MURC in proliferation and migration of VSMCs. MURC-/- VSMCs showed suppression of fetal bovine serum (FCS)-induced proliferation and migration, which were accompanied by reduced RhoA activity. Furthermore, MURC knockdown in VSMCs suppressed TNF-α-induced JNK activation and FCS-induced proliferation and migration. Overexpression of MURC in VSMCs induced RhoA activation, proliferation, and migration in VSMCs. MURC-induced proliferation and migration were inhibited by a ROCK inhibitor.   Conclusion:  MURC regulates VSMC proliferation and migration through the Rho/ROCK pathway. Deficiency of MURC deteriorates AAA accompanied by disruption of the elastic lamellae, which is likely attributable to reduced proliferation and migration of VSMCs.
Abstract 18572: Left Ventricle Reverse Remodeling After Acute Myocardial Infarction Predicted by MVO (CE-CMR). A Meta-Analysis of Prospective Trials
Authors: Jorge Romero, Florentino Lupercio Lopez, Syed Arman Husain, Patricia Chavez, Mario J Garcia
Journal: Circulation (2013)

Background: Microvascular obstruction (MVO) is a predictor for reverse remodeling as evidenced by an increase in left ventricle end diastolic volume index (LVEDVi) and left end systolic volume index (LVESVi) in patients following acute myocardial infarction (AMI). Contrast Enhanced CMR (CE-CMR) is the leading diagnostic modality to access the presence and extent of MVO. Objective: To determine the predictive value of MVO detected by CE-CMR as a predictor for Reverse remodeling in patients with AMI Methods: A systemic review of Medline, Cochrane, and Embase for all the clinical trials using CMR to detect MVO and assessing its association reverse remodeling was performed. Given the high heterogeneity (i.e. I 2 &gt; 25), we used a random effect model. Results: A total of 6 studies with 423 patients (male: 83%, mean age 61 years (SD=+/-4) and average EF of 40% (SD+/-3) fulfilled the inclusion criteria. The overall incidence for MVO was 57% (230) (SD= +/- 7). Head to head comparison of patients with and without evidence of MVO on initial CMR with in 1 week for AMI showed a higher incidence of reverse remodeling on the follow up CMR at a mean time of 6 months (SD+/-1). Patients with evidence of MVO had significantly higher volumes. The mean difference in LVEDVi and LVESVi between the initial and follow up MRI was 8.11 (95% CI 4.49-11.73) and 9.10 (95% CI 6.21-12.18) respectively. Conclusion: MVO detected by CE-CMR is a strong predictor for LV reverse remodeling in patients suffering from acute myocardial infarction.
Abstract 285: Does the Real-Time Audio Feedback From an Automated External Defibrillator Enhance Cardiopulmonary Resuscitation Quality During Emergency Resuscitation?
Authors: Peter O’Hare, Rebecca Di Maio, Hannah Torney, Colette McIntyre, Paul McCanny, Jennifer Adgey
Journal: Circulation (2013)

Objective: The 2010 AHA guidelines have outlined the importance of providing early high-quality CPR in conjunction with an AED to enhance survial outcomes post sudden cardiac arrest. However, there is little information available as to how real-time feedback may positively enhance the quality of compression rates. The purpose of this study was to evaluate the impact of CPR feedback given by out-of-hospital (OOH) responders following SCA. Response to feedback was gauged by analysing changes in the impedance cardiogram (ICG) and ECG waveforms recorded by the AED during OOH resuscitation in an attempt to establish if the rescuer responded to audible instruction. Methods: Data was collected from events recorded by HeartSine Samaritan AEDs over a five month period. A total of nine events were received and assessed. Event files that included the ECG and ICG recordings were downloaded using SaverEvo® Software and analysed. Data also included the time of each instruction, the nature of the instruction (e.g. push harder, push faster, push slower, good compressions) and the associated changes in the ECG and ICG waveforms were interpreted to assess reaction times where appropriate. Findings: A total of 177 instructional CPR prompts were given to the rescuers over nine events, 70 (39.5%) of which resulted in a positive modification of CPR rate or force. On average there was a 1.44 second delay in reaction time to each prompt. Of the 70 positive changes in the ICG, 30 of the cases showed a corresponding change in the ECG indicating that the ICG is a better indicator of CPR efficacy. Conclusions: This study demonstrates that real-time feedback during CPR is beneficial in enhancing the quality of CPR in emergency resuscitation. Even where there was no response to the prompt, CPR at least continued at the same rate suggesting that there was no detrimental affect on the quality of CPR. Furthermore, the results indicate that ICG is an effective way to monitor the quality of rescuer CPR.