tbuckley/cabot-search huggingface dataset:
Metastasis After Radical Prostatectomy or External Beam Radiotherapy for Patients With Clinically Localized Prostate Cancer: A Comparison of Clinical Cohorts Adjusted for Case Mix
Authors: Michael J. Zelefsky, James A. Eastham, Angel M. Cronin, Zvi Fuks, Zhigang Zhang, Yoshiya Yamada, Andrew Vickers, Peter T. Scardino
Journal: Journal of Clinical Oncology (2010)

Purpose We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center. Patients and Methods Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (≥ 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment. Results The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P &lt; .001). Results were similar for prostate cancer–specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression). Conclusion Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer–specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.
Epoxyeicosatrienoic Acid Activates BK Channels in the Cortical Collecting Duct
Authors: Peng Sun, Wen Liu, Dao-Hong Lin, Peng Yue, Rowena Kemp, Lisa M. Satlin, Wen-Hui Wang
Journal: Journal of the American Society of Nephrology (2008)

The cortical collecting duct (CCD), which is involved in renal potassium (K) excretion, expresses cytochrome P450 (CYP)-epoxygenase. Here, we examined the effect of high dietary K on renal expression of CYP2C23 and CYP2J2 in the rat, as well as the role of CYP-epoxygenase-dependent metabolism of arachidonic acid in the regulation of Ca(2+)-activated big-conductance K (BK) channels. By Western blot analysis, high dietary K stimulated the expression of CYP2C23 but not CYP2J2 and increased 11,12-epoxyeicosatrienoic acid (11,12-EET) levels in isolated rat CCD tubules. Application of arachidonic acid increased BK channel activity, and this occurred to a greater extent in rats on a high-K diet compared with a normal-K diet. This effect was unlikely due to arachidonic acid-induced changes in membrane fluidity, because 11,14,17-eicosatrienoic acid did not alter BK channel activity. Inhibiting CYP-epoxygenase but not cyclooxygenase- or CYP-omega-hydroxylase-dependent pathways completely abolished the stimulatory effect of arachidonic acid on BK channel activity. In addition, application of 11,12-EET mimicked the effect of arachidonic acid on BK channel activity, even in the presence of CYP-epoxygenase inhibition. This effect seemed specific to 11,12-EET, because both 8,9- and 14,15-EET failed to stimulate BK channels. Finally, inhibition of CYP-epoxygenase abolished iberiotoxin-sensitive and flow-stimulated but not basal net K secretion in isolated microperfused CCD. In conclusion, high dietary K stimulates the renal CYP-epoxygenase pathway, which plays an important role in activating BK channels and flow-stimulated K secretion in the CCD.
Inflammation and Cognitive Dysfunction in Type 2 Diabetic Carotid Endarterectomy Patients
Authors: Eric J. Heyer, Joanna L. Mergeche, Samuel S. Bruce, E. Sander Connolly
Journal: Diabetes Care (2013)

OBJECTIVE Type 2 diabetic patients have a high incidence of cerebrovascular disease, elevated inflammation, and high risk of developing cognitive dysfunction following carotid endarterectomy (CEA). To elucidate the relationship between inflammation and the risk of cognitive dysfunction in type 2 diabetic patients, we aim to determine whether elevated levels of systemic inflammatory markers are associated with cognitive dysfunction 1 day after CEA. RESEARCH DESIGN AND METHODS One hundred fifteen type 2 diabetic CEA patients and 156 reference surgical patients were recruited with written informed consent in this single-center cohort study. All patients were evaluated with an extensive battery of neuropsychometric tests. Preoperative monocyte counts, HbA1c, C-reactive protein (CRP), intercellular adhesion molecule 1, and matrix metalloproteinase 9 activity levels were obtained. RESULTS In a multivariate logistic regression model constructed to identify predictors of cognitive dysfunction in type 2 diabetic CEA patients, each unit of monocyte counts (odds ratio [OR] 1.76 [95% CI 1.17–2.93]; P = 0.005) and CRP (OR 1.17 [1.10–1.29]; P &amp;lt; 0.001) was significantly associated with higher odds of developing cognitive dysfunction 1 day after CEA in type 2 diabetic patients. CONCLUSIONS Type 2 diabetic patients with elevated levels of preoperative systemic inflammatory markers exhibit more cognitive dysfunction 1 day after CEA. These observations have implications for the preoperative medical management of this high-risk group of surgical patients undergoing carotid revascularization with CEA.
Gemcitabine Plus Docetaxel Versus Docetaxel in Patients With Predominantly Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer: A Randomized, Phase III Study by the Danish Breast Cancer Cooperative Group
Authors: Dorte L. Nielsen, Karsten D. Bjerre, Erik H. Jakobsen, Søren Cold, Lars Stenbygaard, Peter G. Sørensen, Claus Kamby, Susanne Møller, Charlotte L.T. Jørgensen, Michael Andersson
Journal: Journal of Clinical Oncology (2011)

The objective of this phase III study was to compare the efficacy of gemcitabine plus docetaxel (GD) versus docetaxel in patients with advanced breast cancer.Predominantly human epidermal growth factor receptor 2 (HER2) -negative patients were randomly assigned to gemcitabine (1,000 mg/m(2)) on days 1 and 8 plus docetaxel (75 mg/m(2)) on day 8 or to docetaxel (100 mg/m(2)) on day 1, every 21 days. Patients were untreated or had prior (neo)adjuvant chemotherapy or a single anthracycline-based chemotherapy regimen for metastatic breast cancer. The primary end point was time to progression (TTP), and secondary end points were overall survival (OS), response rate (RR), and toxicity.A total of 170 patients were allocated to GD, and 167 were allocated to docetaxel. Median TTP on GD was 10.3 months versus 8.3 months on docetaxel (hazard ratio [HR], 0.77; 95% CI, 0.59 to 1.01; log-rank P = .06). The adjusted Cox proportional model for TTP showed a significant difference favoring the combination (HR, 0.68; 95% CI, 0.51 to 0.90; P = .007). However, RR was similar (GD, 36%; docetaxel, 34%), and OS was not different (P = .57). Grades 3 to 4 neutropenia was common (GD, 75%; docetaxel, 69%); infection was reported in 26% and 21% of patients in the GD and docetaxel groups, respectively. Grades 3 to 4 thrombocytopenia was more frequent with GD (GD, 16%; docetaxel, 0.6%), and peripheral neuropathy was higher with docetaxel (GD, 5%; docetaxel, 16%).GD compared with docetaxel demonstrated increased TTP in metastatic breast cancer. However, RR and OS were similar. Thus, the addition of gemcitabine failed to demonstrate any clinically meaningful benefit when combined with docetaxel.
Phase II Study of Consolidation Paclitaxel After Concurrent Chemoradiation in Poor-Risk Stage III Non–Small-Cell Lung Cancer: SWOG S9712
Authors: Angela M. Davies, Kari Chansky, Derick H.M. Lau, Bryan R. Leigh, Laurie E. Gaspar, Geoffrey R. Weiss, Antoinette J. Wozniak, John J. Crowley, David R. Gandara
Journal: Journal of Clinical Oncology (2006)

A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non-small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort.Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21 days for three cycles.Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%.Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.
Interleukin 10 protects mice from lethal endotoxemia.
Authors: M Howard, T Muchamuel, S Andrade, S Menon
Journal: The Journal of Experimental Medicine (1993)

Interleukin 10 (IL-10) decreases production of IL-1, IL-6, and tumor necrosis factor alpha (TNF-alpha) in vitro, and neutralization of IL-10 in mice leads to elevation of the same monokines. We test here whether this monokine-suppressing property of IL-10 confers on it the capacity to protect mice from lipopolysaccharide-induced shock, a monokine-mediated inflammatory reaction. A single injection of 0.5-1 microgram of recombinant murine IL-10 reproducibly protected BALB/c mice from a lethal intraperitoneal injection of endotoxin. This result was obtained whether the IL-10 was administered concurrently with, or 30 min after the injection of endotoxin. The protective effect of IL-10 was reversed by prior injection of neutralizing anti-IL-10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-alpha release. These data implicate IL-10 as a candidate for treatment of bacterial sepsis, and more generally as an effective antiinflammatory reagent.
Three Considerations Before Advising 5-α-Reductase Inhibitors for Chemoprevention
Authors: Patrick C. Walsh
Journal: Journal of Clinical Oncology (2009)

siderations that strongly influence the decision about the use of 5--reductase inhibitors (5-ARIs) for the chemoprevention of prostate cancer. First, 5-ARIs do not prevent prostate cancer, they just prevent men from undergoing diagnostic biopsies. Because 5-ARIs reduce prostate-specific antigen (PSA) levels by at least 50%, patients and their physicians can be lulled into a false sense of security. In the first sevenyearsoftheProstateCancerPreventionTrial(PCPT),although 25% fewer men on finasteride were diagnosed with prostate cancer, this occurred largely because 15% fewer men underwent a diagnostic biopsy.Inthemenonfinasteridewhoactuallyunderwentabiopsy,the risk of a positive biopsy was reduced by only 10% (biopsies were positive in 26.5% of men on finasteride and in 29.5% of men on placebo; a 3% absolute difference which was not statistically significant [95% CI, 0.81 to 1.0]). 2 Thus,finasteride will have no significant effect on reducing the risk of cancer in men who are followed closely and undergo a biopsy because of an elevated PSA or abnormal digital rectal examination, which is the exact setting where it would be used for prevention. For the patient who watched his father die from pros
Attenuation of nocturnal asthma by cromakalim
Authors: A.J. Williams, T.H. Lee, T. Vyse, F. Chiew, G.M. Cochrane, A.J. Williams, E. Lavender, D.H. Richards, A. Hopkirk, S. Owen, P. Stone, S. Church, A.A. Woodcock
Journal: The Lancet (1990)
Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting
Authors: Quyen Dao, Padma Krishnaswamy, Radmila Kazanegra, Alex Harrison, Rambod Amirnovin, Leslie Lenert, Paul Clopton, Joel Alberto, Patricia Hlavin, Alan S Maisel
Journal: Journal of the American College of Cardiology (2001)
Effect of the Antidepressant Venlafaxine in Functional Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: L VANKERKHOVEN, R LAHEIJ, N APARICIO, W DEBOER, S VANDENHAZEL, A TAN, B WITTEMAN, J JANSEN
Journal: Clinical Gastroenterology and Hepatology (2008)
Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia
Authors: Bob Löwenberg, Gareth Morgan, Gert J. Ossenkoppele, Alan K. Burnett, Pierre Zachée, Ulrich Dührsen, Daan Dierickx, Carsten Müller-Tidow, Pieter Sonneveld, Utz Krug, Elisabeth Bone, Nicolas Flores, Alison F. Richardson, Leon Hooftman, Chris Jenkins, Sonja Zweegman, Faith Davies
Journal: Journal of Clinical Oncology (2010)

To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor.In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome.In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML.This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.
Efficacy and Safety of Rosuvastatin Therapy for Children With Familial Hypercholesterolemia
Authors: Hans J. Avis, Barbara A. Hutten, Claude Gagné, Gisle Langslet, Brian W. McCrindle, Albert Wiegman, Judith Hsia, John J.P. Kastelein, Evan A. Stein
Journal: Journal of the American College of Cardiology (2010)
Functionally distinct NKT cell subsets and subtypes
Authors: Ken-ichiro Seino, Masaru Taniguchi
Journal: The Journal of Experimental Medicine (2005)

Natural killer T (NKT) cells are a population of autoreactive cells that mediate both protective and regulatory immune functions. NKT cells comprise several subsets of cells, but it has been unclear whether these different NKT cell subsets possess distinct functions in vivo. New studies now demonstrate that subsets of NKT cells are indeed functionally distinct and that the specific functions of these cells may be dictated in part by organ-specific mechanisms.
If Mammalian Target of Metformin Indirectly Is Mammalian Target of Rapamycin, Then the Insulin-Like Growth Factor-1 Receptor Axis Will Audit the Efficacy of Metformin in Cancer Clinical Trials
Authors: Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Sonia Del Barco, Begoña Martin-Castillo, Javier A. Menendez
Journal: Journal of Clinical Oncology (2009)
The role of glucocorticoid receptor phosphorylation in Mcl-1 and NOXA gene expression
Authors: James T Lynch, Ramkumar Rajendran, Georgia Xenaki, Ilhem Berrou, Constantinos Demonacos, Marija Krstic-Demonacos
Journal: Molecular Cancer (2010)

Abstract Background The cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) mediated phosphorylation of glucocorticoid receptor (GR) exerts opposite effects on GR transcriptional activity and affects other posttranslational modifications within this protein. The major phosphorylation site of human GR targeted by MAPK family is the serine 226 and multiple kinase complexes phosphorylate receptor at the serine 211 residue. We hypothesize that GR posttranslational modifications are involved in the determination of the cellular fate in human lymphoblastic leukemia cells. We investigated whether UV signalling through alternative GR phosphorylation determined the cell type specificity of glucocorticoids (GCs) mediated apoptosis. Results We have identified putative Glucocorticoid Response Elements (GREs) within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 indicating that they are direct GR transcriptional targets. These genes were differentially regulated in CEM-C7-14, CEM-C1-15 and A549 cells by glucocorticoids and JNK pathway. In addition, our results revealed that the S211 phosphorylation was dominant in CEM-C7-14, whereas the opposite was the case in CEM-C1-15 where prevalence of S226 GR phosphorylation was observed. Furthermore, multiple GR isoforms with cell line specific patterns were identified in CEM-C7-14 cells compared to CEM-C1-15 and A549 cell lines with the same antibodies. Conclusions GR phosphorylation status kinetics, and site specificity as well as isoform variability differ in CEM-C7-14, CEM-C1-15, and A549 cells. The positive or negative response to GCs induced apoptosis in these cell lines is a consequence of the variable equilibrium of NOXA and Mcl-1 gene expression potentially mediated by alternatively phosphorylated GR, as well as the balance of MAPK/CDK pathways controlling GR phosphorylation pattern. Our results provide molecular base and valuable knowledge for improving the GC based therapies of leukaemia.
Analysis of Left Ventricular Wall Motion by Reflected Ultrasound
Authors: IAN G. MCDONALD, HARVEY FEIGENBAUM, SONIA CHANG
Journal: Circulation (1972)

Ultrasound echocardiograms from the septal and posterior left ventricular walls were displayed with a simultaneously recorded electrocardiogram, phonocardiogram, and indirect carotid pulse. These echoes differed in both amplitude and waveform. The contour of the posterior wall echo resembled an inverted ventricular volume curve, while the septal echo was of smaller amplitude and had a characteristic notched appearance. Most of the movement of the left ventricular walls relative to the ultrasound transducer was attributable to systolic contraction and diastolic expansion of the cavity. However, superimposed on this motion due to change in cavity size was movement of the left ventricle as a whole, first anteriorly toward the ultrasound transducer during late systole then posteriorly away from it at the beginning of left ventricular relaxation. These movements added to the amplitude of posterior wall motion but subtracted from the motion of the septum and were responsible for the notch in the waveform of this echo. Attachment superiorly to the aortic root might also have limited septal motion which was less near the base than nearer the apex of the left ventricle. The internal left ventricular dimension measured by ultrasound was standardized by using the mitral valve as a landmark and by recording the motion of the left side of the interventricular septum and endocardial surface of the posterior left ventricular wall simultaneously. This measurement was reproducible. In normal subjects, the ultrasonic dimension measured 4.40 ± 0.28 cm at the beginning of systole and shortened by 35.5 ± 3.9% at a rate of 1.22 ± 0.31 lengths/sec. By contrast, the average figures for six patients with primary myocardial disease were 6.96 ± 0.43 cm, 14.9 ± 4.2%, and 0.64 ± 0.11 lengths/sec. Calculation of such indices of left ventricular size and of rate and extent of myocardial shortening should be useful in the detection of impaired myocardial function and in following its progress.
Time to Hospitalization for Suicide Attempt by the Timing of Parental Suicide During Offspring Early Development
Authors: S. Janet Kuramoto, Bo Runeson, Elizabeth A. Stuart, Paul Lichtenstein, Holly C. Wilcox
Journal: JAMA Psychiatry (2012)

CONTEXT Previous studies have suggested that children who experience parental suicide at earlier ages are at higher risk of future hospitalization for suicide attempt. However, how the trajectories of risk differ by offspring age at the time of parental suicide is currently unknown. OBJECTIVE To study time at risk to suicide attempt hospitalization among offspring of suicide decedents as compared with offspring of unintentional injury decedents by their developmental period at the time of parental death. DESIGN Population-based retrospective cohort study. SETTING Sweden. PARTICIPANTS Twenty-six thousand ninety-six offspring who experienced parental suicide and 32 395 offspring of unintentional injury decedents prior to age 25 years between the years 1973 and 2003. MAIN OUTCOME MEASURE Parametric survival analysis was used to model the time to hospitalization for suicide attempt among offspring who lost a parent during early childhood (0-5 years old), later childhood (6-12 years old), adolescence (13-17 years old), and young adulthood (18-24 years old). RESULTS The risk in offspring who lost a parent to suicide or an unintentional injury during childhood surpassed the other age groups' risk approximately 5 years after the origin and, for the youngest group, continued to rise over decades. Offspring who lost a parent during adolescence or young adulthood were at greatest risk within 1 to 2 years after parental death, and risk declined over time. Offspring who lost a parent to suicide in childhood and young adulthood had earlier onset of hospitalization for suicide attempt compared with offspring who lost a parent to an unintentional injury. CONCLUSIONS The hospitalization risk for suicide attempt in offspring who lost a parent during their childhood is different from those who lost a parent later in development. The results suggest critical windows for careful monitoring and intervention for suicide attempt risk, especially 1 to 2 years after parental death for the older age groups and over decades for childhood survivors of parental death.