tbuckley/cabot-search huggingface dataset:
Abstract 65: β-Adrenergic Signaling Promotes Survival and Proliferation of Mouse Cardiac Progenitor Cells Prior to Lineage Commitment
Authors: Mohsin Khan, Sadia Mohsin, Daniele Avitabile, Jonathan Nguyen, Natalie Gude, Mark A Sussman
Journal: Circulation Research (2012)

Rationale:   Short term β-adrenergic stimulation promotes contractility in response to stress, but is ultimately detrimental in the failing heart due to accrual of cardiomyocyte death. Endogenous myocardial repair may partially offset cardiomyocyte losses, but consequences of long term β-adrenergic drive upon myocardial repair and regeneration are unknown.    Objective:   Modest recovery of cardiac contractility following long term β-adrenergic blockade in the clinical setting may depend, in part, upon restoration of endogenous repair therefore we sought to determine the relationship between β-adrenergic activity and regulation of cardiac progenitor cell (CPC) function and influence upon myocardial repair.    Methods and results:   Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased Akt phosphorylation, up-regulation of eNOS and cyclin D1, and decreased levels of GRK2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by the β1-AR specific antagonist metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed  in vivo  by adoptive transfer of CPC into failing mouse myocardium, concomitant with increased ejection fraction, fractional shortening and hemodynamic performance.    Conclusions:   β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR upon commitment to the myocyte lineage results in loss of early myocyte precursors and ineffective myocardial repair. Thus, β1-AR-specific blockade is likely to provide for enhanced CPC participation in recovery of function in the failing heart.
Small molecule inhibitors of the transmembrane receptor tyrosine kinase Axl as anticancer therapeutics
Authors: Christopher Ireson, Kevin Stewart, Gregoire Pave, James Firth, Jon Travers, Aurore Lejeune, Laurent Rigoreau, Caroline Foxton, Tim Hammonds, Tony Raynham, Lloyd Kelland, Alan Storey, Edel O'Toole, Lorna Stewart
Journal: Cancer Research (2008)

4865   Following stimulation by its endogenous ligand Gas6, the transmembrane receptor tyrosine kinase (RTK) Axl mediates oncogenic transformation through its intracellular kinase domain (ICD). The Gas6/Axl RTK signal transduction pathway operates, although not exclusively, through activation of the phosphatidylinositol 3-kinase (PI3K) Akt pathway. Over-expression of Axl has been demonstrated in many cancer cell lines, prominent amongst which are those derived from colon, breast, lung, ovarian and squamous cell carcinoma. Furthermore, increased expression of Axl is an indicator of poor prognosis in several tumor types and Axl kinase has been shown to play a pivotal role in cell survival, proliferation, migration and tumor angiogenesis. Finally, Axl knockdown with retrovirally delivered short hairpin RNA (shRNA) has been shown to reduce the growth of xenografts derived from human breast MDA-MB-231 cells  in vivo . Consequently, Axl kinase is a promising potential target for therapeutic intervention. The Cancer Research Technology Development Laboratories has recently screened its library of approximately 56,000 diverse small molecule compounds for inhibitors of Axl. The IMAP-based biochemical screen, using kinase domain human Axl and an ATP concentration of 135 µM revealed two distinct chemical series which progressed into a hit to lead programme. Representatives of both series inhibited Axl kinase with nanomolar potency (lowest IC 50  values of 10 and 31 nM respectively) and had drug-like properties. Subsequently, human breast adenocarcinoma MDA-MB-231 cells stimulated with human Gas6 were incubated with derivatives from these series and levels of phosphoAxl and pSer  473  Akt determined as surrogate biomarkers of Axl kinase activity. Several agents with sub-micromolar activity in these cell-based assays are currently progressing into the lead optimisation stage of the project.
Localized, high-risk soft tissue sarcomas (STS) of the extremities and trunk wall in adults: Three versus five cycles of full-dose anthracyclin and ifosfamide adjuvant chemotherapy: A phase III randomized trial from the Italian Sarcoma Group (ISG) and Spanish Sarcoma Group (GEIS).
Authors: A. Gronchi, S. Frustaci, M. Mercuri, J. Martin Broto, A. Lopez-Pousa, L. Mariani, P. Verderio, V. Quagliuolo, P. G. Casali, P. Picci
Journal: Journal of Clinical Oncology (2010)

10003 Background: A previous Italian randomized study showed a survival benefit of adjuvant chemotherapy (CT) in high-risk adult STS patients, and a recent meta-analysis was supportive as well. However, the toxicity of the regimen employed in the previous Italian trial affected the dose intensity of the last 2 cycles. We thus decided to undertake a multicentric international phase III study to compare 3 cycles of the same CT, given pre-operatively, with 3 pre-operative cycles followed by 2 cycles post-operatively. Methods: Patients were randomized either to receive 3 cycles of preoperative CT with epirubicin 120 mg/m2 and ifosfamide 9 g/m2 and G-CSF (Arm A) or to receive the same 3 cycles of preoperative CT followed by 2 further cycles of postoperative CT (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Noninferiority of the primary endpoint, overall survival (OS), was assessed by the confidence interval (CI) of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. Results: Between January 2002 and April 2007, 328 patients were recruited, 164 in each arm. 160 patients received preoperative radiation therapy, 78 in Arm A and 82 in Arm B. Four patients were ineligible and 10 did not receive the allocated treatment at all. At a median follow-up of 50 months (range 21-93 months) 94 deaths were recorded, 46 in Arm A and 48 in Arm B. Five-year OS was 0.69 for the entire group of patients, 0.70 in Arm A and 0.69 in Arm B. The intention-to-treat analysis shows that 3 cycles of full dose CT were not inferior to 5 cycles (one-sided 95% upper confidence limit of 1.33 less than the pre-specified non-inferiority margin of 1.50 with 80% power). Per-protocol analysis confirmed these results. Conclusions: Adjuvant CT is incorporated as an option in most clinical practice guidelines for selected high-risk STS patients. This trial shows that 3 cycles of a full-dose CT are not inferior to 5. They were given pre-operatively, exploiting the added local benefit which CT can provide, possibly in combination with radiation therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD, GlaxoSmithKline, Infinity, Novartis, Pfizer, PharmaMar, sanofi-aventis Novartis, Pfizer, PharmaMar Amgen, ARIAD, GlaxoSmithKline, Infinity, Johnson & Johnson, Lilly, Novartis, Pfizer, PharmaMar, sanofi-aventis, Schering-Plough Novartis, PharmaMar
Abstract 10987: Is There an Association Between Myocardial Flow Reserve as Measured on Rubidium-82 Positron Emission Tomography and Allograft Rejection in Patients Following Cardiac Transplantation?
Authors: Brian A Mc Ardle, Ross A Davies, Gary R Small, Yeung Yam, Haisam Haddad, Lisa M Mielniczuk, Ellamae Stadnick, Ann Guo, Rob S Beanlands, Rob A deKemp, Benjamin Chow
Journal: Circulation (2013)

Background: Cardiac allograft rejection is a key prognostic determinant following cardiac transplantation. Detection of patients with rejection is reliant on histological sampling of the RV. Absolu...
Human papillomavirus (HPV) as a risk factor for the increase in incidence of tonsillar cancer and its expression of E6 and E7
Authors: H. Dahlstrand, L. Hammarstedt, D. Lindquist, W. Ye, T. Dalianis, E. Munck-Wikland
Journal: Journal of Clinical Oncology (2008)

6004 Background: In the last 10 years, several studies have suggested an association between HPV and tonsillar cancer. In line with reports from the US and in Finland, we have found that there is increase in the incidence of tonsillar cancer in Sweden, while no similar increase in incidence was noted for other oral carcinomas. This study investigated whether HPV could be the underlying cause of the increase and whether expression of the oncogenes HPV-16, E6 and E7, could be ascertained. Methods: The incidence of tonsillar cancer from 1970–2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during the same period from patients in the same area were tested for presence of HPV by PCR. E6/E7 mRNA was measured by synthesizing cDNA from extracted RNA and then assayed by real-time PCR. Results: The incidence of tonsillar cancer in Stockholm had increased 2.8 fold in 1970–2002, corresponding to what we previously found for Sweden. During the same period, a 2.9 fold (p<0.001) increase in the proportion of HPV-positive tonsillar cancer cases was observed. The distribution of HPV-positive cases was: 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s, and 32/47 (68%) during 2000–2002. Of the 99 HPV positive samples, 86 were HPV-16, three were HPV-33, one HPV-35, and one HPV-45, while eight could not be typed. HPV-16 E6 and/or E7 was expressed in 50/53 (94%) of assessable HPV-16 positive tonsillar cancer samples; 42 samples expressed both E6 and E7, and 8 samples expressed only E7. Conclusions: A parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors was demonstrated. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. Furthermore, E6 and E7 mRNA expression was found in all but three (94%) of the examined HPV-16 positive samples, emphasizing the role of HPV-16 in the oncogenesis of tonsillar cancer. No significant financial relationships to disclose.
Abstract 14781: Intracoronary Cardiosphere-Derived Cells for Heart Regeneration after Myocardial Infarction: Determinants of Regenerative Efficacy in the Final 1-Year Results of the CADUCEUS Trial
Authors: Konstantinos Malliaras, Ke Cheng, Rachel Smith, Adam Mendizabal, Gary Gerstenblith, Linda Marban, Raj Makkar, Eduardo Marban
Journal: Circulation (2012)
Prognostic significance of BRCA1, PARP1, and PARP2 in sporadic breast cancer
Authors: A. Gennari, M. Sormani, L. Varesco, P. Pronzato, V. Viassolo, V. Mirisola, U. Pfeffer, P. Bruzzi
Journal: Journal of Clinical Oncology (2009)

e22114 Background: Breast cancer susceptibility gene (BRCA1) is a tumor suppressor gene whose mutation is associated with the development of hereditary breast cancer. In sporadic tumors, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, has been suggested to be associated with prognosis. Cells with BRCA1 loss of function are deficient in DNA double strand break repair thus activating poly(ADP-ribose) polymerases (PARPs) whose catalytic activity is immediately stimulated by DNA strand-breaks. The aim of this study was to evaluate the prognostic value of BRCA1 and PARPs (PARP1 and 2) in sporadic breast cancer. Methods: We merged two previously published Affymetrix gene expression datasets: GSE 1456 (159 patients, median follow up 7 years) and GSE 2494 (249 patients, median follow up 10 years). Microarray data preprocessing was carried out using Bioconductor software (gcrma procedure). Expression of BRCA1, PARP1 and PARP2 mRNA were evaluated as continuous variables. Kaplan Meier survival curves and Cox regression analysis (stratified by database) were used to assess the prognostic capability of the identified biomarkers. Results: High mRNA expression of BRCA1, PARP1 and PARP2 was correlated with an adverse prognosis. Relapse Free Survival (RFS) Hazard Ratio was 1.6 (95% CI, 1.2 to 2.1) for BRCA1 (p = 0.002), 1.7 (95% CI, 1.2 to 2.4) for PARP1 (p = 0.002) and 1.7 (95% CI, 1.3 to 2.3) for PARP2 (p = 0.001). By multivariate analysis all 3 genes resulted independently correlated with RFS. When interaction with systemic adjuvant therapy (107 patients treated) was tested, BRCA1 mRNA expression was strongly associated with treatment: HR 2.3 (95% CI, 1.4 to 3.7, p 0.001); p for interaction = 0.06. Conclusions: This study shows that BRCA1, PARP1 and PARP2 are all significantly associated with prognosis in sporadic breast cancer. No significant financial relationships to disclose.
Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.
Authors: J A Ortega, M E Nesbit, H N Sather, L L Robison, G J D'Angio, G D Hammond
Journal: Journal of Clinical Oncology (1987)

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.
Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil before concurrent chemoradiotherapy or concurrent cetuximab-radiotherapy in locally advanced squamous cell carcinoma of the head and neck
Authors: S. Billan, R. Abdah-Bortnyak, F. Mezid, Z. Bernstein, E. Gez, H. Nasrallah, A. Kuten
Journal: Journal of Clinical Oncology (2009)

e17045 Background: Encouraging results have recently been reported in patients with locally advanced squamous cell carcinoma of the head and neck. The present study assessed the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) or concurrent cetuximab-radiotherapy. Methods: Induction chemotherapy consisted of TPF (docetaxel 75 mg/m(2), cisplatin 75 mg/m(2), 5-fluorouracil 750 mg/m(2)/d continuous infusion for 96 h) every three weeks, followed by CHT-RT regimen (radiotherapy 70 Gy total dose fractionated at 2Gy per day, 5 days a week concurrently with weekly cisplatin 40 mg/m(2) or cetuximab with loading dose of 400 one week before starting radiotherapy and 250 weekly during the radiotherapy) 4–7 weeks later. Percutaneus endoscopic gastrectomy inserted before the combined treatment. The National Cancer Institute Common Toxicity Criteria (version 2) were used for classification of adverse events. Results: Between march 2007 and november 2008, 29 previously untreated patients (19 male and 4 female) with stage III-IV squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx were included to the study. The median age was 60 years (range, 56–75 years). The stage distribution was as follows: stage II, 1 patient; stage III, 14 patients; and stage IV, 14 patients. 16 patients had a performance status of 0 and 11 had a performance status of 1. The response rate (RR) after IC was: complete response (CR) for 10 pts (34%), partial response (PR) for 13 pts (57%) and no response (NR) for 3 pts (13%). Toxicity from IC included neutropenia Gr III,IV 25%,neutropenic fever 9%, mucositis and diarrhrea Gr III, IV 22% . 60% of patients completed 3 cycles, 20% received 2 cycles and 20% received only one cycle of TPF. The toxicity from the concurrent phase included mucositis Gr III-IV in 70% of patients,dermatitis Gr III-IV in 43% and no case of neutropenia Gr III-IV. The combined treatment was interrupted only in 4 patients for one week. Conclusions: TPF was well tolerated with high response rate and low rate of acute toxicity. Three cycles of TPF followed by combined treatment are feasible. No significant financial relationships to disclose.
Medical care and emotional distress associated with advanced cancer patients' end-of-life discussions with their physicians
Authors: A. A. Wright, A. Ray, B. Zhang, J. W. Mack, S. L. Mitchell, M. E. Nilsson, E. T. Trice, S. D. Block, P. K. Maciejewski, H. G. Prigerson
Journal: Journal of Clinical Oncology (2008)

6505 Background: Physicians are concerned that end-of-life (EOL) discussions may distress terminally ill patients, and may not offer benefit. Little is known, however, about whether EOL discussions are associated with psychological distress and medical care received at the EOL. Methods: Coping with Cancer (CwC) is an NCI/NIMH-funded, prospective, longitudinal, multi-institutional study of 603 advanced cancer patients. Patients were interviewed on enrollment and followed until death; medical care received in the last week of life was obtained from chart review. Patients who reported having had EOL conversations were compared with those who did not on their degree of emotional distress [e.g. severity of psychological symptoms such as worry and rates of Major Depressive Disorder (MDD) using the Structured Clinical Interview for DSM-IV], terminal illness acknowledgement, treatment preferences, and medical care. Results: 188 of 603 patients (31.2%) reported EOL discussions with physicians. No mental health differences were found. Patients reporting EOL discussions were not more likely to meet criteria for MDD [rates were 7.2% vs. 7.4%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.50–1.90] or feel “nervous or worried” [adjusted least mean squares 2.81 vs. 2.77, t=-0.16, p=0.87]. They were more likely to acknowledge being terminally ill [adjusted OR (AOR)=2.24, CI 1.45–3.44], value comfort care over life extension (AOR=3.23, CI 2.02–5.17), and complete a DNR order (AOR= 3.62, CI 2.36–5.56). Among the 323 CwC decedents, patients reporting EOL conversations were less likely to undergo ventilation (AOR= 0.04, CI 0.004–0.43) or ICU admission (AOR= 0.21, CI 0.05–0.88), and more likely to receive hospice (AOR=2.13, CI 1.13–4.02). After propensity score matching, lower rates of ICU admission (AOR 0.21, CI 0.05–0.88) and ventilation (AOR 0.11, CI 0.01–0.87) remained. Conclusions: EOL care discussions between physicians and patients with advanced cancer are not associated with psychological distress. Furthermore, these discussions may result in increased patient understanding of illness severity, fewer invasive procedures, and lower rates of ICU admission at the EOL. No significant financial relationships to disclose.
An enriched phase I, pharmacokinetic and pharmacodynamic study of the N-cadherin (NCAD) cyclic competitive binder exherin (ADH-1) in patients with solid tumors
Authors: C. Sessa, A. Perotti, M. Maur, A. Fasolo, D. Scaramuzza, A. Braghetti, S. Marsoni, R. K. Malik, W. P. Peters, L. Gianni
Journal: Journal of Clinical Oncology (2006)

3042 Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m 2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3 rd dose level (DL 3, 600 mg/m 2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head &amp; neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m 2 /weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced &gt; grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m 2 ): mean C max 22.1, 37.0, and 50.8μg/mL, respectively; AUC inf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m 2 ; and T 1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented. [Table: see text]
춘계학술대회 : 포스터발표 ; 급성 간질환등 : 정상 간기능 수치를 보이는 비알콜성 지방간 환자들의 임상적 특징
Authors: 오주희, 이소영, 송한얼, 권창일, 김형태, 김수경, 홍성표, 황성규, 박필원, 임규성, 김문종
Journal: Clinical and Molecular Hepatology (2007)