tbuckley/cabot-search huggingface dataset:
A retrospective study evaluating treatment patterns and outcomes in patients receiving trastuzumab for treatment of first-line and second-line metastatic breast cancer (mBC)
Authors: D. Lalla, G. Hess, D. Quach, M. Brammer, J. W. Hill
Journal: Journal of Clinical Oncology (2009)

e12008 Background: Practice patterns for patients with MBC following 1 st line therapy have often continued trastuzumab treatments while changing other chemotherapeutic agents in the regimen. We described treatment patterns, switching patterns and progression in mBC patients treated with a trastuzumab containing regimen for 1 st and second line mBC. Methods: A retrospective, longitudinal, observational study of patients with mBC during 1/1/2003 up to 6/30/2008. The dataset comprised 304,654 cancer patients from 91practice sites across 23 states using Varian or Impac electronic medical records (EMRs). The start and end of a line of therapy was defined by a regimen change or a &gt; 42 day gap in the regimen. In addition to the database analyses, a manual chart review was also conducted for 20% of the study sample to validate the source data and results. Patients were required to be observed for ≥ 9 months from index. Mean, median, standard deviation, and standard error for the duration in days by line and regimen was calculated as well as an overall weighted mean by line. Results: The study sample of 239 patients post-mBC was treated with the following regimens in the Table. Conclusion: Trastuzumab is most frequently given with taxanes in the first and second line settings. In the second line trastuzumab monotherapy, vinorelbine and gemcitabine were also frequently used. First line therapy may influence the selection of second line therapy. As EMRs often reflect care primarily at the practice site, prescribing of oral agents should be further researched. [Table: see text] [Table: see text]
Effect of 3-Methylcholanthrene and Fission Neutron Irradiation, Given Singly or Combined, on Rat Mammary Carcinogenesis
Authors: Claire J. Shellabarger, Rita F. Straub
Journal: JNCI Journal of the National Cancer Institute (1972)

Female Sprague-Dawley rats were given a single, intragastric dose of 40 mg 3-methylcholanthrene on the 42d day of age, or 100 rads of total-body fission neutron radiation on the 52d day, or both, or the sequence of administration of the 2 carcinogenic agents was reversed. When the percentage of rats with mammary adenocarcinoma and the total number of mammary adenocarcinomas were determined at 142 days of age, the 2 carcinogens appeared to produce an additive effect.
Compromised redox homeostasis, altered nitroso–redox balance, and therapeutic possibilities in atrial fibrillation
Authors: Jillian N. Simon, Klemen Ziberna, Barbara Casadei
Journal: Cardiovascular Research (2016)

Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso–redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF.
The effect of socioeconomic status on the survival of ovarian cancer patients
Authors: V. E. Sugiyama, J. Y. Shin, D. S. Kapp, K. Osann, R. D. Cress, G. S. Leiserowitz, C. D. O'Malley, J. K. Chan
Journal: Journal of Clinical Oncology (2008)

5557 Background: To determine the influence of socioeconomic factors on the presentation, treatment, and survival of women diagnosed with epithelial ovarian cancer. Methods: Data were obtained from California Cancer Registry from 1994 to 1996. Census- based socioeconomic (SES) measures were assigned to each patient by linking the patient's address at the time of diagnosis with the census block group SES characteristics. Chemotherapy data were supplemented with data from a physician survey and medical record review. Pearson's Chi-square test was used to evaluate associations between factors and risk of death. Kaplan-Meier and Cox proportional hazard methods were used for analyses. Results: Of 1,491 patients, the median age was 65 years (range: 13–100 years). The 1,172 (78.6%) women were White, 128 (8.6%) Hispanic, 111 (7.4%) Asian, and 67 (4.5%) were Black. 705 (47.3%) patients were classified as poor compared to 786 (52.7%) classified as not poor. 380 (25.5%) were less educated vs. 1,111 (74.5%) who were educated. 558 (37.4%) were blue- collar compared to 933 (62.6%) white-collar workers. Poorer women were more likely to be classified as less educated (47.8% vs. 5.5%; p<0.001), were more likely to be employed as blue collar employees (60.3% vs. 16.9%; p<0.001), and more likely to live in rural regions (26.2% vs. 10.6%; p<0.001). Poorer women were also less likely to receive primary surgery (19.6% vs. 24.8%; p=0.015), and were less likely to receive chemotherapy (21.8% vs. 24.7%; p=0.181). However, there were no differences between the two socioeconomic classes with regards to stage at presentation, histologic cell type, grade of disease, and overall survival. The overall survival of patients was 33.1% vs. 33.2% in the poor vs. non-poor groups (p=0.419). On multivariate analysis younger age, earlier stage, earlier grade, chemotherapy, and primary surgery were important independent prognostic factors for survival. Conclusions: Our data suggests that patients in lower socioeconomic class were less likely to receive chemotherapy and primary surgery; however, socioeconomic class was not an independent prognostic factor for survival in ovarian cancer. No significant financial relationships to disclose.
Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma.
Authors: S A Grossman, M Wharam, V Sheidler, L Kleinberg, M Zeltzman, N Yue, S Piantadosi
Journal: Journal of Clinical Oncology (1997)

PURPOSE To evaluate the activity and toxicity of carmustine (BCNU) and cisplatin administered as a 72-hour continuous intravenous infusion before radiation in adults with newly diagnosed high-grade astrocytomas. PATIENTS AND METHODS Fifty-two patients with a Karnofsky performance status greater than 60 and no prior antineoplastic therapy entered this protocol. The median age of the patients was 55 years. Eighty-eight percent had glioblastoma multiforme and 12% had anaplastic astrocytomas. BCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) were administered concurrently as a 72-hour infusion every 3 to 4 weeks. Radiation was begun 4 weeks after the third cycle of chemotherapy or earlier for progressive disease. Responses required a &gt; or = 50% reduction in contrast-enhancing volume. RESULTS Forty patients (77%) completed three chemotherapy infusions, five (10%) received two infusions, and seven (13%) received only one. Fifty-one patients completed radiation. Seventeen (42%) patients with measurable disease had a partial response (PR) to chemotherapy, 23 (53%) had stable disease (SD), and two (4%) had progressive disease (PD) on chemotherapy. The median survival time for all patients was 13 months. Survival rates at 1, 2, 3, and 5 years were 62%, 19%, 12%, and 5%, respectively. Grade III to IV leukopenia occurred in 32% of patients; 63% received platelet transfusions and 58% required RBCs. Neutropenic fevers were rare and no intracranial hemorrhages or treatment-related deaths were noted. Nausea, vomiting, peripheral neuropathy, hearing loss, and thromboembolic events were relatively common. CONCLUSION This chemotherapy regimen appears to have significant activity and may prolong survival in adults with newly diagnosed high-grade astrocytoma.
Pharmacokinetics and pharmacodynamics of newer fluoroquinolones in patients with lower respiratory tract infections
Authors: Paschalina Kontou, Kalliopi Chatzika, Katerina Manika, Georgia Pitsiou, Maria Sionidou, Ioannis Kioumis
Journal: European Respiratory Journal (2012)

Introduction:  Levofloxacin (LVF) and moxifloxacin (MXF), have been recommended as first line therapy for patients with acute exacerbations of chronic bronchitis and community-acquired pneumonia.   Aim:  The aim of this study is to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of LVF and MXF for lower respiratory tract infections (LRTI).   Methods:  Eighteen patients (2 groups of 9, aged 69.6±8.7 and 74±8.8) with LTRI received 500 mg LVF IV q12h or 400 mg MXF IV q24h. Serial blood samples were obtained at steady state condition (3rd day of therapy). Plasma concentrations were determined by a validated HPLC method. The PD target was evaluated for both antibiotics based on our hospital9s MIC 90  of the most common respiratory pathogens.   Results:  The PK data are presented in Table 1.  Both antibiotics exhibited large volumes of distribution (Vss). They achieved the PD target in all patients against the majority of strains of the commonest respiratory pathogens in our hospital, as shown in table 2.   Conclusions:  LVF and MXF exhibit a favorable PK profile in patients with LRTI. There is adequate PD exposure against most strains of  S. pneumoniae, H. influenzae  and  M. catarrhalis  with low MICs.
Abstract 279: Loss Of Rad GTPase Produces A Sympathomimetic Cardiac Phenotype Leading To Calcium Overload And Arrhythmia.
Authors: Janet R Manning, Guo Yin, John Penn, Catherine Kaminski, Gail Sievert, Jonathan Satin, Douglas A Andres
Journal: Circulation Research (2013)

Background: Rad is a small GTPase that regulates inward calcium current in excitable cells. In human heart failure, calcium dysregulation is accompanied by lowered levels of Rad expression, and dampened responsiveness to beta-adrenergic stimulation. However, the effects of Rad ablation on calcium cycling in the heart have yet to be examined. Hypothesis: Loss of Rad emulates beta-adrenergic stimulation in cardiac myocytes, elevating calcium levels, and promoting after depolarizations. Methods: The role of Rad was evaluated using knockout mice (RadKO)at several levels of biological organization. Inward calcium current, action potentials, fractional shortening, and calcium transients were measured in isolated ventricular myocytes. Functional parameters were recorded in the isolated working heart, and telemetry was used to monitor ECGs in intact freely-roaming mice. Results: Isolated ventricular myoctyes from Rad null mice display increased ICaL density, greater inward current at low voltages, and after depolarizations at low frequencies. Isolated cells exhibit increased diastolic calcium levels and increased dynamic calcium changes in transient amplitude during pacing. Further, RadKO cardiomyocytes develop a significantly greater number of spontaneous calcium transients than wildtype cohorts. Ventricular myocytes and intact working hearts from RadKO mice fail to respond to beta-adrenergic stimulation at the level of channel activation, calcium transient kinetics, and exhibit a significantly dampened change in +dP/dt in the isolated heart. Consistent with these effects, PKA substrates are phosphorylated at baseline in RadKO cardiomyocytes, suggesting tonic PKA activation. Conclusion: These data suggest the new provocative hypothesis that beta-adrenergic-mediated changes in excitation, calcium handling, and heart contraction involve relief of Rad-dependent negative regulation of channel function.
Abstract 111: High Activity Gating of Caveolae-Targeted L-Type Ca <sup>2+</sup> Channels Can Initiate Pathological Hypertrophy
Authors: Catherine A Makarewich, Robert N Correll, Hongyu Zhang, Hui Gao, Baohua Yang, Remus M Berretta, Victor Rizzo, Jeffery D Molkentin, Steven R Houser
Journal: Circulation Research (2012)

Introduction: The source of Ca 2+ that activates pathological cardiac hypertrophy is not clearly defined. We hypothesize that high activity gating of L-type Ca 2+ channels (LTCCs) localized in caveolae signaling microdomains stabilized by caveolin-3 (Cav-3) provides the Ca 2+ influx that locally activates calcineurin (Cn)-mediated nuclear factor of activated T-cells (NFAT) to induce hypertrophic gene expression. We generated novel reagents that specifically activate or inhibit the gating of LTCCs in caveolae for analysis of the hypertrophic program, as well as any potential effect on ICa and contraction. Methods and Results: We targeted the known LTCC inhibitory protein Rem or an LTCC subunit (β2a) that promotes high activity gating specifically to caveolae by fusing them to a caveolin-binding domain peptide (termed Cav-Rem and Cav-β2a). We infected adult feline left ventricular myocytes (AFLVMs) with adenoviruses containing Cav-Rem or Cav-β2a for membrane localization and functional studies. NFAT nuclear translocation was determined by co-infecting AFLVMs with ad-NFAT-GFP and either ad-Cav-Rem or ad-Cav-β2a and pacing cells to induce Ca2+ influx mediated nuclear NFAT-GFP translocation. Membrane fractionation experiments showed that Cav-3 membrane domains contain 26.2 +/- 12.7% of membrane targeted LTCCs and blocking these with Cav-Rem eliminated a small fraction of the LTCC current (&lt;15%) and almost all Ca2+ influx induced NFAT nuclear translocation (&gt;90%), but did not reduce myocyte contractility. Conversely, selective enhancement of LTCC activity within caveolae with Cav-β2a caused a significant increase in NFAT nuclear translocation (&gt;70%) but had no significant effect on contractility. Conclusions: We provide proof of concept that specific Cav-targeted reagents can be used to enhance or inhibit LTCC activity within caveolae microdomains to amplify or block the hypertrophic response. Our results suggest that high activity gating of LTCCs, which is known to be present in the hypertrophied failing human heart, can activate signaling pathways linked to cardiac hypertrophy. Selectively inhibiting these caveolae localized LTCCs could be a novel mechanism to block pathological hypertrophy without reducing cardiac contractility.
Proeasome inhibition with bortezomib (PS-341) in combination with docetaxel (Doc) in prostate cancer (CaP) cells and xenografts
Authors: N. C. Farneth, W. S. Holland, T. Kenosi, T. Kimura, P. N. Lara, D. R. Gandara, P. H. Gumerlock
Journal: Journal of Clinical Oncology (2005)

3192 Background: Doc is an effective chemotherapeutic agent for CaP. It stabilizes the β-subunit of tubulin, phosphorylates and inactivates the anti-apoptotic protein Bcl-2, and stabilizes the tumor suppressor protein p27 resulting in cell cycle arrest at M-phase and apoptosis. PS-341 is an inhibitor of the proteasome, which is necessary for the degradation of cellular proteins. By preventing degradation of proteins such as p27 or p53, PS-341 causes G1 and G2 cell cycle arrest. Because PS-341 inhibits cell cycling, it may be antagonistic to or limit the activity of taxanes, which show their greatest activity in M-phase. Our previous work with Doc plus erlotinib showed that intermittent delivery was more effective than either drug alone or given concurrently. We hypothesized that the combination of Doc and PS-341 would show similar sequence dependence to achieve the greatest cell kill. Methods: Flow cytometric analysis of DNA content was done to estimate the proportion of PC3 (p53 null) or LNCaP (p53 wild-type) cells in each cell cycle phase as well as sub-G1. Western blot analysis was used to evaluate protein levels. Results: In PC3 cells, as single agents Doc was more effective than PS-341 (sub-G1: 21.8% and 7.3%, respectively). In combination, the sequence of Doc→PS-341 (sub-G1: 47.4%) was more effective than either PS-341→Doc (sub-G1: 25.7%) or PS-341 + Doc (sub-G1: 6.3%). In LNCaP cells, there was little difference between Doc and PS-341 as single agents (sub-G1: 18.8% and 14.7%, respectively). However, Doc + PS-341 (sub-G1: 39.3%) given concurrently was more effective than either PS→Doc or Doc→PS (sub-G1: 14.7 and 14.4%). p27 was shown to be up-regulated in all treatment groups, as expected. Initial PC3 xenograft studies showed slightly greater inhibition of tumor growth in combination treatments versus single agents. Conclusions: LNCaP (p53 wild-type) cells showed greater sensitivity to PS-341, particularly when given concurrently with Doc, than PC3 (p53 null) cells. These data support further studies into the role of p53, cell cycle arrest, and sequencing of treatment with PS-341 and Doc in CaP. (U01-CA-62505, N01-CM-17101, ACS-CRTG-0019701-CCE) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Millenium Aventis, Millenium
종설 : 간경변과 간세포암종의 중증도에 따른 예후 판정에 관한 새로운 평점분류: Child-Turcotte-Pugh 평점과 Model of End-Stage Liver Disease (MELD) 평점을 중심으로 한 최근 논란
Authors: 이동후 ( Lee Dong Hu ), 손주현 ( Son Ju Hyeon ), 김태화 ( Kim Tae Hwa )
Journal: Clinical and Molecular Hepatology (2003)

It has been approximately 30 years since Child-Turcotte-Pugh score has been used in patients with liver cirrhosis and hepatocellular carcinoma (HCC). Recently, new prognostic models such as Model for End-Stage Liver disease (MELD), Short- and Long-term Prognostic Indices (STPI and LTPI), Rockall score, and Emory score were proposed for predicting survival in patients with liver cirrhosis treated by transjugular intrahepatic portosystemic shunt (TIPS). In MELD scoring, three independent variables which showed a wide range of results including serum creatinine, serum bilirubin and international normalization ratio(INR) of prothrombin time were evaluated in log. scale in comparison with simply categorized-into-three scoring system of Child-Turcotte-Pugh. The etiology of liver cirrhosis was applied to the score of MELD: alcoholic or cholestatic, 0; viral or others, 1. Concurrent statistic (C-statistic) of MELD (0.73-0.84) was slightly superior or insignificantly different to that (0.67-0.809) of Child-Turcotte-Pugh score. In February 2002, UNOS status 2a and 2b were replaced with MELD score for priority allocation of liver transplantation. (MELD score does not reflect the severity of patients with HCC or metabolic disorders. For assessing prognosis in patients with liver cirrhosis or HCC, there seems little reason to replace the well established Child- Turcotte-Pugh score, Herein the literatures was briefly reviewed(Korean J Hepatol 2003;9:167-179)
Recent Advances in Cardiac β <sub>2</sub> -Adrenergic Signal Transduction
Authors: Rui-Ping Xiao, Heping Cheng, Ying-Ying Zhou, Meike Kuschel, Edward G. Lakatta
Journal: Circulation Research (1999)

Recent studies have added complexities to the conceptual framework of cardiac beta-adrenergic receptor (beta-AR) signal transduction. Whereas the classical linear G(s)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade has been corroborated for beta(1)-AR stimulation, the beta(2)-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G(s), beta(2)-AR couples to pertussis toxin-sensitive G(i) proteins, G(i2) and G(i3). The coupling of beta(2)-AR to G(i) proteins mediates, to a large extent, the differential actions of the beta-AR subtypes on cardiac Ca(2+) handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of G(i) coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in beta(2)-AR-mediated cardiac responses. There is an apparent dissociation of beta(2)-AR-induced augmentations of the intracellular Ca(2+) (Ca(i)) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G(i)-dependent functional compartmentalization of the beta(2)-AR-directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during beta-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these beta-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of beta-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of beta-AR subtypes in healthy and diseased hearts.
Clinical significance of serum epidermal growth factor receptor, vascular endothelial growth factor and soluble interleukin-6 in advanced melanoma patients
Authors: R. Mouawad, O. Rixe, G. Auclerc, D. Khayat, C. Soubrane
Journal: Journal of Clinical Oncology (2004)

7551 Background and aims: Circulating vascular endothelial growth factor (VEGF), soluble EGFR and soluble interleukin-6 (IL-6) are associated with metastatic malignant melanoma disease. However, their relationship remains unclear. The aims of this study is to correlate serum IL-6 to sVEGF-A, or EGFR levels and to investigate the clinical significance of these parameters on the overall survival in metastatic malignant melanoma. Methods and Patients: using a sensitive enzyme-linked immunosorbent assays, VEGF-A, EGFR and IL-6 were measured in sera of 64 patients with a fully documented history of metastatic malignant melanoma patients in comparison with 30 healthy controls. Results: serum levels of VEGF-A, EGFR, and IL-6 were significantly increased in melanoma patients compared with healthy controls (p<0.0001). Elevated serum concentrations of VEGF, and IL-6 but not EGFR were associated with tumor burden. There was a negative correlation between IL-6 levels and soluble EGFR (r=-0.33 p=0.040) and a positive correlation (r = 0.248, P = 0.045) between VEGF-A and IL-6 levels. As shown by univariate analysis, only elevated levels of serum IL-6 was significantly correlated to a shorter survival (Chi-square=5.84, p= 0.009), but not sVEGF-A (Chi-square=2.44, P= 0.11 ) or circulating EGFR (Chi Square = 0.01, p= 0.976). Furthermore, using a multivariate analysis (Cox test), tumor burden (p = 0.0051), LDH level (p = 0.006) and IL-6 (p = 0.004) were identified as independent prognostic variables for overall survival but not sVEGF or EGFR. Conclusions: despite the correlations observed between circulating IL-6 and sVEGF-A or EGFR levels, our results indicate that, in patients with metastatic malignant melanoma, only serum IL-6 level is a predictive factor of overall survival but not sVEGF and circulating EGFR . No significant financial relationships to disclose.