tbuckley/cabot-search huggingface dataset:
Abstract 361: Neuregulin Transcriptional Programming of Embryonic Endothelial Progenitor Cells and Embryonic Stem Cells
Authors: Jijun Hao, Cristi L Galindo, Radwan N Safa, Truc-Linh Tran, Douglas B Sawyer
Journal: Circulation Research (2012)

Jijun Hao, Cristi L. Galindo, Radwan N. Safa, Truc-Linh Tran, Douglas B. Sawyer Neuregulin-1 (NRG-1) plays a critical role in heart development by signaling through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3 and erbB4). Mice with disrupted expression of NRG-1, ErbB2, ErbB3 or ErbB4 die in utero with failure of cardiac development. We have previously shown that NRG-1 has distinct effects on two embryonic progenitor cell populations that express ErbB2 and ErbB3 receptors. In an embryonic endothelial progenitor cell line (eEPCs) NRG-1 treatment induces phosphorylation of Akt, GSK-3β, and Erk1/2, and protects eEPCs against serum deprivation-induced apoptosis. In embryonic stem cells (ESCs) we find that NRG-1 treatment from day 0∼2 induces cardiomyocyte formation by day 8 in culture, and when ErbB3 is knocked down in the ESCs, NRG-1 fails to promote cardiomyogenesis. To understand early molecular events that might regulate these distinct effects, we analyzed global transcriptional changes induced by NRG-1 in both eEPCs and ESCs using microarrays. There were only 244 significantly differential (p value &lt; 0.05, fold-change &gt; 1.5) genes detected in NRG-1-treated ESCs, while NRG-1 induced differential expression of 1,547 transcripts in eEPCs. Based on functional analysis, the most significantly over-represented function (Fishers Exact Test, p value with FDR &lt; 0.05) in ESCs was “cell morphogenesis during differentiation”. In eEPCs, genes regulated via Ras/MAPK signaling were altered, as were those downstream of the Akt-PI3K pathway and calcium signaling. For both cell lines, the most statistically significant transcription factor identified as a regulator of the genes altered in response to NRG-1 was SRF, consistent with a role for NRG-1 in heart development and regeneration. Based on the results of this study, we constructed a putative signaling pathway whereby NRG mediates cardiomyogenesis in pluripotent stem cells that correlates with phenotypic observations.
High-dose cytosine arabinoside: treatment and cellular pharmacology of chronic myelogenous leukemia blast crisis.
Authors: S J Iacoboni, W Plunkett, H M Kantarjian, E Estey, M J Keating, K B McCredie, E J Freireich
Journal: Journal of Clinical Oncology (1986)

Twenty-one patients with chronic myelogenous leukemia (CML) in blastic transformation underwent 22 remission induction attempts with high-dose cytosine arabinoside (ara-C), administered as a two-hour infusion of 3 g/m2 for six to 12 doses. Ara-C doses were administered every 12 hours in 15 patients and every six to ten hours in six patients. Median patient age was 35 years (range, 20 to 62). The median duration of benign phase was 25 months (range, 0 to 167). Morphology of blast crisis blast cells was myeloid in 15 patients and lymphoid in six. Five patients achieved complete remission (CR), three had partial remission (PR), and one had hematologic improvement, for an overall response rate of 41%. Median remission duration was 2.5 months (range, 0.5 to 6 months). Survival duration was 6 months for responding patients and 1.5 months for those with resistant disease. The response rate was similar for patients with myeloid and lymphoid blast crisis (31% v 50%, respectively). The response rate was significantly higher for patients whose benign phase was less than 1 year (75% v 21%, P = .05) and who had prolonged marrow aplasia after ara-C (86% v 27%, P = .05). Myelosuppression was the major dose-limiting toxicity, and cerebellar toxicity occurred in two patients. Intracellular ara-C 5'-triphosphate (ara-CTP) levels were similar in blood and bone marrow leukemic cells and were slightly greater in the cells of responding patients compared to those with resistant disease. We conclude that high-dose ara-C is an effective regimen for CML blast crisis, resulting in a substantial response rate but modest remission duration. Its combination with other agents may further improve the prognosis of patients with this resistant disease.
The Long Drive Ahead to Better Understanding Chronic Traumatic Encephalopathy
Authors: James M. Noble
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Inhibition of human tyrosyl-DNA phosphodiesterase (Tdp1) by neomycin and aminoglycoside antibiotics
Authors: Zhi-Yong Liao, Andrew Jobson, Kurt Kohn, Yves Pommier
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2391 

DNA topoisomerase I (Top1) is the target of camptothecin and novel Top1 inhibitors are in development (Meng et al., Curr Topics Med Chem, 3: 305-320, 2003). Top1 inhibitors induce DNA damage by trapping covalent complexes between the Top1 catalytic tyrosine and the 3’-end of the broken DNA. Recently tyrosyl-DNA phosphodiesterase (Tdp1) was identified as an important enzyme hydrolyzing the tyrosyl-DNA bond thereby generating DNA 3’-phosphate ends. Inhibiting Tdp1 has the potential to enhance the therapeutic effects of Top1 inhibitors (Pommier et al., Mutat Res, 532: 173-203, 2003) ( ). In the present study we report biochemical assays for Tdp1 activity using recombinant Tdp1 enzyme and model substrate oligonucleotides. Neomycin shows stronger inhibition of Tdp1 than its related chemicals paromomycin and lividomycin A. Inhibition of Tdp1 by neomycin is dependent both on the DNA substrate structure and on Tdp1 concentration. Inhibition is stronger with partial duplex DNA than single-stranded DNA substrates. Inhibition by neomycin can be overcome with excess Tdp1. Schiff base assays suggest that neomycin inhibits Tdp1 by interfering with the formation of Tdp1-DNA complexes. To our knowledge, neomycin and aminoglycoside antibiotics are the first Tdp1 inhibitors reported to date. They may be used as leads for further development of Tdp1 inhibitors in combination with Top1 inhibitors.
Abstract 11578: Impact of the Contrast-Induced Nephropathy Definition on Long-term Outcome in Patients With Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Masayoshi Kiyokuni, Masami Kosuge, Toshiaki Ebina, Kiyoshi Hibi, Kengo Tsukahara, Noriaki Iwahashi, Nobuhiko Maejima, Mitsuaki Endo, Yasushi Matsuzawa, Tsutomu Endo, Kazuo Kimura
Journal: Circulation (2012)

Introduction: Contrast-induced nephropathy (CIN) has been shown to be associated with adverse outcomes after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). ...
Secondary platinum therapy in patients with uterine cervical cancer previously treated with platinum chemotherapy
Authors: M. Tanioka, N. Katsumata, T. Hirata, M. Yunokawa, K. Yonemori, T. Kouno, C. Shimizu, K. Tamura, M. Andoh, Y. Fujiwara
Journal: Journal of Clinical Oncology (2009)

5588 Background: Second-line chemotherapy after the front-line platinum based regimens including concurrent chemoradiation (CCRT) has not been established for patients with advanced or recurrent cervical cancer. Platinum based regimens are often selected, but the predictive and prognostic factors of secondary platinum therapy are unclear. We therefore evaluated the relative influence of platinum free interval ( PFI ) between the completion of front-line regimen and the institution of second-line regimen. Methods: This retrospective review was undertaken of 65 patients who received ≥ 2 platinum-based regimens and were assessable for secondary response in National Cancer Center Hospital between 1996 and 2008. We analyzed independent predictive factors associated with secondary response by logistic regression model and prognostic factors associated with subsequent survival by Cox regression model. Results: The median age was 54 years old (range, 28 to 73). The median follow-up of subsequent survival was 11.0 months (1.1 to 66.6). The median PFI was 11.1 months (0.7 to 77.6). Overall secondary response rate was 40%, while response rate for 36 patients after CCRT was 36%. The response increases in frequency with longer PFI ( Table ). Univariate and multivariate analyses using logistic regression model showed PFI for ≥ 9 months (odds ratio [OR] = 0.28; P =.04), PS 0 (OR = 0.19; P =.006) and maximum tumor diameter ≥ 30 mm (OR = 0.23; P =.02) were independent predictive factors of secondary response. Univariate and multivariate analyses using Cox regression model revealed PFI for ≥ 9 months (hazard ratio [HR] = 0.44; P =.005), PS 0 (HR = 0.30; P =.000) and histology of squamous cell carcinoma (HR = 2.20; P =.02) were independent prognostic factors of subsequent survival. Conclusions: Our exploratory study demonstrates that platinum free interval has both predictive and prognostic value for secondary platinum-based treatment for patients with advanced or recurrent cervical cancer. [Table: see text] [Table: see text]
A phase I study of talotrexin (PT-523) in patients with relapsed or refractory non-small cell lung cancer (NSCLC)
Authors: C. S. Rocha Lima, S. V. Orlov, J. Garst, G. M. Manikhas, A. Dowlati, J. A. Quesada, C. Andrews, M. L. Ramirez, G. S. Choy, G. Berk
Journal: Journal of Clinical Oncology (2006)

7142 Background: Talotrexin is a nonpolyglutamatable antifolate which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talotrexin binds more tightly (15-fold, Ki 0.35 pM) to DHFR than methotrexate (MTX). In lung cancer cell lines, talotrexin inhibits tumor cell proliferation at sub- to low nanomolar concentrations and is more potent than MTX in all cell lines tested. We conducted a dose escalation study of talotrexin administered as a 5-minute infusion on Days 1, 8, on a 21-day cycle. The primary objectives of this study are to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) profile, as well as the safety and efficacy. Methods: Patients with confirmed NSCLC stage III/IV or recurrent/refractory disease, failed two-lines of therapy ± an EGFR TK inhibitor, ECOG PS 0–2, were enrolled. The starting dose was based on a Phase I solid tumor trial. Three patients were treated at each dose level in the absence of a dose limiting toxicity (DLT). Intrapatient dose escalation was allowed. All patients received folic acid and vitamin B 12 . Safety assessments were performed by standard laboratory and clinical DLT definitions. Responses were assessed based on RECIST criteria. Plasma talotrexin concentrations were analyzed by a LC/MS/MS method. Concentration-time profiles of talotrexin were analyzed by noncompartmental methods using WinNonlin. Results: Eighteen heavily pre-treated patients were enrolled and received a total of 61 cycles (median 3.4, range 1–7) of talotrexin at 5 dose levels (27–270 mg/m 2 /cycle), Male/Female: 14/4. The tentative MTD is 90 mg/m 2 /dose, with mucositis being the predominate DLT. Two partial responses and 9 stable diseases were observed. Talotrexin exhibits linear PK profile across the 5 dose levels evaluated. PK data (16 patients), C max and AUC 0-∞ exhibited linear PK. Overall mean values (± SD) were CL, 1.31 ± 0.31 L/hr/m 2 , T 1/2z , 6.5 ± 1.4 h, V ss 8.9 ± 2.5 L/m 2 . Conclusions: Talotrexin demonstrated acceptable tolerability with encouraging activity in relapsed or refractory NSCLC patients over multiple cycles of therapy. Phase II studies in NSCLC are planned. [Table: see text]
Liquid Biopsy Based on Circulating Tumour Cells (Ctc) Detection is a Diagnostic and Prognostic Marker in Patients with Pancreatic Solid Tumours
Authors: P. Basile, D. Sefrioui, F. Blanchard, S. Lecleire, F. Clatot, J. Sabourin, P. Michel, F. Di Fiore
Journal: Annals of Oncology (2014)
Hospital admission and readmission for acute exacerbation of COPD. A tough nut to crack
Authors: Michael Steiner
Journal: Thorax (2015)

Reducing acute hospital care for people with long-term conditions has become a key element of health policy as governments strain every sinew to contain the escalating healthcare costs arising from ageing populations. Attention has been drawn to the problem of unscheduled hospitalisation for acute exacerbations of COPD (AECOPD) because it is such a common cause of emergency admission and because there is a high readmission rate following discharge. The latter has driven the perception in many quarters that admissions to hospital should be preventable and, with regards to readmission particularly, may be due to poor quality hospital care. Clinicians are frequently caught in the crossfire of these arguments—under pressure to discharge patients quickly to free up precious hospital bed capacity but also to ensure ‘safe’ discharge to reduce the risk of further presentation. Primary care physicians are experiencing similar pressures to avoid referral to hospital while at the same time providing safe management of the episode in the patient's home.

The impact of an AECOPD on an individual is determined by the composite effects of the severity of the acute event (eg, respiratory infection) and the underlying condition of the patient (the respiratory disease and other factors such as multimorbidity). In making clinical judgements about discharge from hospital clinicians need to also take into account the social and psychological circumstances, particularly the confidence of the patient and their carers that they are ready to leave hospital. It would be fair to say that currently, these judgements are largely subjective and do not routinely incorporate objective measurements of the risk of subsequent readmission to assist in shared decision-making.

Two papers published in this issue of Thorax are relevant to this debate and have the potential to impact on clinical care. Suh et al 1 used parasternal electromyography (EMG) to measure neural …
Serologic Analysis of Nitrosourea-Induced Rat Gliomas&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn4"&gt;4&lt;/xref&gt;
Authors: M Pfreundschuh, H Cravioto, G Hochwald, J Ransohoff
Journal: JNCI Journal of the National Cancer Institute (1982)

Inbred CDF rats (cesarean-delivered F344 rats) were immunized with either a nitrosourea-induced glioma EA-285 or its subline EA-285A and both with and without Corynebacterium parvum. A humoral immune response in syngeneic rats to the immunizing tumor was demonstrated with micromodifications of different rosette assays (immune adherence assay, protein-A assay, and anti-C3-mixed hemadsorption assay). Extensive absorption studies of two immune sera with the highest reactivity revealed two glioma-specific antigens (or two components of one antigen) on the cell surface of the cloned tumor subline. One antigen was present only on the cell surface of the subline of the glioma used for both immunization and absorption analyses. The other antigen appeared on the cell surface of both the cloned subline EA-285A and the parental cell line EA-285. These preliminary studies showed that CDF rats immunized against a syngeneic glioma mounted a humoral immune response that appeared to be individually tumor-specific.
Capecitabine (X) following short-course capecitabine + oxaliplatin (XELOX) in advanced colorectal cancer (CRC): Phase II XelQuali study
Authors: W. Soe, S. Gollins, T. Waddell, J. W. Valle, J. Allen, D. Bentley, J. Morris, A. Lloyd, R. Swindell, M. P. Saunders
Journal: Journal of Clinical Oncology (2008)

15042 Background: Long-term combination therapy is often intolerable in pts with CRC. Short-course chemotherapy, sufficient to downsize potentially operable liver metastases, could be followed by continued single-agent therapy to maintain response and maximise safety, QoL, convenience and costs. Methods: Ambulatory pts (n=45) with previously untreated, advanced, inoperable/metastatic CRC received XELOX (IV oxaliplatin 130mg/m2 d1 + oral X 1,000mg/m2 bid d1–14 q3w) for 4 cycles followed by X 1,250mg/m2 bid d1–14 q3w if at least stable disease (SD, RECIST) was obtained. Pts were treated at 2 UK centres: Christie Hospital, Manchester; North Wales Cancer Treatment Centre, Rhyl. Results: 34 pts received 4 XELOX cycles and 11 pts <4 cycles (mainly due to Aes). Efficacy data are available for 27 pts. Of these, 89% had clinical benefit (SD or better) with XELOX; median PFS and OS in whole population were 6.7 (95% CI 5.7–9.6) and 20.5 (95% CI 12.8–26.3) months, respectively. 33 pts continued with maintenance X, for whom median PFS was 8.2 (95% CI 6.2–12.3) months: 10 of these maintained SD for >3 months, for whom median PFS was 10.6 (95% CI 8.2–12.9) months. Of the 30 pts who received all 4 XELOX cycles followed by X, 11 were rechallenged with XELOX at PD: in these pts median OS was 22.5 (95% CI 14.8–23.5) months from start of trial and 9.9 (95% CI 8.5–13.7) months from restarting XELOX. 4 (8.9%) of the 45 pts enrolled had tumour downsizing, allowing subsequent liver resection. There were no grade 4 Aes (NCI-CTC v.3). Grade 3 Aes during initial XELOX course (n=43): diarrhoea (16%), lethargy (9%), neuropathy (7%), anorexia (5%), and nausea, vomiting, and hand-foot syndrome (each 2%). Grade 3 Aes during maintenance X (n=33): hand-foot syndrome (9%), neuropathy (3%). Grade 3 diarrhoea and neuropathy (1 case each) occurred during XELOX rechallenge (n=10). Conclusions: A short XELOX course followed by maintenance with single-agent X provided a good response rate and survival outcome. Advantages of this schedule include reduced cost, improved safety and convenience to pts and medical/pharmacy personnel. Analysis of QoL data are ongoing and will be presented at the meeting. No significant financial relationships to disclose.
Beyond race: The impact of ethnicity on the treatment outcome of locally advanced head and neck cancer
Authors: C. J. Calfa, M. Escalon, S. Zafar, E. Lopez, V. Patel, S. Patel, L. Feun, L. E. Raez
Journal: Journal of Clinical Oncology (2007)

16500 Background: Self identified racial groups share an unequal burden of head and neck cancer . Recent evidence suggests that outcome among races is different and the causes are multifactorial. Nonetheless, differences among ethnic groups have not been reported. Herein, we decided to analyze differences in treatment response and outcome among our white and Hispanic patient population treated for locally advanced head and neck cancer. Methods: Patients were identified using the tumor registry. We reviewed retrospectively the data from medical records. 100 white Hispanics (WH) and 50 white non-Hispanics (WNH) diagnosed with locally advanced head and neck cancer and treated at our institution from 2004 to 2005, were eligible for the study. Standard statistical analysis, including Kaplan-Meier survival curve and Cox proportional hazard models were used. P value of &lt;0.05 was considered for statistical significance. Results: Preliminary results reveal that, in our study population, median age at diagnosis, gender, performance status (ECOG 0–2) and squamous cell histology did not differ significantly between the two groups. Stage 4 at diagnosis was more commonly observed in Hispanics as opposed to WNH (85.7% vs 68.6%) (P = 0.1). Surgery was more commonly used as an initial treatment option in Hispanics than WNH (42.8% vs 28.6%) (P = 0.18) while chemotherapy was less likely to be used (78.6% vs. 91.4%) (P = 0.15). Hispanics were more likely to smoke than WNH (P = 0.0003) and were equally exposed to chronic alcohol use. Patients from the Hispanic group were more likely to respond to therapy than whites by Chi-squared analysis but this difference was not statistically significant (P = 0.09). No differences were seen in disease free survival. Kaplan-Meier estimate of median overall survival was 16 months for Hispanics vs. 25 months for whites but this difference did not reach statistical significance (P = 0.26). Final analysis will be available at the time of the annual meeting. Conclusion: In our experience, a trend for decrease overall survival was noted in the Hispanic ethnic group. This may be in part due to more advanced stage at presentation. Nonetheless, in order to definitively answer this question, further research is warranted. No significant financial relationships to disclose.
Abstract P370: Healthcare utilization in older adults with chronic heart failure and elevated depressive symptoms: Cardiovascular Health Study
Authors: Mercedes R Carnethon, Joseph A Delaney, Norrina B Allen, Clyde Yancy, Calvin Hirsch, Lesley Curtis
Journal: Circulation (2014)

Background: Elevated depressive symptoms (EDS) are common in adults with heart failure (HF) and their joint prevalence is associated with worse short- (1 year) and long-term health outcomes. The contribution of EDS to healthcare costs and utilization in a contemporary population of older adults with HF is unknown. Hypothesis: Adults with HF who report EDS will have higher annual healthcare costs and use more resources than their counterparts without EDS. Methods: Participants from the Cardiovascular Health Study who developed HF between baseline and the 11-year follow up and whose data were linked to Medicare Part A and Part B claims were included in the analysis (n=441). HF was adjudicated based on review of medical records and physician questionnaires. EDS was determined if participants scored ≥8 on the abbreviated Centers for Epidemiologic Studies Depression scale. Medicare payments were adjusted using the Medical Consumer Price Index and represented in 2009 dollars. Annual healthcare utilization (i.e., total provider visits, inpatient and outpatient visits) is based on Part B. Linear regression with robust variance estimation was used to determine the relationship of EDS with medical costs or provider counts adjusted for confounders. Results: Participants were 75.9 years old (SD= 5.3), 55% female, 15% black, and 147 (33%) had EDS. Within 2 years, 19% of patients with EDS died vs. 14% in those without EDS. Differences in annual costs between participants with and without EDS were not statistically significant. However, participants with EDS had more provider visits than their counterparts (Table). Conclusion: Despite adults with HF and EDS using more healthcare resources than those without EDS, expenditures did not differ. Higher short-term mortality in adults with EDS could be an explanation.